Split (1)

train · 929 rows

id stringlengths 2 20	ch_id stringlengths 2 20	keywords listlengths 0 162	title stringlengths 0 130	authors stringlengths 0 245	abstract stringlengths 0 4.05k	content stringlengths 0 197k	references listlengths 0 142	created_date stringlengths 0 10	updated_date stringlengths 0 10	revised_date stringlengths 0 10	journal stringclasses 1 value	source_url stringclasses 1 value	publication_types listlengths 2 2
hlh	hlh	[ "Familial Erythrophagocytic Lymphohistiocytosis", "Primary Hemophagocytic Lymphohistiocytosis", "Familial Erythrophagocytic Lymphohistiocytosis", "Primary Hemophagocytic Lymphohistiocytosis", "PRF1-Related Familial Hemophagocytic Lymphohistiocytosis (PRF1-fHLH)", "UNC13D-Related Familial Hemophagocytic Lymphohistiocytosis (UNC13D-fHLH)", "STX11-Related Familial Hemophagocytic Lymphohistiocytosis (STX11-fHLH)", "STXBP2-Related Familial Hemophagocytic Lymphohistiocytosis (STXBP2-fHLH)", "Perforin-1", "Protein unc-13 homolog D", "Syntaxin-11", "Syntaxin-binding protein 2", "PRF1", "STX11", "STXBP2", "UNC13D", "Familial Hemophagocytic Lymphohistiocytosis" ]	Familial Hemophagocytic Lymphohistiocytosis	Kejian Zhang, Itziar Astigarraga, Yenan Bryceson, Kai Lehmberg, Rafal Machowicz, Rebecca Marsh, Elena Sieni, Zhao Wang, Kim E Nichols	Summary Familial hemophagocytic lymphohistiocytosis (fHLH), defined as the presence of biallelic pathogenic variants in one of four genes ( The diagnosis of fHLH is established in a proband with suggestive findings by identification of either biallelic pathogenic variants in one of four genes ( Familial HLH is inherited in an autosomal recessive manner. (Autosomal dominant inheritance of If both parents are known to be heterozygous for an fHLH-causing pathogenic variant, each sib of an affected individual has a 25% chance of inheriting biallelic pathogenic variants, a 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial fHLH-causing pathogenic variants. Once the fHLH-causing pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.	Hemophagocytic lymphohistiocytosis (HLH) is a phenotype characterized by critical illness caused by toxic activation of immune cells from different underlying mechanisms. The signs and symptoms of HLH (recurring episodes of hyperinflammation) result from infiltration of organs (e.g., bone marrow, liver, spleen, and brain) by hyperactivated T lymphocytes and macrophages that secrete high levels of proinflammatory cytokines [ HLH may occur as an acquired condition (see ## Diagnosis The diagnosis of familial hemophagocytic lymphohistiocytosis (fHLH) is based on suggestive clinical and laboratory findings and is established by identification of biallelic pathogenic variants in one of four genes: Familial HLH (fHLH) should be suspected in young children with the following clinical findings, supportive laboratory findings, and suggestive family history. Prolonged fever Hepatosplenomegaly Skin rash Lymphadenopathy Neurologic abnormalities [ Increased intracranial pressure, irritability, coma Neck stiffness Hypotonia, hypertonia Seizures Cranial nerve palsies Ataxia Hemiplegia/quadriplegia Blindness For individuals with suspected CNS involvement, brain MRI most commonly shows diffuse or focal white matter changes in the cerebrum and cerebellum [ A normal brain MRI does not eliminate the possibility of CNS involvement, especially in individuals with elevated cerebrospinal fluid protein levels and increased numbers of mononuclear cells (with or without evidence of hemophagocytosis). Prompt recognition and treatment of fHLH are essential to an optimal outcome. To facilitate the identification of HLH, a core set of diagnostic criteria were developed in 1994 and revised in 2004 ( HLH-2004 Diagnostic Criteria A molecular diagnosis consistent with HLH Any 5 of the 8 following clinical and laboratory criteria for HLH: Fever >38.5° C Splenomegaly Cytopenia (affecting ≥2 of 3 lineages in peripheral blood): Hemoglobin <9 g/dL (in infants <4 weeks: Hb <100 g/L) Platelets <100×10 Neutrophils <1.0×10 Hypertriglyceridemia and/or hypofibrinogenemia: fasting triglycerides >3.0 mmol/L (>265 mg/dL) or fibrinogen ≤1.5 g/L Hemophagocytosis in bone marrow, spleen, liver, lymph nodes, or other tissues Low or absent natural killer (NK) cell activity Serum ferritin concentration ≥500 μg/L Soluble CD25 (soluble IL-2 receptor) ≥2400 U/mL From Typically, family history is consistent with The diagnosis of fHLH 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 [ The options for molecular genetic testing include use of a multigene panel or genomic testing. For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Familial Hemophagocytic Lymphohistiocytosis 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. • Prolonged fever • Hepatosplenomegaly • Skin rash • Lymphadenopathy • Neurologic abnormalities [ • Increased intracranial pressure, irritability, coma • Neck stiffness • Hypotonia, hypertonia • Seizures • Cranial nerve palsies • Ataxia • Hemiplegia/quadriplegia • Blindness • Increased intracranial pressure, irritability, coma • Neck stiffness • Hypotonia, hypertonia • Seizures • Cranial nerve palsies • Ataxia • Hemiplegia/quadriplegia • Blindness • Increased intracranial pressure, irritability, coma • Neck stiffness • Hypotonia, hypertonia • Seizures • Cranial nerve palsies • Ataxia • Hemiplegia/quadriplegia • Blindness • A molecular diagnosis consistent with HLH • Any 5 of the 8 following clinical and laboratory criteria for HLH: • Fever >38.5° C • Splenomegaly • Cytopenia (affecting ≥2 of 3 lineages in peripheral blood): • Hemoglobin <9 g/dL (in infants <4 weeks: Hb <100 g/L) • Platelets <100×10 • Neutrophils <1.0×10 • Hypertriglyceridemia and/or hypofibrinogenemia: fasting triglycerides >3.0 mmol/L (>265 mg/dL) or fibrinogen ≤1.5 g/L • Hemophagocytosis in bone marrow, spleen, liver, lymph nodes, or other tissues • Low or absent natural killer (NK) cell activity • Serum ferritin concentration ≥500 μg/L • Soluble CD25 (soluble IL-2 receptor) ≥2400 U/mL • Fever >38.5° C • Splenomegaly • Cytopenia (affecting ≥2 of 3 lineages in peripheral blood): • Hemoglobin <9 g/dL (in infants <4 weeks: Hb <100 g/L) • Platelets <100×10 • Neutrophils <1.0×10 • Hemoglobin <9 g/dL (in infants <4 weeks: Hb <100 g/L) • Platelets <100×10 • Neutrophils <1.0×10 • Hypertriglyceridemia and/or hypofibrinogenemia: fasting triglycerides >3.0 mmol/L (>265 mg/dL) or fibrinogen ≤1.5 g/L • Hemophagocytosis in bone marrow, spleen, liver, lymph nodes, or other tissues • Low or absent natural killer (NK) cell activity • Serum ferritin concentration ≥500 μg/L • Soluble CD25 (soluble IL-2 receptor) ≥2400 U/mL • Fever >38.5° C • Splenomegaly • Cytopenia (affecting ≥2 of 3 lineages in peripheral blood): • Hemoglobin <9 g/dL (in infants <4 weeks: Hb <100 g/L) • Platelets <100×10 • Neutrophils <1.0×10 • Hemoglobin <9 g/dL (in infants <4 weeks: Hb <100 g/L) • Platelets <100×10 • Neutrophils <1.0×10 • Hypertriglyceridemia and/or hypofibrinogenemia: fasting triglycerides >3.0 mmol/L (>265 mg/dL) or fibrinogen ≤1.5 g/L • Hemophagocytosis in bone marrow, spleen, liver, lymph nodes, or other tissues • Low or absent natural killer (NK) cell activity • Serum ferritin concentration ≥500 μg/L • Soluble CD25 (soluble IL-2 receptor) ≥2400 U/mL • Hemoglobin <9 g/dL (in infants <4 weeks: Hb <100 g/L) • Platelets <100×10 • Neutrophils <1.0×10 • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings Familial HLH (fHLH) should be suspected in young children with the following clinical findings, supportive laboratory findings, and suggestive family history. Prolonged fever Hepatosplenomegaly Skin rash Lymphadenopathy Neurologic abnormalities [ Increased intracranial pressure, irritability, coma Neck stiffness Hypotonia, hypertonia Seizures Cranial nerve palsies Ataxia Hemiplegia/quadriplegia Blindness For individuals with suspected CNS involvement, brain MRI most commonly shows diffuse or focal white matter changes in the cerebrum and cerebellum [ A normal brain MRI does not eliminate the possibility of CNS involvement, especially in individuals with elevated cerebrospinal fluid protein levels and increased numbers of mononuclear cells (with or without evidence of hemophagocytosis). Prompt recognition and treatment of fHLH are essential to an optimal outcome. To facilitate the identification of HLH, a core set of diagnostic criteria were developed in 1994 and revised in 2004 ( HLH-2004 Diagnostic Criteria A molecular diagnosis consistent with HLH Any 5 of the 8 following clinical and laboratory criteria for HLH: Fever >38.5° C Splenomegaly Cytopenia (affecting ≥2 of 3 lineages in peripheral blood): Hemoglobin <9 g/dL (in infants <4 weeks: Hb <100 g/L) Platelets <100×10 Neutrophils <1.0×10 Hypertriglyceridemia and/or hypofibrinogenemia: fasting triglycerides >3.0 mmol/L (>265 mg/dL) or fibrinogen ≤1.5 g/L Hemophagocytosis in bone marrow, spleen, liver, lymph nodes, or other tissues Low or absent natural killer (NK) cell activity Serum ferritin concentration ≥500 μg/L Soluble CD25 (soluble IL-2 receptor) ≥2400 U/mL From Typically, family history is consistent with • Prolonged fever • Hepatosplenomegaly • Skin rash • Lymphadenopathy • Neurologic abnormalities [ • Increased intracranial pressure, irritability, coma • Neck stiffness • Hypotonia, hypertonia • Seizures • Cranial nerve palsies • Ataxia • Hemiplegia/quadriplegia • Blindness • Increased intracranial pressure, irritability, coma • Neck stiffness • Hypotonia, hypertonia • Seizures • Cranial nerve palsies • Ataxia • Hemiplegia/quadriplegia • Blindness • Increased intracranial pressure, irritability, coma • Neck stiffness • Hypotonia, hypertonia • Seizures • Cranial nerve palsies • Ataxia • Hemiplegia/quadriplegia • Blindness • A molecular diagnosis consistent with HLH • Any 5 of the 8 following clinical and laboratory criteria for HLH: • Fever >38.5° C • Splenomegaly • Cytopenia (affecting ≥2 of 3 lineages in peripheral blood): • Hemoglobin <9 g/dL (in infants <4 weeks: Hb <100 g/L) • Platelets <100×10 • Neutrophils <1.0×10 • Hypertriglyceridemia and/or hypofibrinogenemia: fasting triglycerides >3.0 mmol/L (>265 mg/dL) or fibrinogen ≤1.5 g/L • Hemophagocytosis in bone marrow, spleen, liver, lymph nodes, or other tissues • Low or absent natural killer (NK) cell activity • Serum ferritin concentration ≥500 μg/L • Soluble CD25 (soluble IL-2 receptor) ≥2400 U/mL • Fever >38.5° C • Splenomegaly • Cytopenia (affecting ≥2 of 3 lineages in peripheral blood): • Hemoglobin <9 g/dL (in infants <4 weeks: Hb <100 g/L) • Platelets <100×10 • Neutrophils <1.0×10 • Hemoglobin <9 g/dL (in infants <4 weeks: Hb <100 g/L) • Platelets <100×10 • Neutrophils <1.0×10 • Hypertriglyceridemia and/or hypofibrinogenemia: fasting triglycerides >3.0 mmol/L (>265 mg/dL) or fibrinogen ≤1.5 g/L • Hemophagocytosis in bone marrow, spleen, liver, lymph nodes, or other tissues • Low or absent natural killer (NK) cell activity • Serum ferritin concentration ≥500 μg/L • Soluble CD25 (soluble IL-2 receptor) ≥2400 U/mL • Fever >38.5° C • Splenomegaly • Cytopenia (affecting ≥2 of 3 lineages in peripheral blood): • Hemoglobin <9 g/dL (in infants <4 weeks: Hb <100 g/L) • Platelets <100×10 • Neutrophils <1.0×10 • Hemoglobin <9 g/dL (in infants <4 weeks: Hb <100 g/L) • Platelets <100×10 • Neutrophils <1.0×10 • Hypertriglyceridemia and/or hypofibrinogenemia: fasting triglycerides >3.0 mmol/L (>265 mg/dL) or fibrinogen ≤1.5 g/L • Hemophagocytosis in bone marrow, spleen, liver, lymph nodes, or other tissues • Low or absent natural killer (NK) cell activity • Serum ferritin concentration ≥500 μg/L • Soluble CD25 (soluble IL-2 receptor) ≥2400 U/mL • Hemoglobin <9 g/dL (in infants <4 weeks: Hb <100 g/L) • Platelets <100×10 • Neutrophils <1.0×10 ## Clinical Findings Prolonged fever Hepatosplenomegaly Skin rash Lymphadenopathy Neurologic abnormalities [ Increased intracranial pressure, irritability, coma Neck stiffness Hypotonia, hypertonia Seizures Cranial nerve palsies Ataxia Hemiplegia/quadriplegia Blindness • Prolonged fever • Hepatosplenomegaly • Skin rash • Lymphadenopathy • Neurologic abnormalities [ • Increased intracranial pressure, irritability, coma • Neck stiffness • Hypotonia, hypertonia • Seizures • Cranial nerve palsies • Ataxia • Hemiplegia/quadriplegia • Blindness • Increased intracranial pressure, irritability, coma • Neck stiffness • Hypotonia, hypertonia • Seizures • Cranial nerve palsies • Ataxia • Hemiplegia/quadriplegia • Blindness • Increased intracranial pressure, irritability, coma • Neck stiffness • Hypotonia, hypertonia • Seizures • Cranial nerve palsies • Ataxia • Hemiplegia/quadriplegia • Blindness ## Supportive Laboratory Findings ## Supportive Imaging Findings For individuals with suspected CNS involvement, brain MRI most commonly shows diffuse or focal white matter changes in the cerebrum and cerebellum [ A normal brain MRI does not eliminate the possibility of CNS involvement, especially in individuals with elevated cerebrospinal fluid protein levels and increased numbers of mononuclear cells (with or without evidence of hemophagocytosis). ## Core HLH Diagnostic Criteria Prompt recognition and treatment of fHLH are essential to an optimal outcome. To facilitate the identification of HLH, a core set of diagnostic criteria were developed in 1994 and revised in 2004 ( HLH-2004 Diagnostic Criteria A molecular diagnosis consistent with HLH Any 5 of the 8 following clinical and laboratory criteria for HLH: Fever >38.5° C Splenomegaly Cytopenia (affecting ≥2 of 3 lineages in peripheral blood): Hemoglobin <9 g/dL (in infants <4 weeks: Hb <100 g/L) Platelets <100×10 Neutrophils <1.0×10 Hypertriglyceridemia and/or hypofibrinogenemia: fasting triglycerides >3.0 mmol/L (>265 mg/dL) or fibrinogen ≤1.5 g/L Hemophagocytosis in bone marrow, spleen, liver, lymph nodes, or other tissues Low or absent natural killer (NK) cell activity Serum ferritin concentration ≥500 μg/L Soluble CD25 (soluble IL-2 receptor) ≥2400 U/mL From • A molecular diagnosis consistent with HLH • Any 5 of the 8 following clinical and laboratory criteria for HLH: • Fever >38.5° C • Splenomegaly • Cytopenia (affecting ≥2 of 3 lineages in peripheral blood): • Hemoglobin <9 g/dL (in infants <4 weeks: Hb <100 g/L) • Platelets <100×10 • Neutrophils <1.0×10 • Hypertriglyceridemia and/or hypofibrinogenemia: fasting triglycerides >3.0 mmol/L (>265 mg/dL) or fibrinogen ≤1.5 g/L • Hemophagocytosis in bone marrow, spleen, liver, lymph nodes, or other tissues • Low or absent natural killer (NK) cell activity • Serum ferritin concentration ≥500 μg/L • Soluble CD25 (soluble IL-2 receptor) ≥2400 U/mL • Fever >38.5° C • Splenomegaly • Cytopenia (affecting ≥2 of 3 lineages in peripheral blood): • Hemoglobin <9 g/dL (in infants <4 weeks: Hb <100 g/L) • Platelets <100×10 • Neutrophils <1.0×10 • Hemoglobin <9 g/dL (in infants <4 weeks: Hb <100 g/L) • Platelets <100×10 • Neutrophils <1.0×10 • Hypertriglyceridemia and/or hypofibrinogenemia: fasting triglycerides >3.0 mmol/L (>265 mg/dL) or fibrinogen ≤1.5 g/L • Hemophagocytosis in bone marrow, spleen, liver, lymph nodes, or other tissues • Low or absent natural killer (NK) cell activity • Serum ferritin concentration ≥500 μg/L • Soluble CD25 (soluble IL-2 receptor) ≥2400 U/mL • Fever >38.5° C • Splenomegaly • Cytopenia (affecting ≥2 of 3 lineages in peripheral blood): • Hemoglobin <9 g/dL (in infants <4 weeks: Hb <100 g/L) • Platelets <100×10 • Neutrophils <1.0×10 • Hemoglobin <9 g/dL (in infants <4 weeks: Hb <100 g/L) • Platelets <100×10 • Neutrophils <1.0×10 • Hypertriglyceridemia and/or hypofibrinogenemia: fasting triglycerides >3.0 mmol/L (>265 mg/dL) or fibrinogen ≤1.5 g/L • Hemophagocytosis in bone marrow, spleen, liver, lymph nodes, or other tissues • Low or absent natural killer (NK) cell activity • Serum ferritin concentration ≥500 μg/L • Soluble CD25 (soluble IL-2 receptor) ≥2400 U/mL • Hemoglobin <9 g/dL (in infants <4 weeks: Hb <100 g/L) • Platelets <100×10 • Neutrophils <1.0×10 ## Family History Typically, family history is consistent with ## Establishing the Diagnosis The diagnosis of fHLH 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 [ The options for molecular genetic testing include use of a multigene panel or genomic testing. For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Familial Hemophagocytic Lymphohistiocytosis 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. • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics Familial hemophagocytic lymphohistiocytosis (fHLH) is an immune deficiency characterized by the overactivation and excessive proliferation of T lymphocytes and macrophages, leading to infiltration and damage of organs including bone marrow, liver, spleen, and brain [ Often fHLH-associated inflammation is triggered by infection, especially with herpes viruses, but it can manifest after infection with many other pathogens, or it can occur in the absence of any detectable infection [ Although manifestations of fHLH are usually evident within the first months or years of life and may develop in utero [ Except for individuals with Familial HLH has not been well studied in adults. The disease may present with acute onset of full-blown HLH manifestations or as a more insidious illness with recurrent bouts of nonspecific features. HLH in adults is often triggered by infection or malignancy [ Individuals with Use of etoposide-containing regimens such as the HLH-94 and HLH-2004 protocols followed by allogeneic hematopoietic stem cell transplantation (HSCT) has improved survival (see Although the age of onset in individuals with Hypomorphic pathogenic variants in Nonsense variants are associated with younger age at onset than missense variants [ Prior to discovery of the genes associated with fHLH, a locus-based naming system was used to identify the distinct genetic causes of this disorder ( Familial Hemophagocytic Lymphohistiocytosis: Gene-Based Names vs Locus-Based Names The estimated prevalence of familial HLH (fHLH) is 1.8 per 100,000 births in Sweden with equal male/female distribution [ The estimated prevalence of the HLH phenotype in Texas has been calculated as 1:100,000 children younger than age 18 years [ Ethnic groups with gene-specific pathogenic variants include the following: A 253-kb inversion with a high prevalence in Scandinavia is also commonly found in North America [ • A 253-kb inversion with a high prevalence in Scandinavia is also commonly found in North America [ • A 253-kb inversion with a high prevalence in Scandinavia is also commonly found in North America [ • A 253-kb inversion with a high prevalence in Scandinavia is also commonly found in North America [ ## Clinical Description Familial hemophagocytic lymphohistiocytosis (fHLH) is an immune deficiency characterized by the overactivation and excessive proliferation of T lymphocytes and macrophages, leading to infiltration and damage of organs including bone marrow, liver, spleen, and brain [ Often fHLH-associated inflammation is triggered by infection, especially with herpes viruses, but it can manifest after infection with many other pathogens, or it can occur in the absence of any detectable infection [ Although manifestations of fHLH are usually evident within the first months or years of life and may develop in utero [ Except for individuals with Familial HLH has not been well studied in adults. The disease may present with acute onset of full-blown HLH manifestations or as a more insidious illness with recurrent bouts of nonspecific features. HLH in adults is often triggered by infection or malignancy [ ## Common Signs and Symptoms Individuals with Use of etoposide-containing regimens such as the HLH-94 and HLH-2004 protocols followed by allogeneic hematopoietic stem cell transplantation (HSCT) has improved survival (see ## Phenotype Correlations by Gene Although the age of onset in individuals with ## Genotype-Phenotype Correlations Hypomorphic pathogenic variants in Nonsense variants are associated with younger age at onset than missense variants [ ## Nomenclature Prior to discovery of the genes associated with fHLH, a locus-based naming system was used to identify the distinct genetic causes of this disorder ( Familial Hemophagocytic Lymphohistiocytosis: Gene-Based Names vs Locus-Based Names ## Prevalence The estimated prevalence of familial HLH (fHLH) is 1.8 per 100,000 births in Sweden with equal male/female distribution [ The estimated prevalence of the HLH phenotype in Texas has been calculated as 1:100,000 children younger than age 18 years [ Ethnic groups with gene-specific pathogenic variants include the following: A 253-kb inversion with a high prevalence in Scandinavia is also commonly found in North America [ • A 253-kb inversion with a high prevalence in Scandinavia is also commonly found in North America [ • A 253-kb inversion with a high prevalence in Scandinavia is also commonly found in North America [ • A 253-kb inversion with a high prevalence in Scandinavia is also commonly found in North America [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this The following reported associations observed with fHLH-causative genes remain an area of investigation. Biallelic and monoallelic pathogenic germline Of 12 adults with chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS), three had biallelic • Biallelic and monoallelic pathogenic germline • Of 12 adults with chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS), three had biallelic ## Differential Diagnosis Several inherited inborn errors of immunity include the hemophagocytic lymphohistiocytosis (HLH) phenotype (resembling familial HLH) as a predominant feature due to defects in lymphocyte cytotoxicity or regulation of the inflammasome, a multi-protein complex that is essential for activation of inflammatory responses (see Inherited Immune Disorders to Consider in the Differential Diagnosis of Familial Hemophagocytic Lymphohistiocytosis abnl = abnormal; AD = autosomal dominant; AR = autosomal recessive; EBV = Epstein-Barr virus; GI = gastrointestinal; HLH = hemophagocytic lymphohistiocytosis; ID = intellectual disability; iNKT = invariant natural killer T (cells); MOI = mode of inheritance; nl = normal; XL = X-linked In addition to the inherited immune disorders summarized in Other Hereditary Disorders to Consider in the Differential Diagnosis of Familial Hemophagocytic Lymphohistiocytosis AD = autosomal dominant; AR = autosomal recessive; CDG = congenital disorders of glycosylation; DiffDx = differential diagnosis; Mat = maternal; MOI = mode of inheritance; XL = X-linked See ## Management No clinical practice guidelines specifically for familial hemophagocytic lymphohistiocytosis (fHLH) have been published; however, a report by the Steering Committee of the Histiocyte Society provides recommendations on the use of etoposide-containing therapies such as the HLH-94 protocol and hematopoietic stem cell transplantation (HSCT) for individuals with HLH, including those with fHLH [ To establish the extent of disease and treatment needs in an individual diagnosed with fHLH, the evaluations summarized in Familial Hemophagocytic Lymphohistiocytosis: Recommended Evaluations Following Initial Diagnosis Respiratory status & hemodynamic instability; Rashes, lymphadenopathy, hepatosplenomegaly, altered skin or hair pigmentation (albinism). Evaluate for ↑ levels of protein & presence of mononuclear cells w/or w/o hemophagocytosis. CSF neopterin levels can also be measured. Community or online Social work involvement; Home nursing. BUN = blood urea nitrogen; CNS = central nervous system; CSF = cerebrospinal fluid; MOI = mode of inheritance Elevated CSF neopterin, a marker of neuroinflammation, has been rarely reported in children with fHLH [ Medical geneticist, certified genetic counselor, certified advanced genetic nurse For a detailed explanation of the treatment for fHLH, see Given the complexity of fHLH diagnosis and treatment, management should be coordinated by or in consultation with a multidisciplinary team of specialists with expertise in fHLH, including specialists from hematology/oncology, bone marrow and stem cell transplantation, immunology, rheumatology, infectious diseases, critical care, neurology, nephrology, pathology, and medical genetics. Familial Hemophagocytic Lymphohistiocytosis: Targeted Therapies Etoposide & dexamethasone Delayed cyclosporine IT methotrexate for persons w/CNS involvement Current standard of care in most centers 29% of affected persons died before HSCT. 19% of affected persons developed late neurologic sequelae. Etoposide, dexamethasone, & cyclosporine IT methotrexate for all affected persons Anti-interferon-gamma antibody (emapalumab) Dexamethasone Other agents when needed CNS = central nervous system; fHLH = familial hemophagocytic lymphohistiocytosis; HLH = hemophagocytic lymphohistiocytosis; HSCT = hematopoietic stem cell transplantation; IT = Intrathecal To be used in preparation for allogeneic HSCT, the only known cure for fHLH. Histiocyte Society HLH-94 and HLH-2004 protocols have substantially increased the survival for individuals with HLH, including those with fHLH. The hypothesis was that this newer treatment regimen might reduce pretransplant mortality and neurologic complications. Typically reserved for those with refractory or relapsed HLH or for those who have intolerance to conventional therapies. HLA typing and initiation of the stem cell donor search should be started as soon as fHLH is suspected. HSCT should be undertaken in children with molecularly confirmed fHLH as early in life as is feasible, both for symptomatic children who have achieved clinical remission of active disease (or as close to remission of active disease as possible) following treatment with chemoimmunotherapy as well as presymptomatic children who have not yet experienced a flare of active inflammation (usually identified based on a positive family history of fHLH) [ In the past, fully myeloablative conditioning regimens containing busulfan and cyclophosphamide were associated with exceptionally high risks of toxicities and mortality in individuals with fHLH. Although reduced-intensity conditioning regimens containing alemtuzumab, fludarabine, and melphalan (which have come into favor over the last decade), are associated with reduced toxicities and improved overall survival, they are associated with high rates of mixed chimerism and secondary graft failure [ Experience with reduced toxicity myeloablative conditioning approaches is growing and results appear promising [ Management of neurologic manifestations, respiratory dysfunction, GI tract manifestations, renal impairment, and other system dysfunctions is per standard of care by primary care health care providers or specialty clinicians. The following supportive care measures should accompany treatment with chemoimmunotherapy and allogenic HSCT: Antibiotics or antiviral agents to treat or prevent infections Antipyretics, intravenous fluids, electrolyte replacement, nutrition support, transfusion of packed red blood cells and platelets, infusions of immunoglobulin, fresh frozen plasma and/or cryoprecipitate Individuals responding to treatment and HSCT are technically not at risk for other organ system involvement. Surveillance focuses on potential complications of HSCT. Surveillance for changes in neurologic manifestations, respiratory function, GI tract manifestations, renal function, and other systems is per standard of care by primary care health care providers or specialty clinicians. The following should be avoided: Live vaccines Exposure to infections Acetaminophen in individuals with liver failure Nonsteroidal anti-inflammatory drugs in individuals with thrombocytopenia Areas of construction or soil manipulation, which increase the risk for fungal infection for individuals with neutropenia Transfusion of non-irradiated blood products in individuals undergoing chemoimmunotherapy and/or allogeneic HSCT, per institutional guidelines Sibs found to have biallelic fHLH-causing pathogenic variants should be carefully monitored for the development of manifestations of active disease (i.e., expectant/watchful waiting), particularly during febrile episodes. Any manifestations of possible active disease should prompt evaluation for splenomegaly, anemia, leukopenia, thrombocytopenia, transaminitis, hypofibrinogenemia/coagulopathy, hypertriglyceridemia, and elevated blood levels of ferritin and soluble IL-2r. If any parameters are abnormal, consultation with a clinician with expertise in fHLH should be initiated. See If a pregnant woman is diagnosed with fHLH, treatment should be tailored and if possible, incorporate non-cytotoxic drugs such as steroids [ Underlying triggers, such as infection, malignancy, and autoimmune disease, should be sought and treated as appropriate. See Several case reports and small case series have described its use in children and adults with active disease (of whom ~6/200 had fHLH) [ A study of 52 children with newly diagnosed HLH revealed an overall response rate to ruxolitinib monotherapy of 69.2% at 28 days, with 42.3% achieving sustained complete remission. The 12-month overall survival rate was 86.4%. Additional studies are ongoing [ Search • Respiratory status & hemodynamic instability; • Rashes, lymphadenopathy, hepatosplenomegaly, altered skin or hair pigmentation (albinism). • Evaluate for ↑ levels of protein & presence of mononuclear cells w/or w/o hemophagocytosis. • CSF neopterin levels can also be measured. • Community or online • Social work involvement; • Home nursing. • Etoposide & dexamethasone • Delayed cyclosporine • IT methotrexate for persons w/CNS involvement • Current standard of care in most centers • 29% of affected persons died before HSCT. • 19% of affected persons developed late neurologic sequelae. • Etoposide, dexamethasone, & cyclosporine • IT methotrexate for all affected persons • Anti-interferon-gamma antibody (emapalumab) • Dexamethasone • Other agents when needed • Antibiotics or antiviral agents to treat or prevent infections • Antipyretics, intravenous fluids, electrolyte replacement, nutrition support, transfusion of packed red blood cells and platelets, infusions of immunoglobulin, fresh frozen plasma and/or cryoprecipitate • Live vaccines • Exposure to infections • Acetaminophen in individuals with liver failure • Nonsteroidal anti-inflammatory drugs in individuals with thrombocytopenia • Areas of construction or soil manipulation, which increase the risk for fungal infection for individuals with neutropenia • Transfusion of non-irradiated blood products in individuals undergoing chemoimmunotherapy and/or allogeneic HSCT, per institutional guidelines • Several case reports and small case series have described its use in children and adults with active disease (of whom ~6/200 had fHLH) [ • A study of 52 children with newly diagnosed HLH revealed an overall response rate to ruxolitinib monotherapy of 69.2% at 28 days, with 42.3% achieving sustained complete remission. The 12-month overall survival rate was 86.4%. Additional studies are ongoing [ ## Evaluations Following Initial Diagnosis To establish the extent of disease and treatment needs in an individual diagnosed with fHLH, the evaluations summarized in Familial Hemophagocytic Lymphohistiocytosis: Recommended Evaluations Following Initial Diagnosis Respiratory status & hemodynamic instability; Rashes, lymphadenopathy, hepatosplenomegaly, altered skin or hair pigmentation (albinism). Evaluate for ↑ levels of protein & presence of mononuclear cells w/or w/o hemophagocytosis. CSF neopterin levels can also be measured. Community or online Social work involvement; Home nursing. BUN = blood urea nitrogen; CNS = central nervous system; CSF = cerebrospinal fluid; MOI = mode of inheritance Elevated CSF neopterin, a marker of neuroinflammation, has been rarely reported in children with fHLH [ Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Respiratory status & hemodynamic instability; • Rashes, lymphadenopathy, hepatosplenomegaly, altered skin or hair pigmentation (albinism). • Evaluate for ↑ levels of protein & presence of mononuclear cells w/or w/o hemophagocytosis. • CSF neopterin levels can also be measured. • Community or online • Social work involvement; • Home nursing. ## Treatment of Manifestations For a detailed explanation of the treatment for fHLH, see Given the complexity of fHLH diagnosis and treatment, management should be coordinated by or in consultation with a multidisciplinary team of specialists with expertise in fHLH, including specialists from hematology/oncology, bone marrow and stem cell transplantation, immunology, rheumatology, infectious diseases, critical care, neurology, nephrology, pathology, and medical genetics. Familial Hemophagocytic Lymphohistiocytosis: Targeted Therapies Etoposide & dexamethasone Delayed cyclosporine IT methotrexate for persons w/CNS involvement Current standard of care in most centers 29% of affected persons died before HSCT. 19% of affected persons developed late neurologic sequelae. Etoposide, dexamethasone, & cyclosporine IT methotrexate for all affected persons Anti-interferon-gamma antibody (emapalumab) Dexamethasone Other agents when needed CNS = central nervous system; fHLH = familial hemophagocytic lymphohistiocytosis; HLH = hemophagocytic lymphohistiocytosis; HSCT = hematopoietic stem cell transplantation; IT = Intrathecal To be used in preparation for allogeneic HSCT, the only known cure for fHLH. Histiocyte Society HLH-94 and HLH-2004 protocols have substantially increased the survival for individuals with HLH, including those with fHLH. The hypothesis was that this newer treatment regimen might reduce pretransplant mortality and neurologic complications. Typically reserved for those with refractory or relapsed HLH or for those who have intolerance to conventional therapies. HLA typing and initiation of the stem cell donor search should be started as soon as fHLH is suspected. HSCT should be undertaken in children with molecularly confirmed fHLH as early in life as is feasible, both for symptomatic children who have achieved clinical remission of active disease (or as close to remission of active disease as possible) following treatment with chemoimmunotherapy as well as presymptomatic children who have not yet experienced a flare of active inflammation (usually identified based on a positive family history of fHLH) [ In the past, fully myeloablative conditioning regimens containing busulfan and cyclophosphamide were associated with exceptionally high risks of toxicities and mortality in individuals with fHLH. Although reduced-intensity conditioning regimens containing alemtuzumab, fludarabine, and melphalan (which have come into favor over the last decade), are associated with reduced toxicities and improved overall survival, they are associated with high rates of mixed chimerism and secondary graft failure [ Experience with reduced toxicity myeloablative conditioning approaches is growing and results appear promising [ Management of neurologic manifestations, respiratory dysfunction, GI tract manifestations, renal impairment, and other system dysfunctions is per standard of care by primary care health care providers or specialty clinicians. The following supportive care measures should accompany treatment with chemoimmunotherapy and allogenic HSCT: Antibiotics or antiviral agents to treat or prevent infections Antipyretics, intravenous fluids, electrolyte replacement, nutrition support, transfusion of packed red blood cells and platelets, infusions of immunoglobulin, fresh frozen plasma and/or cryoprecipitate • Etoposide & dexamethasone • Delayed cyclosporine • IT methotrexate for persons w/CNS involvement • Current standard of care in most centers • 29% of affected persons died before HSCT. • 19% of affected persons developed late neurologic sequelae. • Etoposide, dexamethasone, & cyclosporine • IT methotrexate for all affected persons • Anti-interferon-gamma antibody (emapalumab) • Dexamethasone • Other agents when needed • Antibiotics or antiviral agents to treat or prevent infections • Antipyretics, intravenous fluids, electrolyte replacement, nutrition support, transfusion of packed red blood cells and platelets, infusions of immunoglobulin, fresh frozen plasma and/or cryoprecipitate ## Targeted Therapies Familial Hemophagocytic Lymphohistiocytosis: Targeted Therapies Etoposide & dexamethasone Delayed cyclosporine IT methotrexate for persons w/CNS involvement Current standard of care in most centers 29% of affected persons died before HSCT. 19% of affected persons developed late neurologic sequelae. Etoposide, dexamethasone, & cyclosporine IT methotrexate for all affected persons Anti-interferon-gamma antibody (emapalumab) Dexamethasone Other agents when needed CNS = central nervous system; fHLH = familial hemophagocytic lymphohistiocytosis; HLH = hemophagocytic lymphohistiocytosis; HSCT = hematopoietic stem cell transplantation; IT = Intrathecal To be used in preparation for allogeneic HSCT, the only known cure for fHLH. Histiocyte Society HLH-94 and HLH-2004 protocols have substantially increased the survival for individuals with HLH, including those with fHLH. The hypothesis was that this newer treatment regimen might reduce pretransplant mortality and neurologic complications. Typically reserved for those with refractory or relapsed HLH or for those who have intolerance to conventional therapies. HLA typing and initiation of the stem cell donor search should be started as soon as fHLH is suspected. HSCT should be undertaken in children with molecularly confirmed fHLH as early in life as is feasible, both for symptomatic children who have achieved clinical remission of active disease (or as close to remission of active disease as possible) following treatment with chemoimmunotherapy as well as presymptomatic children who have not yet experienced a flare of active inflammation (usually identified based on a positive family history of fHLH) [ In the past, fully myeloablative conditioning regimens containing busulfan and cyclophosphamide were associated with exceptionally high risks of toxicities and mortality in individuals with fHLH. Although reduced-intensity conditioning regimens containing alemtuzumab, fludarabine, and melphalan (which have come into favor over the last decade), are associated with reduced toxicities and improved overall survival, they are associated with high rates of mixed chimerism and secondary graft failure [ Experience with reduced toxicity myeloablative conditioning approaches is growing and results appear promising [ Management of neurologic manifestations, respiratory dysfunction, GI tract manifestations, renal impairment, and other system dysfunctions is per standard of care by primary care health care providers or specialty clinicians. • Etoposide & dexamethasone • Delayed cyclosporine • IT methotrexate for persons w/CNS involvement • Current standard of care in most centers • 29% of affected persons died before HSCT. • 19% of affected persons developed late neurologic sequelae. • Etoposide, dexamethasone, & cyclosporine • IT methotrexate for all affected persons • Anti-interferon-gamma antibody (emapalumab) • Dexamethasone • Other agents when needed ## Supportive Care The following supportive care measures should accompany treatment with chemoimmunotherapy and allogenic HSCT: Antibiotics or antiviral agents to treat or prevent infections Antipyretics, intravenous fluids, electrolyte replacement, nutrition support, transfusion of packed red blood cells and platelets, infusions of immunoglobulin, fresh frozen plasma and/or cryoprecipitate • Antibiotics or antiviral agents to treat or prevent infections • Antipyretics, intravenous fluids, electrolyte replacement, nutrition support, transfusion of packed red blood cells and platelets, infusions of immunoglobulin, fresh frozen plasma and/or cryoprecipitate ## Surveillance Individuals responding to treatment and HSCT are technically not at risk for other organ system involvement. Surveillance focuses on potential complications of HSCT. Surveillance for changes in neurologic manifestations, respiratory function, GI tract manifestations, renal function, and other systems is per standard of care by primary care health care providers or specialty clinicians. ## Agents/Circumstances to Avoid The following should be avoided: Live vaccines Exposure to infections Acetaminophen in individuals with liver failure Nonsteroidal anti-inflammatory drugs in individuals with thrombocytopenia Areas of construction or soil manipulation, which increase the risk for fungal infection for individuals with neutropenia Transfusion of non-irradiated blood products in individuals undergoing chemoimmunotherapy and/or allogeneic HSCT, per institutional guidelines • Live vaccines • Exposure to infections • Acetaminophen in individuals with liver failure • Nonsteroidal anti-inflammatory drugs in individuals with thrombocytopenia • Areas of construction or soil manipulation, which increase the risk for fungal infection for individuals with neutropenia • Transfusion of non-irradiated blood products in individuals undergoing chemoimmunotherapy and/or allogeneic HSCT, per institutional guidelines ## Evaluation of Relatives at Risk Sibs found to have biallelic fHLH-causing pathogenic variants should be carefully monitored for the development of manifestations of active disease (i.e., expectant/watchful waiting), particularly during febrile episodes. Any manifestations of possible active disease should prompt evaluation for splenomegaly, anemia, leukopenia, thrombocytopenia, transaminitis, hypofibrinogenemia/coagulopathy, hypertriglyceridemia, and elevated blood levels of ferritin and soluble IL-2r. If any parameters are abnormal, consultation with a clinician with expertise in fHLH should be initiated. See ## Pregnancy Management If a pregnant woman is diagnosed with fHLH, treatment should be tailored and if possible, incorporate non-cytotoxic drugs such as steroids [ Underlying triggers, such as infection, malignancy, and autoimmune disease, should be sought and treated as appropriate. See ## Therapies Under Investigation Several case reports and small case series have described its use in children and adults with active disease (of whom ~6/200 had fHLH) [ A study of 52 children with newly diagnosed HLH revealed an overall response rate to ruxolitinib monotherapy of 69.2% at 28 days, with 42.3% achieving sustained complete remission. The 12-month overall survival rate was 86.4%. Additional studies are ongoing [ Search • Several case reports and small case series have described its use in children and adults with active disease (of whom ~6/200 had fHLH) [ • A study of 52 children with newly diagnosed HLH revealed an overall response rate to ruxolitinib monotherapy of 69.2% at 28 days, with 42.3% achieving sustained complete remission. The 12-month overall survival rate was 86.4%. Additional studies are ongoing [ ## Genetic Counseling Familial hemophagocytic lymphohistiocytosis (fHLH) caused by loss-of-function variants in Note: Autosomal dominant inheritance of The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one fHLH-causing pathogenic variant based on family history). Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an fHLH-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an fHLH-causing pathogenic variant, each sib of an affected individual has a 25% chance of inheriting biallelic pathogenic variants, a 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial fHLH-causing pathogenic variants. Sibs who inherit biallelic fHLH-causing pathogenic variants are at risk of developing fHLH; however, intrafamilial clinical variability may be observed and the age of onset, severity, type of symptoms, and rate of progression in asymptomatic sibs cannot be predicted. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Carrier testing for at-risk relatives requires prior identification of the fHLH-causing pathogenic variants in the family. See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once the fHLH-causing pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Such testing is not useful in accurately predicting age of onset, severity, type of symptoms, or rate of progression; however, expectant management is warranted for newborns with the same genotype as the symptomatic proband, as hematopoietic stem cell transplantation prior to onset of symptoms may improve outcome. Differences in perspective may exist among medical professionals and within families regarding the use 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 fHLH-causing pathogenic variant based on family history). • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an fHLH-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an fHLH-causing pathogenic variant, each sib of an affected individual has a 25% chance of inheriting biallelic pathogenic variants, a 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial fHLH-causing pathogenic variants. • Sibs who inherit biallelic fHLH-causing pathogenic variants are at risk of developing fHLH; however, intrafamilial clinical variability may be observed and the age of onset, severity, type of symptoms, and rate of progression in asymptomatic sibs cannot be predicted. • 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 Familial hemophagocytic lymphohistiocytosis (fHLH) caused by loss-of-function variants in Note: Autosomal dominant inheritance of ## Risk to Family Members The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one fHLH-causing pathogenic variant based on family history). Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an fHLH-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an fHLH-causing pathogenic variant, each sib of an affected individual has a 25% chance of inheriting biallelic pathogenic variants, a 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial fHLH-causing pathogenic variants. Sibs who inherit biallelic fHLH-causing pathogenic variants are at risk of developing fHLH; however, intrafamilial clinical variability may be observed and the age of onset, severity, type of symptoms, and rate of progression in asymptomatic sibs cannot be predicted. 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 fHLH-causing pathogenic variant based on family history). • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an fHLH-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an fHLH-causing pathogenic variant, each sib of an affected individual has a 25% chance of inheriting biallelic pathogenic variants, a 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial fHLH-causing pathogenic variants. • Sibs who inherit biallelic fHLH-causing pathogenic variants are at risk of developing fHLH; however, intrafamilial clinical variability may be observed and the age of onset, severity, type of symptoms, and rate of progression in asymptomatic sibs cannot be predicted. • 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 fHLH-causing pathogenic variants in the family. ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including 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 fHLH-causing pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Such testing is not useful in accurately predicting age of onset, severity, type of symptoms, or rate of progression; however, expectant management is warranted for newborns with the same genotype as the symptomatic proband, as hematopoietic stem cell transplantation prior to onset of symptoms may improve outcome. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • • • • • ## Molecular Genetics Familial Hemophagocytic Lymphohistiocytosis: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Familial Hemophagocytic Lymphohistiocytosis ( The result of biallelic pathogenic variants in At the cellular level, syntaxin-11 is a membrane-associated SNARE protein that interacts with other SNARE proteins to drive membrane fusion. Signals from activating receptors recruit syntaxin-11 from recycling endosomes to the plasma membrane in a VAMP-8 dependent manner [ However, two reports provide evidence for three A large 253-kb inversion straddles the The deep intronic variants lie within an intron 1 region that is typically not sequenced; detection will require specific primers. The The deep intronic (c.117+143A>G) variant disrupts an enhancer and has been associated with reduced gene transcription and macrophage activation in a single individual [ Familial Hemophagocytic Lymphohistiocytosis: Notable Pathogenic Variants by Gene Variant assoc w/late-onset (adult) fHLH [ Common variant in population studies of healthy persons; functional effects were studied [ Disruption of lymphocyte-specific enhancer [ Frequent cause of disease in persons of northern European background [ 3' gene inversion that disrupts protein expression High prevalence in Scandinavia & commonly found in North America [ Variants listed in the table have been provided by the author. Variant designation that does not conform to current naming conventions • Variant assoc w/late-onset (adult) fHLH [ • Common variant in population studies of healthy persons; functional effects were studied [ • Disruption of lymphocyte-specific enhancer [ • Frequent cause of disease in persons of northern European background [ • 3' gene inversion that disrupts protein expression • High prevalence in Scandinavia & commonly found in North America [ ## Molecular Pathogenesis The result of biallelic pathogenic variants in At the cellular level, syntaxin-11 is a membrane-associated SNARE protein that interacts with other SNARE proteins to drive membrane fusion. Signals from activating receptors recruit syntaxin-11 from recycling endosomes to the plasma membrane in a VAMP-8 dependent manner [ However, two reports provide evidence for three A large 253-kb inversion straddles the The deep intronic variants lie within an intron 1 region that is typically not sequenced; detection will require specific primers. The The deep intronic (c.117+143A>G) variant disrupts an enhancer and has been associated with reduced gene transcription and macrophage activation in a single individual [ Familial Hemophagocytic Lymphohistiocytosis: Notable Pathogenic Variants by Gene Variant assoc w/late-onset (adult) fHLH [ Common variant in population studies of healthy persons; functional effects were studied [ Disruption of lymphocyte-specific enhancer [ Frequent cause of disease in persons of northern European background [ 3' gene inversion that disrupts protein expression High prevalence in Scandinavia & commonly found in North America [ Variants listed in the table have been provided by the author. Variant designation that does not conform to current naming conventions • Variant assoc w/late-onset (adult) fHLH [ • Common variant in population studies of healthy persons; functional effects were studied [ • Disruption of lymphocyte-specific enhancer [ • Frequent cause of disease in persons of northern European background [ • 3' gene inversion that disrupts protein expression • High prevalence in Scandinavia & commonly found in North America [ ## Chapter Notes The authors of this chapter are members of The North American Consortium for Histiocytosis or The European Consortium for Histiocytosis, multi-institutional consortia in North America and Europe aimed at developing and implementing clinical and translational studies and biological research on histiocytic diseases including fHLH. We respectfully acknowledge all the patients, their families, and our medical colleagues from the Histiocyte Society and elsewhere, who have contributed to our understanding of HLH over the years. Itziar Astigarraga, MD, PhD (2021-present)Yenan Bryceson, PhD (2021-present)Alexandra H Filipovich, MD; Cincinnati Children's Hospital Medical Center (2006-2021)Judith Johnson, MS; Cincinnati Children's Hospital Medical Center (2006-2021)Kai Lehmberg, MD (2021-present)Rafal Machowicz, MD (2021-present)Rebecca Marsh, MD (2006-present)Kim E Nichols, MD (2021-present)Elena Sieni, MD (2021-present)Joyce Villanueva, MT, MBA; Cincinnati Children's Hospital Medical Center (2006-2021)Zhao Wang, MD (2021-present)Kejian Zhang, MD, MBA (2006-present) 6 June 2024 (ma) Revision: 30 September 2021 (bp) Comprehensive update posted live 17 January 2013 (me) Comprehensive update posted live 11 March 2010 (me) Comprehensive update posted live 22 March 2006 (me) Review posted live 21 April 2005 (jj, af, rw) Original submission • 6 June 2024 (ma) Revision: • 30 September 2021 (bp) Comprehensive update posted live • 17 January 2013 (me) Comprehensive update posted live • 11 March 2010 (me) Comprehensive update posted live • 22 March 2006 (me) Review posted live • 21 April 2005 (jj, af, rw) Original submission ## Author Notes The authors of this chapter are members of The North American Consortium for Histiocytosis or The European Consortium for Histiocytosis, multi-institutional consortia in North America and Europe aimed at developing and implementing clinical and translational studies and biological research on histiocytic diseases including fHLH. ## Acknowledgments We respectfully acknowledge all the patients, their families, and our medical colleagues from the Histiocyte Society and elsewhere, who have contributed to our understanding of HLH over the years. ## Author History Itziar Astigarraga, MD, PhD (2021-present)Yenan Bryceson, PhD (2021-present)Alexandra H Filipovich, MD; Cincinnati Children's Hospital Medical Center (2006-2021)Judith Johnson, MS; Cincinnati Children's Hospital Medical Center (2006-2021)Kai Lehmberg, MD (2021-present)Rafal Machowicz, MD (2021-present)Rebecca Marsh, MD (2006-present)Kim E Nichols, MD (2021-present)Elena Sieni, MD (2021-present)Joyce Villanueva, MT, MBA; Cincinnati Children's Hospital Medical Center (2006-2021)Zhao Wang, MD (2021-present)Kejian Zhang, MD, MBA (2006-present) ## Revision History 6 June 2024 (ma) Revision: 30 September 2021 (bp) Comprehensive update posted live 17 January 2013 (me) Comprehensive update posted live 11 March 2010 (me) Comprehensive update posted live 22 March 2006 (me) Review posted live 21 April 2005 (jj, af, rw) Original submission • 6 June 2024 (ma) Revision: • 30 September 2021 (bp) Comprehensive update posted live • 17 January 2013 (me) Comprehensive update posted live • 11 March 2010 (me) Comprehensive update posted live • 22 March 2006 (me) Review posted live • 21 April 2005 (jj, af, rw) Original submission ## Key Sections in This ## References ## Literature Cited	[]	22/3/2006	30/9/2021	6/6/2024	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
hlrcc	hlrcc	[ "Fumarate Hydratase Tumor Predisposition Syndrome (FHTPS)", "Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC)", "Multiple Cutaneous and Uterine Leiomyomatosis (MCL/MCUL)", "Reed's Syndrome", "Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC)", "Multiple Cutaneous and Uterine Leiomyomatosis (MCL/MCUL)", "Reed's Syndrome", "Fumarate Hydratase Tumor Predisposition Syndrome (FHTPS)", "Fumarate hydratase, mitochondrial", "FH", "FH Tumor Predisposition Syndrome" ]		Junne Kamihara, Kris Ann Schultz, Huma Q Rana	Summary Diagnosis of	## Diagnosis Clinical criteria have been proposed for a likely or suspected diagnosis [ Skin-colored to light brown/reddish papules or nodules distributed across the trunk, extremities, and occasionally on the face and neck Most often multiple; may be grouped/clustered, segmental, or disseminated Histopathology shows bundles of smooth muscle fibers with central, long, blunt-edged nuclei [ Tend to be numerous and large Often demonstrate loss of fumarate hydratase (FH) staining and positive cytoplasmic staining for S-(2-succino) cysteine [ Usually classified as atypical histology, with staghorn blood vessels, bizarre nuclei, and alveolar pattern edema [ Usually solitary, highly aggressive renal cell carcinoma (RCC) that metastasizes early Spectrum includes type 2 papillary, undefined papillary, unclassified, tubulocystic, and collecting-duct carcinoma [ 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 histopathologic findings suggest the diagnosis of A For an introduction to multigene panels click When the diagnosis of For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click 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. • Skin-colored to light brown/reddish papules or nodules distributed across the trunk, extremities, and occasionally on the face and neck • Most often multiple; may be grouped/clustered, segmental, or disseminated • Histopathology shows bundles of smooth muscle fibers with central, long, blunt-edged nuclei [ • Tend to be numerous and large • Often demonstrate loss of fumarate hydratase (FH) staining and positive cytoplasmic staining for S-(2-succino) cysteine [ • Usually classified as atypical histology, with staghorn blood vessels, bizarre nuclei, and alveolar pattern edema [ • Usually solitary, highly aggressive renal cell carcinoma (RCC) that metastasizes early • Spectrum includes type 2 papillary, undefined papillary, unclassified, tubulocystic, and collecting-duct carcinoma [ • A • For an introduction to multigene panels click ## Suggestive Findings Skin-colored to light brown/reddish papules or nodules distributed across the trunk, extremities, and occasionally on the face and neck Most often multiple; may be grouped/clustered, segmental, or disseminated Histopathology shows bundles of smooth muscle fibers with central, long, blunt-edged nuclei [ Tend to be numerous and large Often demonstrate loss of fumarate hydratase (FH) staining and positive cytoplasmic staining for S-(2-succino) cysteine [ Usually classified as atypical histology, with staghorn blood vessels, bizarre nuclei, and alveolar pattern edema [ Usually solitary, highly aggressive renal cell carcinoma (RCC) that metastasizes early Spectrum includes type 2 papillary, undefined papillary, unclassified, tubulocystic, and collecting-duct carcinoma [ • Skin-colored to light brown/reddish papules or nodules distributed across the trunk, extremities, and occasionally on the face and neck • Most often multiple; may be grouped/clustered, segmental, or disseminated • Histopathology shows bundles of smooth muscle fibers with central, long, blunt-edged nuclei [ • Tend to be numerous and large • Often demonstrate loss of fumarate hydratase (FH) staining and positive cytoplasmic staining for S-(2-succino) cysteine [ • Usually classified as atypical histology, with staghorn blood vessels, bizarre nuclei, and alveolar pattern edema [ • Usually solitary, highly aggressive renal cell carcinoma (RCC) that metastasizes early • Spectrum includes type 2 papillary, undefined papillary, unclassified, tubulocystic, and collecting-duct carcinoma [ ## 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 histopathologic findings suggest the diagnosis of A For an introduction to multigene panels click When the diagnosis of For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click 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 • For an introduction to multigene panels click ## Option 1 When the phenotypic and histopathologic findings suggest the diagnosis of A For an introduction to multigene panels click • A • For an introduction to multigene panels click ## Option 2 When the diagnosis of For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click 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 RCC = renal cell carcinoma The prevalence of findings is based on cohorts of individuals with an identified Among a cohort of 2,060 females with uterine smooth muscle tumors, a prospective screening program identified a tumor with fumarate hydratase (FH)-deficient morphology in 30 individuals (1.4%). Histologic criteria for FH-deficient morphology included alveolar pattern edema and staghorn-shaped blood vessels under low magnification, and smooth muscle cells with a macronucleolus surrounded by a halo and eosinophilic globules seen under high magnification [ Atypical uterine leiomyoma may also be an indication for germline testing. In one large center, a retrospective review identified that 12 of 144 individuals with uterine leiomyoma (8.3%) were found to have a germline pathogenic variant in Furthermore, not all individuals with In one review of published reports, of 672 individuals diagnosed with HLRCC-related renal cell cancer (RCC) ( A distinct CpG island methylator phenotype (CIMP) has been described for Penetrance is currently unknown. Most studies have focused on families with clinical manifestations; therefore, penetrance estimates will continue to be refined as more population-based testing occurs. Historically, the predisposition to the development of cutaneous leiomyomas was referred to as multiple cutaneous leiomyomatosis (MCL/MCUL). The association of cutaneous and uterine leiomyomas with renal cancer was described in two Finnish families [ Germline The prevalence of Founder variants have been reported in a few populations (see ## Clinical Description RCC = renal cell carcinoma The prevalence of findings is based on cohorts of individuals with an identified Among a cohort of 2,060 females with uterine smooth muscle tumors, a prospective screening program identified a tumor with fumarate hydratase (FH)-deficient morphology in 30 individuals (1.4%). Histologic criteria for FH-deficient morphology included alveolar pattern edema and staghorn-shaped blood vessels under low magnification, and smooth muscle cells with a macronucleolus surrounded by a halo and eosinophilic globules seen under high magnification [ Atypical uterine leiomyoma may also be an indication for germline testing. In one large center, a retrospective review identified that 12 of 144 individuals with uterine leiomyoma (8.3%) were found to have a germline pathogenic variant in Furthermore, not all individuals with In one review of published reports, of 672 individuals diagnosed with HLRCC-related renal cell cancer (RCC) ( A distinct CpG island methylator phenotype (CIMP) has been described for ## Genotype-Phenotype Correlations ## Penetrance Penetrance is currently unknown. Most studies have focused on families with clinical manifestations; therefore, penetrance estimates will continue to be refined as more population-based testing occurs. ## Nomenclature Historically, the predisposition to the development of cutaneous leiomyomas was referred to as multiple cutaneous leiomyomatosis (MCL/MCUL). The association of cutaneous and uterine leiomyomas with renal cancer was described in two Finnish families [ Germline ## Prevalence The prevalence of Founder variants have been reported in a few populations (see ## Genetically Related (Allelic) Disorders Emerging data suggests that specific ## Differential Diagnosis Comparison of Familial Renal Cancer Syndromes Type 2 papillary RCC Undefined papillary RCC Unclassified Tubulocystic Collecting-duct carcinoma Clear cell RCC Papillary & chromophobe cell tumors have been observed. BAP1-inactivated melanocytic tumor (formerly called atypical Spitz tumor) Cutaneous melanoma Basal cell carcinoma Uveal melanoma Malignant mesothelioma (pleural/peritoneal) Rhabdoid meningioma Hybrid oncocytoma/chromophobe tumor Clear cell carcinoma Oncocytoma Fibrofolliculomas/trichodiscomas Acrochordons Angiofibromas Oral papules Cutaneous collagenomas Epidermal cysts Pulmonary cysts Spontaneous pneumothorax Hemangioblastomas of brain, spinal cord, & retina Renal cysts Pheochromocytoma & paraganglioma Pancreatic cysts & neuroendocrine tumors Endolymphatic sac tumors Epididymal & broad ligament cystadenomas RCC = renal cell carcinoma • Type 2 papillary RCC • Undefined papillary RCC • Unclassified • Tubulocystic • Collecting-duct carcinoma • Clear cell RCC • Papillary & chromophobe cell tumors have been observed. • BAP1-inactivated melanocytic tumor (formerly called atypical Spitz tumor) • Cutaneous melanoma • Basal cell carcinoma • Uveal melanoma • Malignant mesothelioma (pleural/peritoneal) • Rhabdoid meningioma • Hybrid oncocytoma/chromophobe tumor • Clear cell carcinoma • Oncocytoma • Fibrofolliculomas/trichodiscomas • Acrochordons • Angiofibromas • Oral papules • Cutaneous collagenomas • Epidermal cysts • Pulmonary cysts • Spontaneous pneumothorax • Hemangioblastomas of brain, spinal cord, & retina • Renal cysts • Pheochromocytoma & paraganglioma • Pancreatic cysts & neuroendocrine tumors • Endolymphatic sac tumors • Epididymal & broad ligament cystadenomas ## Management Surveillance for To establish the extent of disease and needs in an individual diagnosed with Beginning at age 10 yrs to evaluate for renal tumors In pediatrics, the consensus recommendation is screening MRI w/o contrast but w/diffusion-weighted imaging. Abdominal CT scan w/contrast may be considered, although renal MRI is preferred & use of CT should be limited. Blood pressure Fractionated plasma/urine metanephrines Limited whole-body MRI (w/eval of neck, chest, abdomen, & pelvis) AACR = American Association for Cancer Research; MOI = mode of inheritance Pediatric guidelines suggest education about signs and symptoms from teenage years [ Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Surgical excision, especially for solitary or a few symptomatic lesions, is considered standard therapy [ Lesions may also be treated by carbon dioxide laser, cryotherapy, or electrodessication [ Lesions have a high rate of recurrence [ Medications are used as an adjunct for pain relief and may include drugs that lead to vasodilation (such as nitroglycerin, nifedipine, phenoxybenzamine, or doxazosin) and/or drugs for neuropathic pain (such as gabapentin, pregabalin, and duloxetine) [ In one small randomized controlled trial, intralesional botulinum toxin improved quality of life [ Medical therapies include gonadotropin-releasing hormone agonists and intrauterine devices releasing progesterone [ Surgical options include myomectomy and hysterectomy. If surgery is performed, careful histologic examination is recommended to differentiate between atypical smooth muscle neoplasm and leiomyosarcoma. Expert opinion should be sought with a urologic oncology surgeon familiar with Nonsurgical approaches such as surveillance, cryoablation, and radiofrequency ablation are not appropriate for the management of Treatment with erlotinib plus bevacizumab demonstrated benefit in individuals with HLRCC-related metastatic RCC [ Cabozantinib plus nivolumab may be useful. Regular surveillance with an emphasis on early detection of RCC by clinicians familiar with the clinical manifestations of Renal MRI w/contrast w/1- to 3-mm slices through kidneys is preferred. In pediatrics, the consensus recommendation is screening MRI w/o contrast but w/diffusion-weighted imaging. Abdominal CT w/contrast may be used as an alternative, but MRI is preferred. Annually starting at age 10 yrs Note: The utility or benefit of screening for RCC in persons w/ Early detection of renal tumors is important. Renal tumors should be evaluated by urologic oncology surgeon familiar w/ AACR = American Association for Cancer Research; RCC = renal cell carcinoma Pediatric guidelines suggest education regarding signs and symptoms of Consensus recommendations for surveillance of RCC were developed in the context of an international HLRCC symposium. Renal ultrasound is not recommended for primary surveillance due to low sensitivity to detect small lesions [ MRI avoids radiation exposure, though gadolinium-based contrast agents – which are incompletely eliminated from the body – are currently used. However, there are currently no known adverse health effects from gadolinium retention in individuals with normal renal function. NCI-PDQ Consensus pediatric cancer predisposition guidelines developed at an AACR workshop recommend starting at age 10 years [ Surveillance by an expert in this condition is indicated. In the right clinical scenario, renal ultrasound may be used to further characterize a cystic lesion but should never be used to replace MRI or CT as a primary surveillance modality. Only in individuals with specific It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives of an affected individual by molecular genetic testing for the Identify as early as possible those who would benefit from early surveillance and treatment; Reduce costly screening procedures in those who have not inherited the pathogenic variant. Although surveillance may also be considered for at-risk family members who have not undergone molecular genetic testing or while testing is pending, definitive predictive testing is recommended as soon as possible. Recommendations vary regarding the most appropriate age at which to perform predictive testing for a familial germline See Targeting of tumor vasculature and glucose transport has been attempted using bevacizumab and erlotinib. A single-center, single-arm trial currently open in China includes individuals with locally advanced or metastatic FH-deficient RCC and treatment with a tyrosine kinase inhibitor (lenvatinib) and an anti-PD-1 inhibitor (tislelizumab) as first-line therapy ( An open Phase II clinical trial focuses on the combination of bevacizumab, erlotinib, and atelzolizumab in HLRCC-related advanced/metastatic RCC ( Fumarate accumulation in fumarate hydratase (FH)-deficient cells may lead to a defect in homologous recombination double-strand break repair. This suggests a vulnerability to poly ADP-ribose polymerase (PARP) inhibition, demonstrated in cell lines and in mice with FH-deficient tumors [ Search • Beginning at age 10 yrs to evaluate for renal tumors • In pediatrics, the consensus recommendation is screening MRI w/o contrast but w/diffusion-weighted imaging. • Abdominal CT scan w/contrast may be considered, although renal MRI is preferred & use of CT should be limited. • Blood pressure • Fractionated plasma/urine metanephrines • Limited whole-body MRI (w/eval of neck, chest, abdomen, & pelvis) • Surgical excision, especially for solitary or a few symptomatic lesions, is considered standard therapy [ • Lesions may also be treated by carbon dioxide laser, cryotherapy, or electrodessication [ • Lesions have a high rate of recurrence [ • Medications are used as an adjunct for pain relief and may include drugs that lead to vasodilation (such as nitroglycerin, nifedipine, phenoxybenzamine, or doxazosin) and/or drugs for neuropathic pain (such as gabapentin, pregabalin, and duloxetine) [ • In one small randomized controlled trial, intralesional botulinum toxin improved quality of life [ • Medical therapies include gonadotropin-releasing hormone agonists and intrauterine devices releasing progesterone [ • Surgical options include myomectomy and hysterectomy. If surgery is performed, careful histologic examination is recommended to differentiate between atypical smooth muscle neoplasm and leiomyosarcoma. • Expert opinion should be sought with a urologic oncology surgeon familiar with • Nonsurgical approaches such as surveillance, cryoablation, and radiofrequency ablation are not appropriate for the management of • Treatment with erlotinib plus bevacizumab demonstrated benefit in individuals with HLRCC-related metastatic RCC [ • Cabozantinib plus nivolumab may be useful. • Renal MRI w/contrast w/1- to 3-mm slices through kidneys is preferred. • In pediatrics, the consensus recommendation is screening MRI w/o contrast but w/diffusion-weighted imaging. • Abdominal CT w/contrast may be used as an alternative, but MRI is preferred. • Annually starting at age 10 yrs • Note: The utility or benefit of screening for RCC in persons w/ • Early detection of renal tumors is important. • Renal tumors should be evaluated by urologic oncology surgeon familiar w/ • Identify as early as possible those who would benefit from early surveillance and treatment; • Reduce costly screening procedures in those who have not inherited the pathogenic variant. • Targeting of tumor vasculature and glucose transport has been attempted using bevacizumab and erlotinib. • A single-center, single-arm trial currently open in China includes individuals with locally advanced or metastatic FH-deficient RCC and treatment with a tyrosine kinase inhibitor (lenvatinib) and an anti-PD-1 inhibitor (tislelizumab) as first-line therapy ( • An open Phase II clinical trial focuses on the combination of bevacizumab, erlotinib, and atelzolizumab in HLRCC-related advanced/metastatic RCC ( ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Beginning at age 10 yrs to evaluate for renal tumors In pediatrics, the consensus recommendation is screening MRI w/o contrast but w/diffusion-weighted imaging. Abdominal CT scan w/contrast may be considered, although renal MRI is preferred & use of CT should be limited. Blood pressure Fractionated plasma/urine metanephrines Limited whole-body MRI (w/eval of neck, chest, abdomen, & pelvis) AACR = American Association for Cancer Research; MOI = mode of inheritance Pediatric guidelines suggest education about signs and symptoms from teenage years [ Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Beginning at age 10 yrs to evaluate for renal tumors • In pediatrics, the consensus recommendation is screening MRI w/o contrast but w/diffusion-weighted imaging. • Abdominal CT scan w/contrast may be considered, although renal MRI is preferred & use of CT should be limited. • Blood pressure • Fractionated plasma/urine metanephrines • Limited whole-body MRI (w/eval of neck, chest, abdomen, & pelvis) ## Treatment of Manifestations Surgical excision, especially for solitary or a few symptomatic lesions, is considered standard therapy [ Lesions may also be treated by carbon dioxide laser, cryotherapy, or electrodessication [ Lesions have a high rate of recurrence [ Medications are used as an adjunct for pain relief and may include drugs that lead to vasodilation (such as nitroglycerin, nifedipine, phenoxybenzamine, or doxazosin) and/or drugs for neuropathic pain (such as gabapentin, pregabalin, and duloxetine) [ In one small randomized controlled trial, intralesional botulinum toxin improved quality of life [ Medical therapies include gonadotropin-releasing hormone agonists and intrauterine devices releasing progesterone [ Surgical options include myomectomy and hysterectomy. If surgery is performed, careful histologic examination is recommended to differentiate between atypical smooth muscle neoplasm and leiomyosarcoma. Expert opinion should be sought with a urologic oncology surgeon familiar with Nonsurgical approaches such as surveillance, cryoablation, and radiofrequency ablation are not appropriate for the management of Treatment with erlotinib plus bevacizumab demonstrated benefit in individuals with HLRCC-related metastatic RCC [ Cabozantinib plus nivolumab may be useful. • Surgical excision, especially for solitary or a few symptomatic lesions, is considered standard therapy [ • Lesions may also be treated by carbon dioxide laser, cryotherapy, or electrodessication [ • Lesions have a high rate of recurrence [ • Medications are used as an adjunct for pain relief and may include drugs that lead to vasodilation (such as nitroglycerin, nifedipine, phenoxybenzamine, or doxazosin) and/or drugs for neuropathic pain (such as gabapentin, pregabalin, and duloxetine) [ • In one small randomized controlled trial, intralesional botulinum toxin improved quality of life [ • Medical therapies include gonadotropin-releasing hormone agonists and intrauterine devices releasing progesterone [ • Surgical options include myomectomy and hysterectomy. If surgery is performed, careful histologic examination is recommended to differentiate between atypical smooth muscle neoplasm and leiomyosarcoma. • Expert opinion should be sought with a urologic oncology surgeon familiar with • Nonsurgical approaches such as surveillance, cryoablation, and radiofrequency ablation are not appropriate for the management of • Treatment with erlotinib plus bevacizumab demonstrated benefit in individuals with HLRCC-related metastatic RCC [ • Cabozantinib plus nivolumab may be useful. ## Surveillance Regular surveillance with an emphasis on early detection of RCC by clinicians familiar with the clinical manifestations of Renal MRI w/contrast w/1- to 3-mm slices through kidneys is preferred. In pediatrics, the consensus recommendation is screening MRI w/o contrast but w/diffusion-weighted imaging. Abdominal CT w/contrast may be used as an alternative, but MRI is preferred. Annually starting at age 10 yrs Note: The utility or benefit of screening for RCC in persons w/ Early detection of renal tumors is important. Renal tumors should be evaluated by urologic oncology surgeon familiar w/ AACR = American Association for Cancer Research; RCC = renal cell carcinoma Pediatric guidelines suggest education regarding signs and symptoms of Consensus recommendations for surveillance of RCC were developed in the context of an international HLRCC symposium. Renal ultrasound is not recommended for primary surveillance due to low sensitivity to detect small lesions [ MRI avoids radiation exposure, though gadolinium-based contrast agents – which are incompletely eliminated from the body – are currently used. However, there are currently no known adverse health effects from gadolinium retention in individuals with normal renal function. NCI-PDQ Consensus pediatric cancer predisposition guidelines developed at an AACR workshop recommend starting at age 10 years [ Surveillance by an expert in this condition is indicated. In the right clinical scenario, renal ultrasound may be used to further characterize a cystic lesion but should never be used to replace MRI or CT as a primary surveillance modality. Only in individuals with specific • Renal MRI w/contrast w/1- to 3-mm slices through kidneys is preferred. • In pediatrics, the consensus recommendation is screening MRI w/o contrast but w/diffusion-weighted imaging. • Abdominal CT w/contrast may be used as an alternative, but MRI is preferred. • Annually starting at age 10 yrs • Note: The utility or benefit of screening for RCC in persons w/ • Early detection of renal tumors is important. • Renal tumors should be evaluated by urologic oncology surgeon familiar w/ ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives of an affected individual by molecular genetic testing for the Identify as early as possible those who would benefit from early surveillance and treatment; Reduce costly screening procedures in those who have not inherited the pathogenic variant. Although surveillance may also be considered for at-risk family members who have not undergone molecular genetic testing or while testing is pending, definitive predictive testing is recommended as soon as possible. Recommendations vary regarding the most appropriate age at which to perform predictive testing for a familial germline See • Identify as early as possible those who would benefit from early surveillance and treatment; • Reduce costly screening procedures in those who have not inherited the pathogenic variant. ## Therapies Under Investigation Targeting of tumor vasculature and glucose transport has been attempted using bevacizumab and erlotinib. A single-center, single-arm trial currently open in China includes individuals with locally advanced or metastatic FH-deficient RCC and treatment with a tyrosine kinase inhibitor (lenvatinib) and an anti-PD-1 inhibitor (tislelizumab) as first-line therapy ( An open Phase II clinical trial focuses on the combination of bevacizumab, erlotinib, and atelzolizumab in HLRCC-related advanced/metastatic RCC ( Fumarate accumulation in fumarate hydratase (FH)-deficient cells may lead to a defect in homologous recombination double-strand break repair. This suggests a vulnerability to poly ADP-ribose polymerase (PARP) inhibition, demonstrated in cell lines and in mice with FH-deficient tumors [ Search • Targeting of tumor vasculature and glucose transport has been attempted using bevacizumab and erlotinib. • A single-center, single-arm trial currently open in China includes individuals with locally advanced or metastatic FH-deficient RCC and treatment with a tyrosine kinase inhibitor (lenvatinib) and an anti-PD-1 inhibitor (tislelizumab) as first-line therapy ( • An open Phase II clinical trial focuses on the combination of bevacizumab, erlotinib, and atelzolizumab in HLRCC-related advanced/metastatic RCC ( ## Genetic Counseling Some individuals diagnosed with Some individuals diagnosed with If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance (penetrance is currently unknown), early death of a parent before the onset of symptoms, or late onset of the disease in an affected parent. Therefore, If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. If a parent of a proband has an If the If the parents are clinically unaffected but their genetic status is unknown, sibs of a proband are presumed to be at increased risk for Each child of an individual with It is not possible to precisely predict the likelihood of manifestations, age of onset, severity and type of features, or rate of disease progression in offspring who inherit the See Management, Predictive testing for at-risk family members is possible once the Molecular genetic testing of at-risk family members is appropriate to identify the need for clinical surveillance. Those who have a pathogenic variant should be offered regular lifelong The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Genetic counseling for individuals known to be heterozygous for an Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • Some individuals diagnosed with • Some individuals diagnosed with • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance (penetrance is currently unknown), early death of a parent before the onset of symptoms, or late onset of the disease in an affected parent. Therefore, • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • If a parent of a proband has an • If the • If the parents are clinically unaffected but their genetic status is unknown, sibs of a proband are presumed to be at increased risk for • Each child of an individual with • It is not possible to precisely predict the likelihood of manifestations, age of onset, severity and type of features, or rate of disease progression in offspring who inherit the • Predictive testing for at-risk family members is possible once the • Molecular genetic testing of at-risk family members is appropriate to identify the need for clinical surveillance. Those who have a pathogenic variant should be offered regular lifelong • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • Genetic counseling for individuals known to be heterozygous for an ## Mode of Inheritance ## Risk to Family Members Some individuals diagnosed with Some individuals diagnosed with If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance (penetrance is currently unknown), early death of a parent before the onset of symptoms, or late onset of the disease in an affected parent. Therefore, If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. If a parent of a proband has an If the If the parents are clinically unaffected but their genetic status is unknown, sibs of a proband are presumed to be at increased risk for Each child of an individual with It is not possible to precisely predict the likelihood of manifestations, age of onset, severity and type of features, or rate of disease progression in offspring who inherit the • Some individuals diagnosed with • Some individuals diagnosed with • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance (penetrance is currently unknown), early death of a parent before the onset of symptoms, or late onset of the disease in an affected parent. Therefore, • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • If a parent of a proband has an • If the • If the parents are clinically unaffected but their genetic status is unknown, sibs of a proband are presumed to be at increased risk for • Each child of an individual with • It is not possible to precisely predict the likelihood of manifestations, age of onset, severity and type of features, or rate of disease progression in offspring who inherit the ## Related Genetic Counseling Issues See Management, Predictive testing for at-risk family members is possible once the Molecular genetic testing of at-risk family members is appropriate to identify the need for clinical surveillance. Those who have a pathogenic variant should be offered regular lifelong The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Genetic counseling for individuals known to be heterozygous for an • Predictive testing for at-risk family members is possible once the • Molecular genetic testing of at-risk family members is appropriate to identify the need for clinical surveillance. Those who have a pathogenic variant should be offered regular lifelong • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • Genetic counseling for individuals known to be heterozygous for an ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • ## Molecular Genetics FH Tumor Predisposition Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for FH Tumor Predisposition Syndrome ( Germline pathogenic variants in Within FH-deficient renal cell cancer (RCC), there is impaired oxidative phosphorylation and a shift to aerobic glycolysis, known as the Warburg effect. AMP-activated protein kinase levels are decreased, with a variety of downstream effects including decreased p53 levels, lower cellular iron levels, and stabilization of hypoxia-inducible factor (HIF) 1-alpha and increased expression of Other work also suggests that fumarate accumulation in FH-deficient cells leads to defective homologous recombination double-strand break repair, which may provide an additional approach for therapeutic investigation (see FH = fumarate hydratase Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions. Designation is based on the FH isoform targeted to the cytosol versus the one targeted to the mitochondrion (see ## Molecular Pathogenesis Germline pathogenic variants in Within FH-deficient renal cell cancer (RCC), there is impaired oxidative phosphorylation and a shift to aerobic glycolysis, known as the Warburg effect. AMP-activated protein kinase levels are decreased, with a variety of downstream effects including decreased p53 levels, lower cellular iron levels, and stabilization of hypoxia-inducible factor (HIF) 1-alpha and increased expression of Other work also suggests that fumarate accumulation in FH-deficient cells leads to defective homologous recombination double-strand break repair, which may provide an additional approach for therapeutic investigation (see FH = fumarate hydratase Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions. Designation is based on the FH isoform targeted to the cytosol versus the one targeted to the mitochondrion (see ## Chapter Notes First and foremost, the authors would like to express our gratitude to all the individuals and families with Junne Kamihara, MD, PhD (2020-present)Manop Pithukpakorn, MD; Mahidol University, Bangkok (2006-2020)Huma Q Rana, MD (2020-present)Kris Ann Schultz, MD (2020-present)Jorge R Toro, MD; National Cancer Institute (2006-2020) 8 May 2025 (sw) Comprehensive update posted live 2 April 2020 (sw) Comprehensive update posted live 6 August 2015 (me) Comprehensive update posted live 2 November 2010 (me) Comprehensive update posted live 31 July 2006 (me) Review posted live 6 March 2006 (jrt) Original submission • 8 May 2025 (sw) Comprehensive update posted live • 2 April 2020 (sw) Comprehensive update posted live • 6 August 2015 (me) Comprehensive update posted live • 2 November 2010 (me) Comprehensive update posted live • 31 July 2006 (me) Review posted live • 6 March 2006 (jrt) Original submission ## Acknowledgments First and foremost, the authors would like to express our gratitude to all the individuals and families with ## Author History Junne Kamihara, MD, PhD (2020-present)Manop Pithukpakorn, MD; Mahidol University, Bangkok (2006-2020)Huma Q Rana, MD (2020-present)Kris Ann Schultz, MD (2020-present)Jorge R Toro, MD; National Cancer Institute (2006-2020) ## Revision History 8 May 2025 (sw) Comprehensive update posted live 2 April 2020 (sw) Comprehensive update posted live 6 August 2015 (me) Comprehensive update posted live 2 November 2010 (me) Comprehensive update posted live 31 July 2006 (me) Review posted live 6 March 2006 (jrt) Original submission • 8 May 2025 (sw) Comprehensive update posted live • 2 April 2020 (sw) Comprehensive update posted live • 6 August 2015 (me) Comprehensive update posted live • 2 November 2010 (me) Comprehensive update posted live • 31 July 2006 (me) Review posted live • 6 March 2006 (jrt) Original submission ## References Menko FH, Maher ER, Schmidt LS, Middelton LA, Aittomäki K, Tomlinson I, Richard S, Linehan WM. Hereditary leiomyomatosis and renal cell cancer (HLRCC): renal cancer risk, surveillance and treatment. Fam Cancer. 2014;13:637-44. Schultz KAP, Rednam SP, Kamihara J, Doros L, Achatz MI, Wasserman JD, Diller LR, Brugières L, Druker H, Schneider KA, McGee RB, Foulkes WD. PTEN, DICER1, FH, and their associated tumor susceptibility syndromes: clinical features, genetics, and surveillance recommendations in childhood. Clin Cancer Res. 2017;23:e76-e82. • Menko FH, Maher ER, Schmidt LS, Middelton LA, Aittomäki K, Tomlinson I, Richard S, Linehan WM. Hereditary leiomyomatosis and renal cell cancer (HLRCC): renal cancer risk, surveillance and treatment. Fam Cancer. 2014;13:637-44. • Schultz KAP, Rednam SP, Kamihara J, Doros L, Achatz MI, Wasserman JD, Diller LR, Brugières L, Druker H, Schneider KA, McGee RB, Foulkes WD. PTEN, DICER1, FH, and their associated tumor susceptibility syndromes: clinical features, genetics, and surveillance recommendations in childhood. Clin Cancer Res. 2017;23:e76-e82. ## Published Guidelines / Consensus Statements Menko FH, Maher ER, Schmidt LS, Middelton LA, Aittomäki K, Tomlinson I, Richard S, Linehan WM. Hereditary leiomyomatosis and renal cell cancer (HLRCC): renal cancer risk, surveillance and treatment. Fam Cancer. 2014;13:637-44. Schultz KAP, Rednam SP, Kamihara J, Doros L, Achatz MI, Wasserman JD, Diller LR, Brugières L, Druker H, Schneider KA, McGee RB, Foulkes WD. PTEN, DICER1, FH, and their associated tumor susceptibility syndromes: clinical features, genetics, and surveillance recommendations in childhood. Clin Cancer Res. 2017;23:e76-e82. • Menko FH, Maher ER, Schmidt LS, Middelton LA, Aittomäki K, Tomlinson I, Richard S, Linehan WM. Hereditary leiomyomatosis and renal cell cancer (HLRCC): renal cancer risk, surveillance and treatment. Fam Cancer. 2014;13:637-44. • Schultz KAP, Rednam SP, Kamihara J, Doros L, Achatz MI, Wasserman JD, Diller LR, Brugières L, Druker H, Schneider KA, McGee RB, Foulkes WD. PTEN, DICER1, FH, and their associated tumor susceptibility syndromes: clinical features, genetics, and surveillance recommendations in childhood. Clin Cancer Res. 2017;23:e76-e82. ## Literature Cited	[]	31/7/2006	8/5/2025	13/8/2020	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
hmdpc	hmdpc	[ "Dystonia/Parkinsonism, Hypermanganesemia, Polycythemia, and Chronic Liver Disease", "HMNDYT1", "Dystonia/Parkinsonism, Hypermanganesemia, Polycythemia, and Chronic Liver Disease", "HMNDYT1", "Calcium/manganese antiporter SLC30A10", "SLC30A10", "Hypermanganesemia with Dystonia 1" ]	Hypermanganesemia with Dystonia 1	Karin Tuschl, Peter T Clayton, Sidney M Gospe, Philippa B Mills	Summary Hypermanganesemia with dystonia 1 (HMNDYT1) is characterized by the following: A movement disorder resulting from manganese accumulation in the basal ganglia Whole-blood manganese concentrations that often exceed 2000 nmol/L (normal: <320 nmol/L) Polycythemia Hepatomegaly with variable hepatic fibrosis/cirrhosis Neurologic findings can manifest in childhood (ages 2-15 years) as four-limb dystonia, leading to a characteristic high-stepping gait ("cock-walk gait"), dysarthria, fine tremor, and bradykinesia or on occasion spastic paraplegia; or in adulthood as parkinsonism (shuffling gait, rigidity, bradykinesia, hypomimia, and monotone speech) unresponsive to L-dopa treatment. The diagnosis of HMNDYT1 is established in a proband with suggestive findings and biallelic pathogenic variants in HMNDYT1 is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an	## Diagnosis Hypermanganesemia with dystonia 1 (HMNDYT1) presents as a movement disorder associated with manganese accumulation in the basal ganglia. No consensus clinical diagnostic criteria have been published. HMNDYT1 An early- and a late-onset form exist: T T Note: Normalization of manganese blood levels (see Whole-blood manganese concentrations are elevated in all affected individuals. Average in affected individuals is greater than 2,000 nmol/L (normal: <320 nmol/L). In contrast, blood manganese concentration in acquired hypermanganesemia is usually less than 2,000 nmol/L. The majority of affected individuals reported to date have evidence of hepatic involvement that includes hepatomegaly, elevated transaminases (alanine transaminase, aspartate transaminase), and unconjugated hyperbilirubinemia. Liver ultrasound examination or MRI can confirm hepatomegaly and features of liver cirrhosis. Pathologic features on liver biopsy / postmortem examination in six affected individuals included fibrosis, steatosis, and micronodular cirrhosis. Note: One individual with hepatomegaly and micronodular cirrhosis had no laboratory evidence of hepatic dysfunction [ Hepatic manganese content is highly elevated. Rhodanine staining confirms deposition of manganese in hepatocytes. Copper and zinc content can also be affected with mild elevation in hepatic levels [ 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 HMNDYT1 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 Hypermanganesemia with Dystonia 1 See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • Whole-blood manganese concentrations are elevated in all affected individuals. Average in affected individuals is greater than 2,000 nmol/L (normal: <320 nmol/L). • In contrast, blood manganese concentration in acquired hypermanganesemia is usually less than 2,000 nmol/L. • The majority of affected individuals reported to date have evidence of hepatic involvement that includes hepatomegaly, elevated transaminases (alanine transaminase, aspartate transaminase), and unconjugated hyperbilirubinemia. • Liver ultrasound examination or MRI can confirm hepatomegaly and features of liver cirrhosis. • Pathologic features on liver biopsy / postmortem examination in six affected individuals included fibrosis, steatosis, and micronodular cirrhosis. • Note: One individual with hepatomegaly and micronodular cirrhosis had no laboratory evidence of hepatic dysfunction [ • Hepatic manganese content is highly elevated. Rhodanine staining confirms deposition of manganese in hepatocytes. Copper and zinc content can also be affected with mild elevation in hepatic levels [ • The majority of affected individuals reported to date have evidence of hepatic involvement that includes hepatomegaly, elevated transaminases (alanine transaminase, aspartate transaminase), and unconjugated hyperbilirubinemia. • Liver ultrasound examination or MRI can confirm hepatomegaly and features of liver cirrhosis. • Pathologic features on liver biopsy / postmortem examination in six affected individuals included fibrosis, steatosis, and micronodular cirrhosis. • Note: One individual with hepatomegaly and micronodular cirrhosis had no laboratory evidence of hepatic dysfunction [ • Hepatic manganese content is highly elevated. Rhodanine staining confirms deposition of manganese in hepatocytes. Copper and zinc content can also be affected with mild elevation in hepatic levels [ • The majority of affected individuals reported to date have evidence of hepatic involvement that includes hepatomegaly, elevated transaminases (alanine transaminase, aspartate transaminase), and unconjugated hyperbilirubinemia. • Liver ultrasound examination or MRI can confirm hepatomegaly and features of liver cirrhosis. • Pathologic features on liver biopsy / postmortem examination in six affected individuals included fibrosis, steatosis, and micronodular cirrhosis. • Note: One individual with hepatomegaly and micronodular cirrhosis had no laboratory evidence of hepatic dysfunction [ • Hepatic manganese content is highly elevated. Rhodanine staining confirms deposition of manganese in hepatocytes. Copper and zinc content can also be affected with mild elevation in hepatic levels [ ## Suggestive Findings HMNDYT1 An early- and a late-onset form exist: T T Note: Normalization of manganese blood levels (see Whole-blood manganese concentrations are elevated in all affected individuals. Average in affected individuals is greater than 2,000 nmol/L (normal: <320 nmol/L). In contrast, blood manganese concentration in acquired hypermanganesemia is usually less than 2,000 nmol/L. The majority of affected individuals reported to date have evidence of hepatic involvement that includes hepatomegaly, elevated transaminases (alanine transaminase, aspartate transaminase), and unconjugated hyperbilirubinemia. Liver ultrasound examination or MRI can confirm hepatomegaly and features of liver cirrhosis. Pathologic features on liver biopsy / postmortem examination in six affected individuals included fibrosis, steatosis, and micronodular cirrhosis. Note: One individual with hepatomegaly and micronodular cirrhosis had no laboratory evidence of hepatic dysfunction [ Hepatic manganese content is highly elevated. Rhodanine staining confirms deposition of manganese in hepatocytes. Copper and zinc content can also be affected with mild elevation in hepatic levels [ 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. • Whole-blood manganese concentrations are elevated in all affected individuals. Average in affected individuals is greater than 2,000 nmol/L (normal: <320 nmol/L). • In contrast, blood manganese concentration in acquired hypermanganesemia is usually less than 2,000 nmol/L. • The majority of affected individuals reported to date have evidence of hepatic involvement that includes hepatomegaly, elevated transaminases (alanine transaminase, aspartate transaminase), and unconjugated hyperbilirubinemia. • Liver ultrasound examination or MRI can confirm hepatomegaly and features of liver cirrhosis. • Pathologic features on liver biopsy / postmortem examination in six affected individuals included fibrosis, steatosis, and micronodular cirrhosis. • Note: One individual with hepatomegaly and micronodular cirrhosis had no laboratory evidence of hepatic dysfunction [ • Hepatic manganese content is highly elevated. Rhodanine staining confirms deposition of manganese in hepatocytes. Copper and zinc content can also be affected with mild elevation in hepatic levels [ • The majority of affected individuals reported to date have evidence of hepatic involvement that includes hepatomegaly, elevated transaminases (alanine transaminase, aspartate transaminase), and unconjugated hyperbilirubinemia. • Liver ultrasound examination or MRI can confirm hepatomegaly and features of liver cirrhosis. • Pathologic features on liver biopsy / postmortem examination in six affected individuals included fibrosis, steatosis, and micronodular cirrhosis. • Note: One individual with hepatomegaly and micronodular cirrhosis had no laboratory evidence of hepatic dysfunction [ • Hepatic manganese content is highly elevated. Rhodanine staining confirms deposition of manganese in hepatocytes. Copper and zinc content can also be affected with mild elevation in hepatic levels [ • The majority of affected individuals reported to date have evidence of hepatic involvement that includes hepatomegaly, elevated transaminases (alanine transaminase, aspartate transaminase), and unconjugated hyperbilirubinemia. • Liver ultrasound examination or MRI can confirm hepatomegaly and features of liver cirrhosis. • Pathologic features on liver biopsy / postmortem examination in six affected individuals included fibrosis, steatosis, and micronodular cirrhosis. • Note: One individual with hepatomegaly and micronodular cirrhosis had no laboratory evidence of hepatic dysfunction [ • Hepatic manganese content is highly elevated. Rhodanine staining confirms deposition of manganese in hepatocytes. Copper and zinc content can also be affected with mild elevation in hepatic levels [ ## Clinical Findings An early- and a late-onset form exist: ## Brain MRI T T Note: Normalization of manganese blood levels (see ## Laboratory Findings Whole-blood manganese concentrations are elevated in all affected individuals. Average in affected individuals is greater than 2,000 nmol/L (normal: <320 nmol/L). In contrast, blood manganese concentration in acquired hypermanganesemia is usually less than 2,000 nmol/L. The majority of affected individuals reported to date have evidence of hepatic involvement that includes hepatomegaly, elevated transaminases (alanine transaminase, aspartate transaminase), and unconjugated hyperbilirubinemia. Liver ultrasound examination or MRI can confirm hepatomegaly and features of liver cirrhosis. Pathologic features on liver biopsy / postmortem examination in six affected individuals included fibrosis, steatosis, and micronodular cirrhosis. Note: One individual with hepatomegaly and micronodular cirrhosis had no laboratory evidence of hepatic dysfunction [ Hepatic manganese content is highly elevated. Rhodanine staining confirms deposition of manganese in hepatocytes. Copper and zinc content can also be affected with mild elevation in hepatic levels [ • Whole-blood manganese concentrations are elevated in all affected individuals. Average in affected individuals is greater than 2,000 nmol/L (normal: <320 nmol/L). • In contrast, blood manganese concentration in acquired hypermanganesemia is usually less than 2,000 nmol/L. • The majority of affected individuals reported to date have evidence of hepatic involvement that includes hepatomegaly, elevated transaminases (alanine transaminase, aspartate transaminase), and unconjugated hyperbilirubinemia. • Liver ultrasound examination or MRI can confirm hepatomegaly and features of liver cirrhosis. • Pathologic features on liver biopsy / postmortem examination in six affected individuals included fibrosis, steatosis, and micronodular cirrhosis. • Note: One individual with hepatomegaly and micronodular cirrhosis had no laboratory evidence of hepatic dysfunction [ • Hepatic manganese content is highly elevated. Rhodanine staining confirms deposition of manganese in hepatocytes. Copper and zinc content can also be affected with mild elevation in hepatic levels [ • The majority of affected individuals reported to date have evidence of hepatic involvement that includes hepatomegaly, elevated transaminases (alanine transaminase, aspartate transaminase), and unconjugated hyperbilirubinemia. • Liver ultrasound examination or MRI can confirm hepatomegaly and features of liver cirrhosis. • Pathologic features on liver biopsy / postmortem examination in six affected individuals included fibrosis, steatosis, and micronodular cirrhosis. • Note: One individual with hepatomegaly and micronodular cirrhosis had no laboratory evidence of hepatic dysfunction [ • Hepatic manganese content is highly elevated. Rhodanine staining confirms deposition of manganese in hepatocytes. Copper and zinc content can also be affected with mild elevation in hepatic levels [ • The majority of affected individuals reported to date have evidence of hepatic involvement that includes hepatomegaly, elevated transaminases (alanine transaminase, aspartate transaminase), and unconjugated hyperbilirubinemia. • Liver ultrasound examination or MRI can confirm hepatomegaly and features of liver cirrhosis. • Pathologic features on liver biopsy / postmortem examination in six affected individuals included fibrosis, steatosis, and micronodular cirrhosis. • Note: One individual with hepatomegaly and micronodular cirrhosis had no laboratory evidence of hepatic dysfunction [ • Hepatic manganese content is highly elevated. Rhodanine staining confirms deposition of manganese in hepatocytes. Copper and zinc content can also be affected with mild elevation in hepatic levels [ ## 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 HMNDYT1 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 Hypermanganesemia with Dystonia 1 See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 Hypermanganesemia with Dystonia 1 See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Clinical Characteristics To date, 48 individuals have been identified with biallelic pathogenic variants in Hypermanganesemia with Dystonia 1: Frequency of Select Features The neurologic signs and symptoms of the childhood-onset form are primarily extrapyramidal and include dystonia, dysarthria, and rigidity. Four-limb dystonia manifests with difficulties walking and a high-stepping gait ("cock walk gait"), dystonic posturing, and painful extensor spasms. Fine motor impairment causes problems with writing and drawing and inability to perform rapid alternating movements of the hands (dysdiadochokinesis). Dystonia of the tongue can lead to dysarthria [ Isolated corticospinal tract involvement has been described in one affected individual. Typical neurologic signs of spastic paraparesis (e.g., spasticity, hyperreflexia, extensor plantar responses) were found [ Sensorimotor axonal polyneuropathy has been described in two affected individuals with the late-onset neurologic presentation [ Whole-blood manganese concentrations are elevated in the majority of affected individuals. Due to limited data, the onset of hypermanganesemia is not accurately known. Raised whole-blood manganese concentrations have been recorded in affected children as young as age three years [ Hypermanganesemia due to environmental overexposure (including parenteral nutrition) and acquired hepatocerebral degeneration in persons with end-stage liver disease must be excluded. See Note: Blood manganese concentrations of heterozygotes (i.e., carriers of one All affected individuals reported to date had polycythemia at the time of diagnosis. Polycythemia can precede the onset of neurologic manifestations; therefore, affected individuals often undergo repeat phlebotomies prior to identification of the correct diagnosis [ The spectrum of hepatic involvement ranges from mild hepatomegaly to hepatic failure in early adulthood [ In the majority of affected individuals, transaminases are mildly elevated [ Significant phenotypic variability with regard to hepatic involvement is apparent even within the same family: The two brothers reported by Postmortem studies in an individual with SLC30A10 deficiency showed yellow-gray mottling of the basal ganglia associated with severe neuronal loss, astrocytosis, myelin loss, spongiosis, and rhodanine-positive deposits particularly in the globus pallidus, while other basal ganglia were affected to a lesser extent. Gliosis of the white matter and axonal loss of the corticospinal tracts were observed [ No genotype-phenotype correlations have been identified. A total of 48 affected individuals from 25 families are known worldwide [ ## Clinical Description To date, 48 individuals have been identified with biallelic pathogenic variants in Hypermanganesemia with Dystonia 1: Frequency of Select Features The neurologic signs and symptoms of the childhood-onset form are primarily extrapyramidal and include dystonia, dysarthria, and rigidity. Four-limb dystonia manifests with difficulties walking and a high-stepping gait ("cock walk gait"), dystonic posturing, and painful extensor spasms. Fine motor impairment causes problems with writing and drawing and inability to perform rapid alternating movements of the hands (dysdiadochokinesis). Dystonia of the tongue can lead to dysarthria [ Isolated corticospinal tract involvement has been described in one affected individual. Typical neurologic signs of spastic paraparesis (e.g., spasticity, hyperreflexia, extensor plantar responses) were found [ Sensorimotor axonal polyneuropathy has been described in two affected individuals with the late-onset neurologic presentation [ Whole-blood manganese concentrations are elevated in the majority of affected individuals. Due to limited data, the onset of hypermanganesemia is not accurately known. Raised whole-blood manganese concentrations have been recorded in affected children as young as age three years [ Hypermanganesemia due to environmental overexposure (including parenteral nutrition) and acquired hepatocerebral degeneration in persons with end-stage liver disease must be excluded. See Note: Blood manganese concentrations of heterozygotes (i.e., carriers of one All affected individuals reported to date had polycythemia at the time of diagnosis. Polycythemia can precede the onset of neurologic manifestations; therefore, affected individuals often undergo repeat phlebotomies prior to identification of the correct diagnosis [ The spectrum of hepatic involvement ranges from mild hepatomegaly to hepatic failure in early adulthood [ In the majority of affected individuals, transaminases are mildly elevated [ Significant phenotypic variability with regard to hepatic involvement is apparent even within the same family: The two brothers reported by Postmortem studies in an individual with SLC30A10 deficiency showed yellow-gray mottling of the basal ganglia associated with severe neuronal loss, astrocytosis, myelin loss, spongiosis, and rhodanine-positive deposits particularly in the globus pallidus, while other basal ganglia were affected to a lesser extent. Gliosis of the white matter and axonal loss of the corticospinal tracts were observed [ ## Neurologic Findings The neurologic signs and symptoms of the childhood-onset form are primarily extrapyramidal and include dystonia, dysarthria, and rigidity. Four-limb dystonia manifests with difficulties walking and a high-stepping gait ("cock walk gait"), dystonic posturing, and painful extensor spasms. Fine motor impairment causes problems with writing and drawing and inability to perform rapid alternating movements of the hands (dysdiadochokinesis). Dystonia of the tongue can lead to dysarthria [ Isolated corticospinal tract involvement has been described in one affected individual. Typical neurologic signs of spastic paraparesis (e.g., spasticity, hyperreflexia, extensor plantar responses) were found [ Sensorimotor axonal polyneuropathy has been described in two affected individuals with the late-onset neurologic presentation [ ## Hypermanganesemia Whole-blood manganese concentrations are elevated in the majority of affected individuals. Due to limited data, the onset of hypermanganesemia is not accurately known. Raised whole-blood manganese concentrations have been recorded in affected children as young as age three years [ Hypermanganesemia due to environmental overexposure (including parenteral nutrition) and acquired hepatocerebral degeneration in persons with end-stage liver disease must be excluded. See Note: Blood manganese concentrations of heterozygotes (i.e., carriers of one ## Polycythemia All affected individuals reported to date had polycythemia at the time of diagnosis. Polycythemia can precede the onset of neurologic manifestations; therefore, affected individuals often undergo repeat phlebotomies prior to identification of the correct diagnosis [ ## Liver Disease The spectrum of hepatic involvement ranges from mild hepatomegaly to hepatic failure in early adulthood [ In the majority of affected individuals, transaminases are mildly elevated [ Significant phenotypic variability with regard to hepatic involvement is apparent even within the same family: The two brothers reported by ## Other ## Pathology Postmortem studies in an individual with SLC30A10 deficiency showed yellow-gray mottling of the basal ganglia associated with severe neuronal loss, astrocytosis, myelin loss, spongiosis, and rhodanine-positive deposits particularly in the globus pallidus, while other basal ganglia were affected to a lesser extent. Gliosis of the white matter and axonal loss of the corticospinal tracts were observed [ ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been identified. ## Prevalence A total of 48 affected individuals from 25 families are known worldwide [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Environmental exposure has been described in workers in mining and welding industries who inhale manganese-laden dust or fumes, in individuals ingesting contaminated drinking water, and in drug addicts who use intravenous methcathinone contaminated with potassium permanganate [ Total parenteral nutrition has been associated with manganese toxicity because the control mechanisms of manganese absorption in the gut and subsequent hepatic excretion are bypassed [ Acquired hepatocerebral degeneration is observed in those with advanced hepatic cirrhosis or portosystemic shunts, in which impaired biliary excretion of manganese results in manganese accumulation in the basal ganglia, causing a debilitating movement disorder [ Other conditions to consider in the differential diagnosis of hypermanganesemia with dystonia 1 (HMNDYT1) include the following: Hereditary Disorders in the Differential Diagnosis of Hypermanganesemia with Dystonia 1 DD = developmental delay; DiffDx = differential diagnosis; DYT = dystonia; HSP = hereditary spastic paraplegia; HMNDYT1 = hypermanganesemia with dystonia 1; PD = Parkinson disease An estimated 5%-10% of all Parkinson disease is attributed to pathogenic variants in single genes (monogenic Parkinson disease). Early-onset adult Parkinson disease (PD) = onset at age 20-50 years. Late-onset adult PD = onset after age 50 years. Seven of the ten genetically defined types of neurodegeneration with brain iron accumulation are inherited in an autosomal recessive manner. Exceptions: neuroferritinopathy, an autosomal dominant disorder caused by a pathogenic variant in To date, more than 80 genetic types of hereditary spastic paraplegia (HSP) have been defined by genetic linkage analysis and identification of HSP-related gene variants. Autosomal dominant, autosomal recessive, X-linked, and maternally inherited (mitochondrial) forms of HSP have been identified. • Environmental exposure has been described in workers in mining and welding industries who inhale manganese-laden dust or fumes, in individuals ingesting contaminated drinking water, and in drug addicts who use intravenous methcathinone contaminated with potassium permanganate [ • Total parenteral nutrition has been associated with manganese toxicity because the control mechanisms of manganese absorption in the gut and subsequent hepatic excretion are bypassed [ • Acquired hepatocerebral degeneration is observed in those with advanced hepatic cirrhosis or portosystemic shunts, in which impaired biliary excretion of manganese results in manganese accumulation in the basal ganglia, causing a debilitating movement disorder [ • • • ## Management No clinical practice guidelines for hypermanganesemia with dystonia 1 (HMNDYT1) have been published. To establish the extent of disease and needs of an individual diagnosed with HMNDYT1, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Hypermanganesemia with Dystonia 1 Neurologic exam for dystonia, parkinsonism, & spasticity Incl eval of (1) ambulation & speech & (2) swallowing & nutritional status Community or Social work involvement for parental/family 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 Hypermanganesemia with Dystonia 1 Regular chelation therapy can stabilize blood manganese levels, improve neurologic symptoms, & halt liver disease. See Chelation therapy should be continued lifelong. CBC & renal function incl urinalysis are assessed at baseline & then monthly. Monitoring may be extended to every 2 mos once on stable dose. While on treatment, monitor every 2 mos incl: serum concentration of electrolytes, calcium, phosphate, magnesium; renal & liver function; full blood count; & serum concentrations of trace metals incl zinc, copper, & selenium to ensure no secondary effects on these metals. If available, blood manganese levels can be monitored at similar intervals. Iron is a competitive inhibitor of intestinal manganese uptake; despite normal iron levels, iron therapy can ↓ blood manganese levels & resolve polycythemia. To avoid iron toxicity, monitor serum iron & total iron binding capacity regularly; if serum iron >80% of total iron binding capacity, stop or ↓ iron supplementation. CBC = complete blood count; IV = intravenous; OT = occupational therapy; PT = physical therapy Adverse effects of chelation therapy with disodium calcium edetate include hypocalcemia, nephrotoxicity, trace metal and vitamin deficiency, and thrombocytopenia and leukopenia [ Treatment may need to be discontinued if the following occur: White blood count <3.5x10 Neutrophils <2x10 Platelets <150x10 >2+ proteinuria on >1 occasion (and no evidence of infection) The above cut-off values are based on guidelines for D-penicillamine treatment [ Chelation therapy and iron supplementation may prevent primary disease manifestations in affected sibs who are asymptomatic (see Recommended Surveillance for Individuals with Hypermanganesemia with Dystonia 1 Foods very high in manganese (cloves; saffron; nuts; mussels; dark chocolate; pumpkin, sesame, and sunflower seeds) should be avoided. It is appropriate to clarify the genetic status of apparently asymptomatic sibs of a proband in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Chelation therapy and iron supplementation can potentially prevent primary disease manifestations in affected sibs who are asymptomatic (see Periodic monitoring of whole-blood manganese concentration and hemoglobin is recommended if the genetic status of a sib is unknown (i.e., if a sib has not undergone molecular genetic testing for the See For an affected fetus, no prenatal treatment is recommended as the disease does not manifest before early childhood. For an affected mother, no data or information on pregnancy management are available. Search • Neurologic exam for dystonia, parkinsonism, & spasticity • Incl eval of (1) ambulation & speech & (2) swallowing & nutritional status • Community or • Social work involvement for parental/family support; • Home nursing referral. • Regular chelation therapy can stabilize blood manganese levels, improve neurologic symptoms, & halt liver disease. • See • Chelation therapy should be continued lifelong. • CBC & renal function incl urinalysis are assessed at baseline & then monthly. • Monitoring may be extended to every 2 mos once on stable dose. • While on treatment, monitor every 2 mos incl: serum concentration of electrolytes, calcium, phosphate, magnesium; renal & liver function; full blood count; & serum concentrations of trace metals incl zinc, copper, & selenium to ensure no secondary effects on these metals. • If available, blood manganese levels can be monitored at similar intervals. • Iron is a competitive inhibitor of intestinal manganese uptake; despite normal iron levels, iron therapy can ↓ blood manganese levels & resolve polycythemia. • To avoid iron toxicity, monitor serum iron & total iron binding capacity regularly; if serum iron >80% of total iron binding capacity, stop or ↓ iron supplementation. • White blood count <3.5x10 • Neutrophils <2x10 • Platelets <150x10 • >2+ proteinuria on >1 occasion (and no evidence of infection) ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with HMNDYT1, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Hypermanganesemia with Dystonia 1 Neurologic exam for dystonia, parkinsonism, & spasticity Incl eval of (1) ambulation & speech & (2) swallowing & nutritional status Community or Social work involvement for parental/family support; Home nursing referral. MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Neurologic exam for dystonia, parkinsonism, & spasticity • Incl eval of (1) ambulation & speech & (2) swallowing & nutritional status • Community or • Social work involvement for parental/family support; • Home nursing referral. ## Treatment of Manifestations Treatment of Manifestations in Individuals with Hypermanganesemia with Dystonia 1 Regular chelation therapy can stabilize blood manganese levels, improve neurologic symptoms, & halt liver disease. See Chelation therapy should be continued lifelong. CBC & renal function incl urinalysis are assessed at baseline & then monthly. Monitoring may be extended to every 2 mos once on stable dose. While on treatment, monitor every 2 mos incl: serum concentration of electrolytes, calcium, phosphate, magnesium; renal & liver function; full blood count; & serum concentrations of trace metals incl zinc, copper, & selenium to ensure no secondary effects on these metals. If available, blood manganese levels can be monitored at similar intervals. Iron is a competitive inhibitor of intestinal manganese uptake; despite normal iron levels, iron therapy can ↓ blood manganese levels & resolve polycythemia. To avoid iron toxicity, monitor serum iron & total iron binding capacity regularly; if serum iron >80% of total iron binding capacity, stop or ↓ iron supplementation. CBC = complete blood count; IV = intravenous; OT = occupational therapy; PT = physical therapy Adverse effects of chelation therapy with disodium calcium edetate include hypocalcemia, nephrotoxicity, trace metal and vitamin deficiency, and thrombocytopenia and leukopenia [ Treatment may need to be discontinued if the following occur: White blood count <3.5x10 Neutrophils <2x10 Platelets <150x10 >2+ proteinuria on >1 occasion (and no evidence of infection) The above cut-off values are based on guidelines for D-penicillamine treatment [ • Regular chelation therapy can stabilize blood manganese levels, improve neurologic symptoms, & halt liver disease. • See • Chelation therapy should be continued lifelong. • CBC & renal function incl urinalysis are assessed at baseline & then monthly. • Monitoring may be extended to every 2 mos once on stable dose. • While on treatment, monitor every 2 mos incl: serum concentration of electrolytes, calcium, phosphate, magnesium; renal & liver function; full blood count; & serum concentrations of trace metals incl zinc, copper, & selenium to ensure no secondary effects on these metals. • If available, blood manganese levels can be monitored at similar intervals. • Iron is a competitive inhibitor of intestinal manganese uptake; despite normal iron levels, iron therapy can ↓ blood manganese levels & resolve polycythemia. • To avoid iron toxicity, monitor serum iron & total iron binding capacity regularly; if serum iron >80% of total iron binding capacity, stop or ↓ iron supplementation. • White blood count <3.5x10 • Neutrophils <2x10 • Platelets <150x10 • >2+ proteinuria on >1 occasion (and no evidence of infection) ## Adverse Effects of Chelation Therapy Adverse effects of chelation therapy with disodium calcium edetate include hypocalcemia, nephrotoxicity, trace metal and vitamin deficiency, and thrombocytopenia and leukopenia [ Treatment may need to be discontinued if the following occur: White blood count <3.5x10 Neutrophils <2x10 Platelets <150x10 >2+ proteinuria on >1 occasion (and no evidence of infection) The above cut-off values are based on guidelines for D-penicillamine treatment [ • White blood count <3.5x10 • Neutrophils <2x10 • Platelets <150x10 • >2+ proteinuria on >1 occasion (and no evidence of infection) ## Prevention of Primary Manifestations Chelation therapy and iron supplementation may prevent primary disease manifestations in affected sibs who are asymptomatic (see ## Surveillance Recommended Surveillance for Individuals with Hypermanganesemia with Dystonia 1 ## Agents/Circumstances to Avoid Foods very high in manganese (cloves; saffron; nuts; mussels; dark chocolate; pumpkin, sesame, and sunflower seeds) should be avoided. ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic sibs of a proband in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Chelation therapy and iron supplementation can potentially prevent primary disease manifestations in affected sibs who are asymptomatic (see Periodic monitoring of whole-blood manganese concentration and hemoglobin is recommended if the genetic status of a sib is unknown (i.e., if a sib has not undergone molecular genetic testing for the See ## Pregnancy Management For an affected fetus, no prenatal treatment is recommended as the disease does not manifest before early childhood. For an affected mother, no data or information on pregnancy management are available. ## Therapies Under Investigation Search ## Genetic Counseling Hypermanganesemia with dystonia 1 (HMNDYT1) is inherited in an autosomal recessive manner. The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for 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 Significant phenotypic variability may be observed between affected sibs, particularly with regard to liver disease, which may be absent or mild in some individuals while their sibs develop chronic liver disease and associated complications. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. No data on fertility in individuals with HMNDYT1 are available. Assuming that reproduction is possible, the offspring of an affected individual are obligate heterozygotes (carriers) for a pathogenic variant in Carrier testing for at-risk relatives requires prior identification of the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for 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 • Significant phenotypic variability may be observed between affected sibs, particularly with regard to liver disease, which may be absent or mild in some individuals while their sibs develop chronic liver disease and associated complications. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • No data on fertility in individuals with HMNDYT1 are available. • Assuming that reproduction is possible, the offspring of an affected individual are obligate heterozygotes (carriers) for a pathogenic variant in • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance Hypermanganesemia with dystonia 1 (HMNDYT1) is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for 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 Significant phenotypic variability may be observed between affected sibs, particularly with regard to liver disease, which may be absent or mild in some individuals while their sibs develop chronic liver disease and associated complications. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. No data on fertility in individuals with HMNDYT1 are available. Assuming that reproduction is possible, the offspring of an affected individual are obligate heterozygotes (carriers) for a pathogenic variant in • 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 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 • Significant phenotypic variability may be observed between affected sibs, particularly with regard to liver disease, which may be absent or mild in some individuals while their sibs develop chronic liver disease and associated complications. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • No data on fertility in individuals with HMNDYT1 are available. • Assuming that reproduction is possible, the offspring of an affected individual are obligate heterozygotes (carriers) for a pathogenic variant in ## 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 Hypermanganesemia with Dystonia 1: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Hypermanganesemia with Dystonia 1 ( SLC30A10 is a member of the SLC30 solute carrier subfamily of the cation diffusion facilitator (CDF) family. Human SLC30A10 is a protein of 485 amino acids [ Pathogenic variants in SLC30A10 localizes to the apical domain of hepatocytes and enterocytes where it facilitates manganese excretion. Studies in mice have confirmed that loss of SLC30A10 function leads to impaired biliary and intestinal manganese elimination with subsequent accumulation of manganese in the liver and brain [ ## Molecular Pathogenesis SLC30A10 is a member of the SLC30 solute carrier subfamily of the cation diffusion facilitator (CDF) family. Human SLC30A10 is a protein of 485 amino acids [ Pathogenic variants in SLC30A10 localizes to the apical domain of hepatocytes and enterocytes where it facilitates manganese excretion. Studies in mice have confirmed that loss of SLC30A10 function leads to impaired biliary and intestinal manganese elimination with subsequent accumulation of manganese in the liver and brain [ ## Chapter Notes The authors are studying the mechanisms underlying manganese neurotoxicity and inherited manganese transporter defects at the University College London (UCL) Great Ormond Street Institute of Child Health. Tuschl Lab website: Dr Karin Tuschl UCL website: 23 December 2021 (ha) Comprehensive update posted live 9 February 2017 (ha) Comprehensive update posted live 11 September 2014 (me) Comprehensive update posted live 30 August 2012 (me) Review posted live 1 June 2012 (kt) Original submission • 23 December 2021 (ha) Comprehensive update posted live • 9 February 2017 (ha) Comprehensive update posted live • 11 September 2014 (me) Comprehensive update posted live • 30 August 2012 (me) Review posted live • 1 June 2012 (kt) Original submission ## Author Notes The authors are studying the mechanisms underlying manganese neurotoxicity and inherited manganese transporter defects at the University College London (UCL) Great Ormond Street Institute of Child Health. Tuschl Lab website: Dr Karin Tuschl UCL website: ## Revision History 23 December 2021 (ha) Comprehensive update posted live 9 February 2017 (ha) Comprehensive update posted live 11 September 2014 (me) Comprehensive update posted live 30 August 2012 (me) Review posted live 1 June 2012 (kt) Original submission • 23 December 2021 (ha) Comprehensive update posted live • 9 February 2017 (ha) Comprehensive update posted live • 11 September 2014 (me) Comprehensive update posted live • 30 August 2012 (me) Review posted live • 1 June 2012 (kt) Original submission ## References ## Literature Cited Representative brain MRI of an affected individual A. Transaxial T B. Sagittal T C. Transaxial T	[]	30/8/2012	23/12/2021	8/11/2012	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
hmerf	hmerf	[ "HMERF", "MFM-Titinopathy", "Myofibrillar Myopathy with Early Respiratory Failure", "MFM-Titinopathy", "Myofibrillar Myopathy with Early Respiratory Failure", "HMERF", "Titin", "TTN", "Hereditary Myopathy with Early Respiratory Failure" ]	Hereditary Myopathy with Early Respiratory Failure	Gerald Pfeffer, Patrick F Chinnery	Summary Hereditary myopathy with early respiratory failure (HMERF) is a slowly progressive myopathy that typically begins in the third to fifth decades of life. The usual presenting findings are gait disturbance relating to distal leg weakness or nocturnal respiratory symptoms due to respiratory muscle weakness. Weakness eventually generalizes and affects both proximal and distal muscles. Most affected individuals require walking aids within a few years of onset; some progress to wheelchair dependence and require nocturnal noninvasive ventilatory support about ten years after onset. The phenotype varies even among individuals within the same family: some remain ambulant until their 70s whereas others may require ventilator support in their 40s. The diagnosis of HMERF is established in a proband with typical clinical findings and/or a heterozygous pathogenic variant in the region of HMERF is inherited in an autosomal dominant manner with variable expressivity. Most individuals diagnosed with HMERF have an affected parent; to date,	## Diagnosis Hereditary myopathy with early respiratory failure (HMERF) is a slowly progressive myopathy with typical onset in adulthood. The diagnosis of this rare disorder is not supported by any formal diagnostic criteria at this time. Diagnosis of hereditary myopathy with early respiratory failure (HMERF) Adult-onset muscle disease with onset typically between ages 30 and 50 years (range 22-71 years) The first symptoms usually relate to weakness of the distal leg muscles and may include foot drop or frequent falls. Weakness may also involve the proximal muscles of the lower extremities, proximal and/or distal muscles of the upper extremities, and axial muscles. Affected individuals may appear quite muscular even when weakness is present [ In particular, hypertrophy of the calf muscles is frequently reported [ Serum creatine kinase is usually mildly elevated (range: normal to 1,000 units/L). Evidence of respiratory muscle weakness early in the disease course Note: Since affected individuals may not report symptoms, they need to be specifically asked about orthopnea, dyspnea on exertion, and excessive daytime sleepiness. Family history consistent with autosomal dominant inheritance Note: Muscle MRI findings and muscle pathology studies can identify supportive evidence but may not be specific to this disorder (see The diagnosis of HMERF Note: All HMERF-associated 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 [ * Rare individuals have been reported to be homozygous for the 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 HMERF is broad, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of HMERF molecular genetic testing approaches can include For an introduction to multigene panels click When the diagnosis of HMERF is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Hereditary Myopathy with Early Respiratory Failure (HMERF) See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click To date, all pathogenic variants associated with HMERF are located in the Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • Adult-onset muscle disease with onset typically between ages 30 and 50 years (range 22-71 years) • The first symptoms usually relate to weakness of the distal leg muscles and may include foot drop or frequent falls. • Weakness may also involve the proximal muscles of the lower extremities, proximal and/or distal muscles of the upper extremities, and axial muscles. • Affected individuals may appear quite muscular even when weakness is present [ • In particular, hypertrophy of the calf muscles is frequently reported [ • Serum creatine kinase is usually mildly elevated (range: normal to 1,000 units/L). • The first symptoms usually relate to weakness of the distal leg muscles and may include foot drop or frequent falls. • Weakness may also involve the proximal muscles of the lower extremities, proximal and/or distal muscles of the upper extremities, and axial muscles. • Affected individuals may appear quite muscular even when weakness is present [ • In particular, hypertrophy of the calf muscles is frequently reported [ • Serum creatine kinase is usually mildly elevated (range: normal to 1,000 units/L). • Evidence of respiratory muscle weakness early in the disease course • Note: Since affected individuals may not report symptoms, they need to be specifically asked about orthopnea, dyspnea on exertion, and excessive daytime sleepiness. • Family history consistent with autosomal dominant inheritance • The first symptoms usually relate to weakness of the distal leg muscles and may include foot drop or frequent falls. • Weakness may also involve the proximal muscles of the lower extremities, proximal and/or distal muscles of the upper extremities, and axial muscles. • Affected individuals may appear quite muscular even when weakness is present [ • In particular, hypertrophy of the calf muscles is frequently reported [ • Serum creatine kinase is usually mildly elevated (range: normal to 1,000 units/L). • For an introduction to multigene panels click ## Suggestive Findings Diagnosis of hereditary myopathy with early respiratory failure (HMERF) Adult-onset muscle disease with onset typically between ages 30 and 50 years (range 22-71 years) The first symptoms usually relate to weakness of the distal leg muscles and may include foot drop or frequent falls. Weakness may also involve the proximal muscles of the lower extremities, proximal and/or distal muscles of the upper extremities, and axial muscles. Affected individuals may appear quite muscular even when weakness is present [ In particular, hypertrophy of the calf muscles is frequently reported [ Serum creatine kinase is usually mildly elevated (range: normal to 1,000 units/L). Evidence of respiratory muscle weakness early in the disease course Note: Since affected individuals may not report symptoms, they need to be specifically asked about orthopnea, dyspnea on exertion, and excessive daytime sleepiness. Family history consistent with autosomal dominant inheritance Note: Muscle MRI findings and muscle pathology studies can identify supportive evidence but may not be specific to this disorder (see • Adult-onset muscle disease with onset typically between ages 30 and 50 years (range 22-71 years) • The first symptoms usually relate to weakness of the distal leg muscles and may include foot drop or frequent falls. • Weakness may also involve the proximal muscles of the lower extremities, proximal and/or distal muscles of the upper extremities, and axial muscles. • Affected individuals may appear quite muscular even when weakness is present [ • In particular, hypertrophy of the calf muscles is frequently reported [ • Serum creatine kinase is usually mildly elevated (range: normal to 1,000 units/L). • The first symptoms usually relate to weakness of the distal leg muscles and may include foot drop or frequent falls. • Weakness may also involve the proximal muscles of the lower extremities, proximal and/or distal muscles of the upper extremities, and axial muscles. • Affected individuals may appear quite muscular even when weakness is present [ • In particular, hypertrophy of the calf muscles is frequently reported [ • Serum creatine kinase is usually mildly elevated (range: normal to 1,000 units/L). • Evidence of respiratory muscle weakness early in the disease course • Note: Since affected individuals may not report symptoms, they need to be specifically asked about orthopnea, dyspnea on exertion, and excessive daytime sleepiness. • Family history consistent with autosomal dominant inheritance • The first symptoms usually relate to weakness of the distal leg muscles and may include foot drop or frequent falls. • Weakness may also involve the proximal muscles of the lower extremities, proximal and/or distal muscles of the upper extremities, and axial muscles. • Affected individuals may appear quite muscular even when weakness is present [ • In particular, hypertrophy of the calf muscles is frequently reported [ • Serum creatine kinase is usually mildly elevated (range: normal to 1,000 units/L). ## Establishing the Diagnosis The diagnosis of HMERF Note: All HMERF-associated 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 [ * Rare individuals have been reported to be homozygous for the 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 HMERF is broad, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of HMERF molecular genetic testing approaches can include For an introduction to multigene panels click When the diagnosis of HMERF is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Hereditary Myopathy with Early Respiratory Failure (HMERF) See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click To date, all pathogenic variants associated with HMERF are located in the Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • For an introduction to multigene panels click ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of HMERF 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 HMERF is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Hereditary Myopathy with Early Respiratory Failure (HMERF) See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click To date, all pathogenic variants associated with HMERF are located in the Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Clinical Characteristics Hereditary myopathy with early respiratory failure (HMERF) is a slowly progressive myopathy that typically begins in the third to fifth decades of life [ The usual presenting findings are gait disturbance relating to distal leg weakness or nocturnal respiratory symptoms due to respiratory muscle weakness. Weakness eventually generalizes and affects both proximal and distal muscles. The specific findings described with this disorder include the presence of "cheetah-print" aggregates [ Otherwise, features of myofibrillar myopathy such as eosinophilic cytoplasmic inclusions on hematoxylin and eosin staining and cytoplasmic bodies on electron microscopy may be present, but are not specific for HMERF. Other nonspecific myopathic findings may be present. A distinctive feature of this condition is the early diaphragmatic weakness that often occurs while individuals are still ambulant, which is typical of only a few other rare diseases (see Most individuals require walking aids within a few years of onset, most commonly ankle-foot orthoses. Some will progress to wheelchair dependence and require nocturnal noninvasive ventilatory support about ten years after onset. Weakness of respiratory muscles also progresses with time. Affected individuals become increasingly vulnerable to pulmonary infections as respiratory function deteriorates. Of note, the phenotype varies even among individuals within the same family [ Presumably life expectancy is decreased in this disorder, but because of the rarity of the condition, studies have not formally addressed this question. From the experience of the authors, individuals with this condition are more susceptible to pulmonary complications (due to the respiratory muscle weakness), which may result in early morbidity and mortality [ Although clinical variability is observed with HMERF-related Penetrance appears to depend on the pathogenic variant. For the common The Because the other pathogenic variants have only been described in a few individuals to date [ Hereditary myopathy with early respiratory failure (HMERF) has previously been termed: Myopathy with respiratory failure and myofibrillar aggregates [ Hereditary cytoplasmic body myopathy with early respiratory failure [ Hereditary inclusion body myopathy with early respiratory failure [ The authors prefer the term "myofibrillar myopathy-titinopathy" [ The prevalence of HMERF is not known, but it is most likely under-recognized because of its broad phenotypic spectrum and relatively recent discovery of its underlying genetic etiology. Two studies have indicated that about 5% of persons with an undiagnosed myofibrillar myopathy have a • Myopathy with respiratory failure and myofibrillar aggregates [ • Hereditary cytoplasmic body myopathy with early respiratory failure [ • Hereditary inclusion body myopathy with early respiratory failure [ ## Clinical Description Hereditary myopathy with early respiratory failure (HMERF) is a slowly progressive myopathy that typically begins in the third to fifth decades of life [ The usual presenting findings are gait disturbance relating to distal leg weakness or nocturnal respiratory symptoms due to respiratory muscle weakness. Weakness eventually generalizes and affects both proximal and distal muscles. The specific findings described with this disorder include the presence of "cheetah-print" aggregates [ Otherwise, features of myofibrillar myopathy such as eosinophilic cytoplasmic inclusions on hematoxylin and eosin staining and cytoplasmic bodies on electron microscopy may be present, but are not specific for HMERF. Other nonspecific myopathic findings may be present. A distinctive feature of this condition is the early diaphragmatic weakness that often occurs while individuals are still ambulant, which is typical of only a few other rare diseases (see Most individuals require walking aids within a few years of onset, most commonly ankle-foot orthoses. Some will progress to wheelchair dependence and require nocturnal noninvasive ventilatory support about ten years after onset. Weakness of respiratory muscles also progresses with time. Affected individuals become increasingly vulnerable to pulmonary infections as respiratory function deteriorates. Of note, the phenotype varies even among individuals within the same family [ Presumably life expectancy is decreased in this disorder, but because of the rarity of the condition, studies have not formally addressed this question. From the experience of the authors, individuals with this condition are more susceptible to pulmonary complications (due to the respiratory muscle weakness), which may result in early morbidity and mortality [ ## Presentation The usual presenting findings are gait disturbance relating to distal leg weakness or nocturnal respiratory symptoms due to respiratory muscle weakness. Weakness eventually generalizes and affects both proximal and distal muscles. ## Muscle Findings The specific findings described with this disorder include the presence of "cheetah-print" aggregates [ Otherwise, features of myofibrillar myopathy such as eosinophilic cytoplasmic inclusions on hematoxylin and eosin staining and cytoplasmic bodies on electron microscopy may be present, but are not specific for HMERF. Other nonspecific myopathic findings may be present. ## Respiratory Findings A distinctive feature of this condition is the early diaphragmatic weakness that often occurs while individuals are still ambulant, which is typical of only a few other rare diseases (see ## Progression Most individuals require walking aids within a few years of onset, most commonly ankle-foot orthoses. Some will progress to wheelchair dependence and require nocturnal noninvasive ventilatory support about ten years after onset. Weakness of respiratory muscles also progresses with time. Affected individuals become increasingly vulnerable to pulmonary infections as respiratory function deteriorates. Of note, the phenotype varies even among individuals within the same family [ ## Life Expectancy Presumably life expectancy is decreased in this disorder, but because of the rarity of the condition, studies have not formally addressed this question. From the experience of the authors, individuals with this condition are more susceptible to pulmonary complications (due to the respiratory muscle weakness), which may result in early morbidity and mortality [ ## Genotype-Phenotype Correlations Although clinical variability is observed with HMERF-related ## Penetrance Penetrance appears to depend on the pathogenic variant. For the common The Because the other pathogenic variants have only been described in a few individuals to date [ ## Nomenclature Hereditary myopathy with early respiratory failure (HMERF) has previously been termed: Myopathy with respiratory failure and myofibrillar aggregates [ Hereditary cytoplasmic body myopathy with early respiratory failure [ Hereditary inclusion body myopathy with early respiratory failure [ The authors prefer the term "myofibrillar myopathy-titinopathy" [ • Myopathy with respiratory failure and myofibrillar aggregates [ • Hereditary cytoplasmic body myopathy with early respiratory failure [ • Hereditary inclusion body myopathy with early respiratory failure [ ## Prevalence The prevalence of HMERF is not known, but it is most likely under-recognized because of its broad phenotypic spectrum and relatively recent discovery of its underlying genetic etiology. Two studies have indicated that about 5% of persons with an undiagnosed myofibrillar myopathy have a ## Genetically Related (Allelic) Disorders Phenotypes other than those discussed in this Autosomal recessive limb-girdle muscular dystrophy LGMDR10, titin-related (OMIM Early-onset myopathy with fatal cardiomyopathy (also known as • • Autosomal recessive limb-girdle muscular dystrophy LGMDR10, titin-related (OMIM • • Early-onset myopathy with fatal cardiomyopathy (also known as ## Differential Diagnosis Disorders to Consider in the Differential Diagnosis of Hereditary Myopathy with Early Respiratory Failure Presence of combined upper & lower motor neuron signs Early atrophy of hand muscles Characteristic neurophysiologic abnormalities Typically presents w/weakness of facial & proximal arm muscles (esp shoulder & hip girdle) Highly variable disease severity Absence of early respiratory failure Presence of facial weakness Proximal muscle weakness Respiratory insufficiency Early diaphragmatic weakness while still ambulant Pathologic findings Muscle MRI abnormalities Weakness & wasting restricted to limb musculature (proximal > distal) Subtypes LGMD2I ( Significant overlap in clinical, MRI, & pathologic features w/HMERF; some individuals w/HMERF meet diagnostic criteria for MFM on muscle biopsy. Slowly progressive weakness that can involve both proximal & distal muscles Distal muscle weakness present in ~80% of individuals Respiratory muscle weakness can occur esp in Highly variable muscle disease May present w/distal muscle weakness & respiratory muscle involvement Distribution of muscle weakness, usually incl face or eyelids Variable multisystem features incl: myotonia; cataracts; cognitive deficits; cardiac arrhythmia; endocrine & GI dysfunction Fatigability Bulbar muscles often affected Electrodecremental response demonstrated on nerve conduction studies Jittery motor unit potentials on single-fiber electromyography Most affected individuals are seropositive for AchR or MuSK antibodies. AD = autosomal dominant; AR = autosomal recessive; GI = gastrointestinal; HMERF = hereditary myopathy with early respiratory failure; MOI = mode of inheritance; NA = not applicable; XL = X-linked See The diagnosis of FSHD1 is established in a proband with characteristic clinical features by identification of a heterozygous pathogenic contraction of the D4Z4 repeat array in the subtelomeric region of chromosome 4q35 on a chromosome 4 permissive haplotype. The diagnosis of FSHD2 is established in a proband by identification of hypomethylation of the D4Z4 repeat array in the subtelomeric region of chromosome 4q35 on a chromosome 4 permissive haplotype. Hypomethylation of the D4Z4 repeat array can be due to a heterozygous pathogenic variant in See DM1 is caused by expansion of a CTG trinucleotide repeat in the noncoding region of Other similar clinical presentations may occur atypically with other disorders and may be considered on a case-by-case basis. The individual should be evaluated in the context of coexisting medical conditions, medication use, and/or toxic exposures. Reversible or treatable medical conditions such as endocrine disorders, autoimmune disease, or nutritional deficiencies should be considered when appropriate. An example of a toxic exposure is a single case report of colchicine use causing isolated respiratory muscle weakness that resolved on discontinuation of treatment [ • Presence of combined upper & lower motor neuron signs • Early atrophy of hand muscles • Characteristic neurophysiologic abnormalities • Typically presents w/weakness of facial & proximal arm muscles (esp shoulder & hip girdle) • Highly variable disease severity • Absence of early respiratory failure • Presence of facial weakness • Proximal muscle weakness • Respiratory insufficiency • Early diaphragmatic weakness while still ambulant • Pathologic findings • Muscle MRI abnormalities • Weakness & wasting restricted to limb musculature (proximal > distal) • Subtypes LGMD2I ( • Significant overlap in clinical, MRI, & pathologic features w/HMERF; some individuals w/HMERF meet diagnostic criteria for MFM on muscle biopsy. • Slowly progressive weakness that can involve both proximal & distal muscles • Distal muscle weakness present in ~80% of individuals • Respiratory muscle weakness can occur esp in • Highly variable muscle disease • May present w/distal muscle weakness & respiratory muscle involvement • Distribution of muscle weakness, usually incl face or eyelids • Variable multisystem features incl: myotonia; cataracts; cognitive deficits; cardiac arrhythmia; endocrine & GI dysfunction • Fatigability • Bulbar muscles often affected • Electrodecremental response demonstrated on nerve conduction studies • Jittery motor unit potentials on single-fiber electromyography • Most affected individuals are seropositive for AchR or MuSK antibodies. ## Management To establish the extent of disease and needs in an individual diagnosed with hereditary myopathy with early respiratory failure (HMERF), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with HMERF OT = occupational therapy; PT = physical therapy At present no disease-modifying therapy exists. Management is supportive. Because of the rarity of this disorder, no formal treatment guidelines have been developed, although general recommendations based on clinical experience are provided in Treatment of Manifestations in Individuals with HMERF BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; OT = occupational therapy; PT = physical therapy No specific guidelines are in place for surveillance of this disorder; general recommendations are provided in Recommended Surveillance for Individuals with HMERF See Information is insufficient to determine if particular issues in HMERF relate to pregnancy. In general, onset of symptoms occurs after the age of childbearing. However, a pregnant woman with early manifestations of HMERF or at risk for HMERF should be considered at high risk because of the associated respiratory muscle weakness and the increased physiologic demands of pregnancy. Consultation with a high-risk maternal-fetal medicine specialist is recommended when possible. Search ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with hereditary myopathy with early respiratory failure (HMERF), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with HMERF OT = occupational therapy; PT = physical therapy ## Treatment of Manifestations At present no disease-modifying therapy exists. Management is supportive. Because of the rarity of this disorder, no formal treatment guidelines have been developed, although general recommendations based on clinical experience are provided in Treatment of Manifestations in Individuals with HMERF BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; OT = occupational therapy; PT = physical therapy ## Surveillance No specific guidelines are in place for surveillance of this disorder; general recommendations are provided in Recommended Surveillance for Individuals with HMERF ## Evaluation of Relatives at Risk See ## Pregnancy Management Information is insufficient to determine if particular issues in HMERF relate to pregnancy. In general, onset of symptoms occurs after the age of childbearing. However, a pregnant woman with early manifestations of HMERF or at risk for HMERF should be considered at high risk because of the associated respiratory muscle weakness and the increased physiologic demands of pregnancy. Consultation with a high-risk maternal-fetal medicine specialist is recommended when possible. ## Therapies Under Investigation Search ## Genetic Counseling Hereditary myopathy with early respiratory failure (HMERF) is inherited in an autosomal dominant manner with variable expressivity. Note: The Most individuals diagnosed with HMERF are heterozygous for a To date, Molecular genetic testing is recommended for the parents of a proband with an apparent If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include germline mosaicism in a parent or a The family history of some individuals diagnosed with HMERF may appear to the negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, a milder phenotype, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed until appropriate 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 If the proband has a known If the parents have not been tested for the If both parents are heterozygous for the Each child of an individual with heterozygous HMERF-associated pathogenic variants has a 50% chance of inheriting the All offspring of an individual with biallelic p.Pro30091Leu pathogenic variants will be heterozygous for the Predictive testing for at-risk relatives is possible once the Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. For more information, see the National Society of Genetic Counselors In a family with an established diagnosis of HMERF it is appropriate to consider testing of symptomatic individuals regardless of age. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • Most individuals diagnosed with HMERF are heterozygous for a • To date, • Molecular genetic testing is recommended for the parents of a proband with an apparent • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include germline mosaicism in a parent or a • The family history of some individuals diagnosed with HMERF may appear to the negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, a milder phenotype, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed until appropriate 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 • If the proband has a known • If the parents have not been tested for the • If both parents are heterozygous for the • Each child of an individual with heterozygous HMERF-associated pathogenic variants has a 50% chance of inheriting the • All offspring of an individual with biallelic p.Pro30091Leu pathogenic variants will be heterozygous for the • Predictive testing for at-risk relatives is possible once the • Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. • For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. • For more information, see the National Society of Genetic Counselors • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance Hereditary myopathy with early respiratory failure (HMERF) is inherited in an autosomal dominant manner with variable expressivity. Note: The ## Risk to Family Members Most individuals diagnosed with HMERF are heterozygous for a To date, Molecular genetic testing is recommended for the parents of a proband with an apparent If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include germline mosaicism in a parent or a The family history of some individuals diagnosed with HMERF may appear to the negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, a milder phenotype, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed until appropriate 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 If the proband has a known If the parents have not been tested for the If both parents are heterozygous for the Each child of an individual with heterozygous HMERF-associated pathogenic variants has a 50% chance of inheriting the All offspring of an individual with biallelic p.Pro30091Leu pathogenic variants will be heterozygous for the • Most individuals diagnosed with HMERF are heterozygous for a • To date, • Molecular genetic testing is recommended for the parents of a proband with an apparent • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include germline mosaicism in a parent or a • The family history of some individuals diagnosed with HMERF may appear to the negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, a milder phenotype, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed until appropriate 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 • If the proband has a known • If the parents have not been tested for the • If both parents are heterozygous for the • Each child of an individual with heterozygous HMERF-associated pathogenic variants has a 50% chance of inheriting the • All offspring of an individual with biallelic p.Pro30091Leu pathogenic variants will be heterozygous for the ## Related Genetic Counseling Issues Predictive testing for at-risk relatives is possible once the Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. For more information, see the National Society of Genetic Counselors In a family with an established diagnosis of HMERF it is appropriate to consider testing of symptomatic individuals regardless of age. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • Predictive testing for at-risk relatives is possible once the • Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. • 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 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 France Canada United Kingdom • • • • France • • • • • Canada • • • United Kingdom • ## Molecular Genetics Hereditary Myopathy with Early Respiratory Failure: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Hereditary Myopathy with Early Respiratory Failure ( Titin is the molecular scaffold protein that spans half of the sarcomere. Pathogenic variants in different domains of titin can result in different disorders affecting muscle tissue, with combinations of cardiomyopathy, proximal myopathy, distal myopathy, and respiratory failure, the presentation of which can range from congenital to very late onset. Pathogenic variants causing HMERF are all located within the 119th fibronectin-3 domain of titin (see exon designations below). The function of this domain and disease mechanism of HMERF are unknown. Genetic constructs expressing the FN119 domain with HMERF-associated variants demonstrated reduced solubility compared to normal [ The FN119 domain exon corresponds to the following: Notable Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions Previously used reference sequences: AJ277892.2, Q8WZ42.4 ## Molecular Pathogenesis Titin is the molecular scaffold protein that spans half of the sarcomere. Pathogenic variants in different domains of titin can result in different disorders affecting muscle tissue, with combinations of cardiomyopathy, proximal myopathy, distal myopathy, and respiratory failure, the presentation of which can range from congenital to very late onset. Pathogenic variants causing HMERF are all located within the 119th fibronectin-3 domain of titin (see exon designations below). The function of this domain and disease mechanism of HMERF are unknown. Genetic constructs expressing the FN119 domain with HMERF-associated variants demonstrated reduced solubility compared to normal [ The FN119 domain exon corresponds to the following: Notable Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions Previously used reference sequences: AJ277892.2, Q8WZ42.4 ## Chapter Notes GP is an Assistant Professor and clinical neurologist at the University of Calgary and Department of Clinical Neurosciences. He is the recipient of funding from the Canada Foundation for Innovation, and Muscular Dystrophy Canada. PFC is an Honorary Consultant Neurologist at Newcastle upon Tyne Foundation Hospitals NHS Trust, a Wellcome Trust Senior Fellow in Clinical Science (084980/Z/08/Z), and a UK NIHR Senior Investigator. PFC receives additional support from the Wellcome Trust Centre for Mitochondrial Research (096919Z/11/Z), the Medical Research Council (UK) Centre for Translational Research in Neuromuscular Diseases, and EU FP7 TIRCON, and the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University. 12 December 2024 (sw) Revision: added 14 April 2022 (gm) Revision: correction of nomenclature for 119th fibronectin-3 domain of titin (see 19 March 2020 (ha) Comprehensive update posted live 27 February 2014 (me) Review posted live 5 December 2013 (gp) Original submission • 12 December 2024 (sw) Revision: added • 14 April 2022 (gm) Revision: correction of nomenclature for 119th fibronectin-3 domain of titin (see • 19 March 2020 (ha) Comprehensive update posted live • 27 February 2014 (me) Review posted live • 5 December 2013 (gp) Original submission ## Acknowledgments GP is an Assistant Professor and clinical neurologist at the University of Calgary and Department of Clinical Neurosciences. He is the recipient of funding from the Canada Foundation for Innovation, and Muscular Dystrophy Canada. PFC is an Honorary Consultant Neurologist at Newcastle upon Tyne Foundation Hospitals NHS Trust, a Wellcome Trust Senior Fellow in Clinical Science (084980/Z/08/Z), and a UK NIHR Senior Investigator. PFC receives additional support from the Wellcome Trust Centre for Mitochondrial Research (096919Z/11/Z), the Medical Research Council (UK) Centre for Translational Research in Neuromuscular Diseases, and EU FP7 TIRCON, and the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University. ## Revision History 12 December 2024 (sw) Revision: added 14 April 2022 (gm) Revision: correction of nomenclature for 119th fibronectin-3 domain of titin (see 19 March 2020 (ha) Comprehensive update posted live 27 February 2014 (me) Review posted live 5 December 2013 (gp) Original submission • 12 December 2024 (sw) Revision: added • 14 April 2022 (gm) Revision: correction of nomenclature for 119th fibronectin-3 domain of titin (see • 19 March 2020 (ha) Comprehensive update posted live • 27 February 2014 (me) Review posted live • 5 December 2013 (gp) Original submission ## References ## Literature Cited	[]	27/2/2014	19/3/2020	12/12/2024	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
hna	hna	[ "Hereditary Brachial Plexus Neuropathy", "Neuritis with Brachial Predilection", "Hereditary Brachial Plexus Neuropathy", "Neuritis with Brachial Predilection", "Septin-9", "SEPTIN9", "Hereditary Neuralgic Amyotrophy" ]	Hereditary Neuralgic Amyotrophy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY	Nens van Alfen, Mark C Hannibal, Phillip F Chance, Baziel GM van Engelen	Summary Hereditary neuralgic amyotrophy (HNA) is characterized by sudden onset of severe, non-abating pain in the shoulder girdle and/or the upper limb and amyotrophy (muscle wasting or atrophy) that typically develops within two weeks of the onset of severe pain. Other sites may also be involved in an attack; sensory symptoms, present in the majority of affected individuals, can include hypoesthesia (decreased sensation) and paresthesias. Onset is typically in the second or third decade (median age 28 years). Although attacks appear to become less frequent with age, residual deficits accumulate with subsequent attacks. In some families, non-neurologic findings (characteristic craniofacial features, bifid uvula or cleft palate, short stature, and/or partial syndactyly of the fingers or toes) are present. The diagnosis of HNA is based on clinical findings. Hereditary neuralgic amyotrophy is inherited in an autosomal dominant manner. Most individuals diagnosed with HNA have an affected parent; the proportion of cases caused by a	## Diagnosis Hereditary neuralgic amyotrophy (HNA) is an episodic disorder diagnosed clinically using criteria developed by the European CMT Consortium; see modified criteria ( Sensory and motor nerves are typically affected; occasionally autonomic nerve injury also occurs. HNA is characterized in 95% of cases by the following: HNA Diagnostic Criteria 2nd or 3rd decade of life (median: 28 yrs) Earlier or later onset Acute, uni- or bilateral brachial plexopathy Severe pain preceding onset of weakness by days to a few wks Predominantly motor deficits Number of episodes variable (1-20) Precipitating factors: infections, immunizations, surgery, parturition, unusually strenuous exercise of affected limb, exposure to cold Attack recurrence (75%) Sensory symptoms (70%) Lumbar plexus (33%) &/or phrenic nerve (14%) involved Cranial nerve involved Dysmorphic features Abortive attacks (pain is not followed by weakness) Weakness preceding onset of pain by days to wks Long intervals between attacks (up to many yrs) No pain during an attack (5%) Autosomal dominant inheritance Simplex case (i.e., single occurrence in a family) Patchy or multifocal distribution of abnormalities More prominent motor loss than sensory loss Sensory abnormalities (80%) Autonomic symptoms (15%) Mononeuropathy Absent or diminished tendon reflexes in affected limbs Muscle weakness and atrophy Relapsing/remitting course w/symptom-free intervals Recovery incomplete; persisting neurologic deficit especially after repeated attacks in the same limb Complete recovery w/out residual deficit between attacks Chronic undulating course w/out completely symptom-free intervals Signs of denervation or reinnervation in clinically weak muscles seen on EMG Reduced amplitude of CMAP in muscles innervated by affected nerves Reduced amplitudes of sensory nerve action potentials in affected nerves Identification of a presumed pathogenic variant or duplication in Linkage to the SEPT9 locus on chromosome 17q25 Absence of linkage to the SEPT9 locus on chromosome 17q25 CMAP = compound muscle action potential; EMG = electromyogram Modified from Most commonly recurrent laryngeal nerve (19%) or facial nerve Most commonly ocular hypotelorism, epicanthal folds, cleft palate, bifid uvula, excessive neck or arm skin folds Exclusion criterion: Signs of generalized neuropathy Such as abnormal sweating in affected arm or, rarely, Horner syndrome Most commonly long thoracic, anterior interosseus, or phrenic nerve Exclusion criterion: Slow progression of motor impairment over >3 months Exclusion criterion: Electrophysiologic signs of systemic generalized neuropathy Exclusion criteria: a The percentage of families in the US who appear not to be genetically linked to the SEPT9 locus is estimated at 15%. The percentage of families in other countries (e.g., the Netherlands) who appear not to be genetically linked to the SEPT9 locus may be much higher [unpublished/preliminary data]. Molecular Genetic Testing Used in Hereditary Neuralgic Amyotrophy See See The ability of the test method used to detect a variant that is present in the indicated gene The proportion may be higher or lower depending on country or region of origin [ 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 In families with HNA linked to Testing that identifies exon or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. Both a founder duplication and nonrecurrent duplications (with unique breakpoints) have been reported [ In families with HNA linked to Confirmation of the diagnosis in persons in whom a clinical diagnosis of HNA is suspected requires molecular genetic testing to identify the pathogenic variant in If sequence analysis of • 2nd or 3rd decade of life (median: 28 yrs) • Earlier or later onset • Acute, uni- or bilateral brachial plexopathy • Severe pain preceding onset of weakness by days to a few wks • Predominantly motor deficits • Number of episodes variable (1-20) • Precipitating factors: infections, immunizations, surgery, parturition, unusually strenuous exercise of affected limb, exposure to cold • Attack recurrence (75%) • Sensory symptoms (70%) • Lumbar plexus (33%) &/or phrenic nerve (14%) involved • Cranial nerve involved • Dysmorphic features • Abortive attacks (pain is not followed by weakness) • Weakness preceding onset of pain by days to wks • Long intervals between attacks (up to many yrs) • No pain during an attack (5%) • Autosomal dominant inheritance • Simplex case (i.e., single occurrence in a family) • Patchy or multifocal distribution of abnormalities • More prominent motor loss than sensory loss • Sensory abnormalities (80%) • Autonomic symptoms (15%) • Mononeuropathy • Absent or diminished tendon reflexes in affected limbs • Muscle weakness and atrophy • Relapsing/remitting course w/symptom-free intervals • Recovery incomplete; persisting neurologic deficit especially after repeated attacks in the same limb • Complete recovery w/out residual deficit between attacks • Chronic undulating course w/out completely symptom-free intervals • Signs of denervation or reinnervation in clinically weak muscles seen on EMG • Reduced amplitude of CMAP in muscles innervated by affected nerves • Reduced amplitudes of sensory nerve action potentials in affected nerves • Identification of a presumed pathogenic variant or duplication in • Linkage to the SEPT9 locus on chromosome 17q25 • Absence of linkage to the SEPT9 locus on chromosome 17q25 • The percentage of families in the US who appear not to be genetically linked to the SEPT9 locus is estimated at 15%. • The percentage of families in other countries (e.g., the Netherlands) who appear not to be genetically linked to the SEPT9 locus may be much higher [unpublished/preliminary data]. • Confirmation of the diagnosis in persons in whom a clinical diagnosis of HNA is suspected requires molecular genetic testing to identify the pathogenic variant in • If sequence analysis of ## Clinical Diagnosis Hereditary neuralgic amyotrophy (HNA) is an episodic disorder diagnosed clinically using criteria developed by the European CMT Consortium; see modified criteria ( Sensory and motor nerves are typically affected; occasionally autonomic nerve injury also occurs. HNA is characterized in 95% of cases by the following: HNA Diagnostic Criteria 2nd or 3rd decade of life (median: 28 yrs) Earlier or later onset Acute, uni- or bilateral brachial plexopathy Severe pain preceding onset of weakness by days to a few wks Predominantly motor deficits Number of episodes variable (1-20) Precipitating factors: infections, immunizations, surgery, parturition, unusually strenuous exercise of affected limb, exposure to cold Attack recurrence (75%) Sensory symptoms (70%) Lumbar plexus (33%) &/or phrenic nerve (14%) involved Cranial nerve involved Dysmorphic features Abortive attacks (pain is not followed by weakness) Weakness preceding onset of pain by days to wks Long intervals between attacks (up to many yrs) No pain during an attack (5%) Autosomal dominant inheritance Simplex case (i.e., single occurrence in a family) Patchy or multifocal distribution of abnormalities More prominent motor loss than sensory loss Sensory abnormalities (80%) Autonomic symptoms (15%) Mononeuropathy Absent or diminished tendon reflexes in affected limbs Muscle weakness and atrophy Relapsing/remitting course w/symptom-free intervals Recovery incomplete; persisting neurologic deficit especially after repeated attacks in the same limb Complete recovery w/out residual deficit between attacks Chronic undulating course w/out completely symptom-free intervals Signs of denervation or reinnervation in clinically weak muscles seen on EMG Reduced amplitude of CMAP in muscles innervated by affected nerves Reduced amplitudes of sensory nerve action potentials in affected nerves Identification of a presumed pathogenic variant or duplication in Linkage to the SEPT9 locus on chromosome 17q25 Absence of linkage to the SEPT9 locus on chromosome 17q25 CMAP = compound muscle action potential; EMG = electromyogram Modified from Most commonly recurrent laryngeal nerve (19%) or facial nerve Most commonly ocular hypotelorism, epicanthal folds, cleft palate, bifid uvula, excessive neck or arm skin folds Exclusion criterion: Signs of generalized neuropathy Such as abnormal sweating in affected arm or, rarely, Horner syndrome Most commonly long thoracic, anterior interosseus, or phrenic nerve Exclusion criterion: Slow progression of motor impairment over >3 months Exclusion criterion: Electrophysiologic signs of systemic generalized neuropathy Exclusion criteria: a • 2nd or 3rd decade of life (median: 28 yrs) • Earlier or later onset • Acute, uni- or bilateral brachial plexopathy • Severe pain preceding onset of weakness by days to a few wks • Predominantly motor deficits • Number of episodes variable (1-20) • Precipitating factors: infections, immunizations, surgery, parturition, unusually strenuous exercise of affected limb, exposure to cold • Attack recurrence (75%) • Sensory symptoms (70%) • Lumbar plexus (33%) &/or phrenic nerve (14%) involved • Cranial nerve involved • Dysmorphic features • Abortive attacks (pain is not followed by weakness) • Weakness preceding onset of pain by days to wks • Long intervals between attacks (up to many yrs) • No pain during an attack (5%) • Autosomal dominant inheritance • Simplex case (i.e., single occurrence in a family) • Patchy or multifocal distribution of abnormalities • More prominent motor loss than sensory loss • Sensory abnormalities (80%) • Autonomic symptoms (15%) • Mononeuropathy • Absent or diminished tendon reflexes in affected limbs • Muscle weakness and atrophy • Relapsing/remitting course w/symptom-free intervals • Recovery incomplete; persisting neurologic deficit especially after repeated attacks in the same limb • Complete recovery w/out residual deficit between attacks • Chronic undulating course w/out completely symptom-free intervals • Signs of denervation or reinnervation in clinically weak muscles seen on EMG • Reduced amplitude of CMAP in muscles innervated by affected nerves • Reduced amplitudes of sensory nerve action potentials in affected nerves • Identification of a presumed pathogenic variant or duplication in • Linkage to the SEPT9 locus on chromosome 17q25 • Absence of linkage to the SEPT9 locus on chromosome 17q25 ## Molecular Genetic Testing The percentage of families in the US who appear not to be genetically linked to the SEPT9 locus is estimated at 15%. The percentage of families in other countries (e.g., the Netherlands) who appear not to be genetically linked to the SEPT9 locus may be much higher [unpublished/preliminary data]. Molecular Genetic Testing Used in Hereditary Neuralgic Amyotrophy See See The ability of the test method used to detect a variant that is present in the indicated gene The proportion may be higher or lower depending on country or region of origin [ 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 In families with HNA linked to Testing that identifies exon or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. Both a founder duplication and nonrecurrent duplications (with unique breakpoints) have been reported [ In families with HNA linked to • The percentage of families in the US who appear not to be genetically linked to the SEPT9 locus is estimated at 15%. • The percentage of families in other countries (e.g., the Netherlands) who appear not to be genetically linked to the SEPT9 locus may be much higher [unpublished/preliminary data]. ## Testing Strategy Confirmation of the diagnosis in persons in whom a clinical diagnosis of HNA is suspected requires molecular genetic testing to identify the pathogenic variant in If sequence analysis of • Confirmation of the diagnosis in persons in whom a clinical diagnosis of HNA is suspected requires molecular genetic testing to identify the pathogenic variant in • If sequence analysis of ## Clinical Characteristics The attacks comprise severe aching, burning, or stabbing pains, most often in the shoulders, neck, and/or arm region, followed by multifocal atrophy and paresis. Usually the brachial plexus is involved. In one third of cases, the involvement is bilateral, although severity is usually asymmetric. Attacks appear to become less frequent with age. The most comprehensive review of attack features in both HNA and sporadic idiopathic neuralgic amyotrophy (see The long thoracic and suprascapular nerves are affected in about 70% of cases. Other frequently involved nerves are the axillary, musculocutanous, radial, and anterior interosseus. Lower plexus involvement (median motor and ulnar distribution) occurs in about 5% [ In many cases the muscle weakness may go unnoticed, especially if it only affects the periscapular muscles such as the serratus anterior, rhomboids or subscapularis. Functionally, however, the resulting scapular instability often causes pain, limitation of movement, and exercise intolerance of the affected limb that can persist for months to years. Sensory symptoms, present in the majority of affected individuals, are often overlooked. They can include the following: Hypoesthesia (decreased sensation) located anywhere from the shoulder to the fingertips; found in 85% of individuals Paresthesias; reported in more than 50% of attacks Vasomotor changes in the arm; reported in 15% of attacks. This autonomic dysfunction of the cervical sympathetic nerves can result in hand edema or vasomotor instability [ While the shoulder and arm are primarily affected by attacks in HNA, other sites that may also be involved in an attack include the following: Lumbosacral plexus in ~33% of attacks Phrenic nerve palsy in 14% of attacks; may cause orthopnea, respiratory distress and sleep disturbance Recurrent laryngeal nerve in 3% of attacks; may cause vocal cord paresis resulting in hoarseness and hypophonia Facial nerve or other cranial nerves (rarely) Two patterns of HNA attacks are described: The prognosis for eventual recovery of neurologic function in neuralgic amyotrophy is guarded, with residual deficits accumulating with additional attacks. Excessive partial circumferential skin folds of the neck and arms are also characteristic features [ Biopsy of sural or superficial radial nerves is rarely performed in this disorder. The only finding described in the majority of biopsies is focal decreases in myelinated fibers within individual nerve fascicles [ In families with pathogenic variants in In one family that appears to have HNA but does not segregate with markers flanking Studies based on clinical criteria suggest that the penetrance is between 80% and greater than 90% for all individuals with HNA, not taking into account the underlying cause of the disorder [ Data regarding penetrance in relation to Out-of-date terms previously used for hereditary neuralgic amyotrophy include the following: Familial brachial plexus neuritis Heredofamilial neuritis with brachial plexus predilection The prevalence of HNA is unknown. About 300 families are known worldwide. The prevalence of HNA is estimated to be about an order of magnitude less than that of idiopathic neuralgic amyotrophy (Parsonage-Turner syndrome), which has an estimated incidence of 1.64:100,000/year to 3:100,000/year [ Prevalence of any brachial neuritis was estimated to be 3:10,000 in the London (UK) area [ The actual prevalence of these disorders is likely to be higher because of underdiagnosis. Sixty percent of individuals with neuralgic amyotrophy seen at the Nijmegen clinical center were first diagnosed with a different disorder [ • Hypoesthesia (decreased sensation) located anywhere from the shoulder to the fingertips; found in 85% of individuals • Paresthesias; reported in more than 50% of attacks • Vasomotor changes in the arm; reported in 15% of attacks. This autonomic dysfunction of the cervical sympathetic nerves can result in hand edema or vasomotor instability [ • Lumbosacral plexus in ~33% of attacks • Phrenic nerve palsy in 14% of attacks; may cause orthopnea, respiratory distress and sleep disturbance • Recurrent laryngeal nerve in 3% of attacks; may cause vocal cord paresis resulting in hoarseness and hypophonia • Facial nerve or other cranial nerves (rarely) • Familial brachial plexus neuritis • Heredofamilial neuritis with brachial plexus predilection ## Clinical Description The attacks comprise severe aching, burning, or stabbing pains, most often in the shoulders, neck, and/or arm region, followed by multifocal atrophy and paresis. Usually the brachial plexus is involved. In one third of cases, the involvement is bilateral, although severity is usually asymmetric. Attacks appear to become less frequent with age. The most comprehensive review of attack features in both HNA and sporadic idiopathic neuralgic amyotrophy (see The long thoracic and suprascapular nerves are affected in about 70% of cases. Other frequently involved nerves are the axillary, musculocutanous, radial, and anterior interosseus. Lower plexus involvement (median motor and ulnar distribution) occurs in about 5% [ In many cases the muscle weakness may go unnoticed, especially if it only affects the periscapular muscles such as the serratus anterior, rhomboids or subscapularis. Functionally, however, the resulting scapular instability often causes pain, limitation of movement, and exercise intolerance of the affected limb that can persist for months to years. Sensory symptoms, present in the majority of affected individuals, are often overlooked. They can include the following: Hypoesthesia (decreased sensation) located anywhere from the shoulder to the fingertips; found in 85% of individuals Paresthesias; reported in more than 50% of attacks Vasomotor changes in the arm; reported in 15% of attacks. This autonomic dysfunction of the cervical sympathetic nerves can result in hand edema or vasomotor instability [ While the shoulder and arm are primarily affected by attacks in HNA, other sites that may also be involved in an attack include the following: Lumbosacral plexus in ~33% of attacks Phrenic nerve palsy in 14% of attacks; may cause orthopnea, respiratory distress and sleep disturbance Recurrent laryngeal nerve in 3% of attacks; may cause vocal cord paresis resulting in hoarseness and hypophonia Facial nerve or other cranial nerves (rarely) Two patterns of HNA attacks are described: The prognosis for eventual recovery of neurologic function in neuralgic amyotrophy is guarded, with residual deficits accumulating with additional attacks. Excessive partial circumferential skin folds of the neck and arms are also characteristic features [ Biopsy of sural or superficial radial nerves is rarely performed in this disorder. The only finding described in the majority of biopsies is focal decreases in myelinated fibers within individual nerve fascicles [ • Hypoesthesia (decreased sensation) located anywhere from the shoulder to the fingertips; found in 85% of individuals • Paresthesias; reported in more than 50% of attacks • Vasomotor changes in the arm; reported in 15% of attacks. This autonomic dysfunction of the cervical sympathetic nerves can result in hand edema or vasomotor instability [ • Lumbosacral plexus in ~33% of attacks • Phrenic nerve palsy in 14% of attacks; may cause orthopnea, respiratory distress and sleep disturbance • Recurrent laryngeal nerve in 3% of attacks; may cause vocal cord paresis resulting in hoarseness and hypophonia • Facial nerve or other cranial nerves (rarely) ## Genotype-Phenotype Correlations In families with pathogenic variants in In one family that appears to have HNA but does not segregate with markers flanking ## Penetrance Studies based on clinical criteria suggest that the penetrance is between 80% and greater than 90% for all individuals with HNA, not taking into account the underlying cause of the disorder [ Data regarding penetrance in relation to ## Nomenclature Out-of-date terms previously used for hereditary neuralgic amyotrophy include the following: Familial brachial plexus neuritis Heredofamilial neuritis with brachial plexus predilection • Familial brachial plexus neuritis • Heredofamilial neuritis with brachial plexus predilection ## Prevalence The prevalence of HNA is unknown. About 300 families are known worldwide. The prevalence of HNA is estimated to be about an order of magnitude less than that of idiopathic neuralgic amyotrophy (Parsonage-Turner syndrome), which has an estimated incidence of 1.64:100,000/year to 3:100,000/year [ Prevalence of any brachial neuritis was estimated to be 3:10,000 in the London (UK) area [ The actual prevalence of these disorders is likely to be higher because of underdiagnosis. Sixty percent of individuals with neuralgic amyotrophy seen at the Nijmegen clinical center were first diagnosed with a different disorder [ ## Genetically Related (Allelic) Disorders No other phenotypes are known to be associated with germline pathogenic variants in The Note: There is no known relationship between HNA and AML. ## Differential Diagnosis Acute pain in the shoulder and upper arm region may be caused by neurologic or non-neurologic disorders. If all the pain, paresis, and sensory symptoms are in the same cervical root distribution, a degenerative or acute disk rupture cervical radiculopathy must be considered. Cervical spondylosis may have referred arm pain that is position- or activity-dependent, with no focal deficits and a fluctuating course. Imaging studies such as MRI or CT scan may exclude vertebral or space-occupying causes. The focus, however, should be on the clinical picture, as approximately 50% of affected adults usually show degenerative changes on cervical spine MRI. Complex regional pain syndrome involving the shoulder or arm has predominantly vasomotor symptoms, with subacute onset of diffuse pain and weakness with progression. Other rare neurologic disorders could include mononeuritis multiplex (peripheral nervous system vasculitis), multifocal motor neuropathy, or brachial amyotrophic diplegia, but these tend to have subacute onset and the latter two disorders are usually painless. Electromyography (EMG) and nerve conduction studies help to distinguish radiculopathies; examination of unaffected limbs excludes generalized peripheral neuropathies. In extremely rare cases, an acute painful brachial plexopathy is found as the only sign of an underlying Shoulder joint pathology (e.g., bursitis, calcifying tendonitis) or rotator cuff injury may cause pain that is exacerbated by joint movement and relieved by rest or passive immobilization. Brachial plexopathy may also be caused by trauma, surgery, or prior irradiation: Lower plexus lesions may be seen in the case of a Pancoast tumor or true neurogenic thoracic outlet syndrome. A peripheral nerve or nerve sheath tumor may involve the plexus, as could direct peripheral nervous system infections such as neuroborreliosis or HIV. The main differential diagnosis in an individual presenting with an acute-onset, painful, multifocal, brachial plexopathy is neuralgic amyotrophy in either its hereditary or idiopathic form. HNA is clinically similar to its sporadic counterpart, idiopathic neuralgic amyotrophy (INA). The disorders share the same precipitating factors, signs, and symptoms. INA, also called brachial neuritis or Parsonage-Turner syndrome, is estimated to be about ten times more common than HNA. HNA is distinguished from INA by its familial recurrence, earlier average age of onset, more severe pain in the acute stage, more frequent involvement of nerves outside of the brachial plexus, higher rate of recurrence, and greater eventual disability. However, no single feature in a given individual can distinguish hereditary from sporadic neuralgic amyotrophy; this distinction is based on a positive family history and/or the presence of the typical dysmorphic features. Excluding the Like HNA, Schilbach-Rott syndrome is characterized by short stature, cutaneous syndactyly, ocular hypotelorism, and cleft palate [ A subset of individuals with Michelin tire baby syndrome (with what now may be known as "circumferential skin creases, Kunze type") also may share the following with HNA: craniofacial features (including relatively closely spaced eyes and short palpebral fissures), cleft palate, and circumferential skin folds [ • If all the pain, paresis, and sensory symptoms are in the same cervical root distribution, a degenerative or acute disk rupture cervical radiculopathy must be considered. • Cervical spondylosis may have referred arm pain that is position- or activity-dependent, with no focal deficits and a fluctuating course. Imaging studies such as MRI or CT scan may exclude vertebral or space-occupying causes. The focus, however, should be on the clinical picture, as approximately 50% of affected adults usually show degenerative changes on cervical spine MRI. • Complex regional pain syndrome involving the shoulder or arm has predominantly vasomotor symptoms, with subacute onset of diffuse pain and weakness with progression. • Other rare neurologic disorders could include mononeuritis multiplex (peripheral nervous system vasculitis), multifocal motor neuropathy, or brachial amyotrophic diplegia, but these tend to have subacute onset and the latter two disorders are usually painless. Electromyography (EMG) and nerve conduction studies help to distinguish radiculopathies; examination of unaffected limbs excludes generalized peripheral neuropathies. • In extremely rare cases, an acute painful brachial plexopathy is found as the only sign of an underlying • Shoulder joint pathology (e.g., bursitis, calcifying tendonitis) or rotator cuff injury may cause pain that is exacerbated by joint movement and relieved by rest or passive immobilization. • Lower plexus lesions may be seen in the case of a Pancoast tumor or true neurogenic thoracic outlet syndrome. • A peripheral nerve or nerve sheath tumor may involve the plexus, as could direct peripheral nervous system infections such as neuroborreliosis or HIV. • Like HNA, Schilbach-Rott syndrome is characterized by short stature, cutaneous syndactyly, ocular hypotelorism, and cleft palate [ • A subset of individuals with Michelin tire baby syndrome (with what now may be known as "circumferential skin creases, Kunze type") also may share the following with HNA: craniofacial features (including relatively closely spaced eyes and short palpebral fissures), cleft palate, and circumferential skin folds [ ## Management To establish the extent of disease in an individual diagnosed with hereditary neuralgic amyotrophy, the following evaluations are recommended: Comprehensive neuromuscular evaluation Needle EMG to identify the severity and extent of denervation and reinnervation Evaluation of phrenic nerve involvement by chest x-ray, ultrasound/fluoroscopic evaluation of diaphragm movement, and pulmonary function tests in seated and supine positions Clinical genetics consultation For a practical overview of the physical examination and the value of additional investigations in neuralgic amyotrophy see Currently, no effective therapy is proven to abort or shorten an HNA attack. Treatment of acute episodes of pain and weakness with corticosteroids has been proposed based on retrospective analysis of cases [ For severe paresis of the serratus anterior muscle persisting more than one year, corrective surgery can be considered to increase scapular stability, for example by a split pectoralis major muscle transfer. Patients with phrenic nerve palsy need consultation with a respiratory specialist and can benefit from noninvasive nocturnal positive pressure ventilation. For a clinical overview of neurologic and rehabilitative management, see As chronic pain resulting from altered biomechanics of the shoulder or upper extremity tends to develop during the first one to two years, follow up every six to 12 months after the initial diagnosis is recommended. Although immunizations have been known to precede and possibly trigger attacks, it is still recommended that they be given on the usual recommended schedule because the risk of immunization precipitating an attack is probably low [based on expert opinion]. Patients with persistent weakness and especially scapular instability should be cautioned to avoid overexerting the affected limb. See Women with HNA should be monitored in the post-partum interval for the development of symptoms. Prompt treatment with corticosteroids or similar agents may ameliorate an HNA attack. In an open-label study of oral prednisone in adults with INA or HNA (60 mg/day for one week, followed by a one week taper by 10 mg/day with a last dose of 5 mg) the only statistically significant finding was a reduction in the time for paresis recovery [ An additional review of the Dutch experience revealed the following: Relative to the untreated patients, a significantly higher proportion of the patients receiving oral prednisolone recovered early from their pareses. Taken in the first month, prednisolone tended to decrease the average duration of the initial pain, although this finding was not statistically significant. Functional recovery set in earlier, with significantly more treated patients achieving full recovery within a year or reporting a ‘‘good’’ outcome within six months. Side effects occurred in 20% of patients, but did not result in discontinuation of treatment [ A randomized placebo-controlled trial of oral prednisone conducted in the Netherlands was terminated after three years because of insufficient recruitment within the specified time frame. No treatment effect could be demonstrated in the 13 persons in the primary treatment and placebo arm; however, the small number of participants precluded any definite conclusions. Experimental immunosuppressive therapies that have been used in other inflammatory polyneuropathies, but for which there are limited data available for treatment of attacks in HNA, include the following: Methylprednisolone, intravenous 30 mg/kg (or 1.0 g in adults) every 24 hours for three days [ Intravenous immune globulin, 0.4 g/kg/day for five days [ Search • Comprehensive neuromuscular evaluation • Needle EMG to identify the severity and extent of denervation and reinnervation • Evaluation of phrenic nerve involvement by chest x-ray, ultrasound/fluoroscopic evaluation of diaphragm movement, and pulmonary function tests in seated and supine positions • Clinical genetics consultation • Relative to the untreated patients, a significantly higher proportion of the patients receiving oral prednisolone recovered early from their pareses. • Taken in the first month, prednisolone tended to decrease the average duration of the initial pain, although this finding was not statistically significant. • Functional recovery set in earlier, with significantly more treated patients achieving full recovery within a year or reporting a ‘‘good’’ outcome within six months. • Side effects occurred in 20% of patients, but did not result in discontinuation of treatment [ • Methylprednisolone, intravenous 30 mg/kg (or 1.0 g in adults) every 24 hours for three days [ • Intravenous immune globulin, 0.4 g/kg/day for five days [ ## Evaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with hereditary neuralgic amyotrophy, the following evaluations are recommended: Comprehensive neuromuscular evaluation Needle EMG to identify the severity and extent of denervation and reinnervation Evaluation of phrenic nerve involvement by chest x-ray, ultrasound/fluoroscopic evaluation of diaphragm movement, and pulmonary function tests in seated and supine positions Clinical genetics consultation For a practical overview of the physical examination and the value of additional investigations in neuralgic amyotrophy see • Comprehensive neuromuscular evaluation • Needle EMG to identify the severity and extent of denervation and reinnervation • Evaluation of phrenic nerve involvement by chest x-ray, ultrasound/fluoroscopic evaluation of diaphragm movement, and pulmonary function tests in seated and supine positions • Clinical genetics consultation ## Treatment of Manifestations Currently, no effective therapy is proven to abort or shorten an HNA attack. Treatment of acute episodes of pain and weakness with corticosteroids has been proposed based on retrospective analysis of cases [ For severe paresis of the serratus anterior muscle persisting more than one year, corrective surgery can be considered to increase scapular stability, for example by a split pectoralis major muscle transfer. Patients with phrenic nerve palsy need consultation with a respiratory specialist and can benefit from noninvasive nocturnal positive pressure ventilation. For a clinical overview of neurologic and rehabilitative management, see ## Surveillance As chronic pain resulting from altered biomechanics of the shoulder or upper extremity tends to develop during the first one to two years, follow up every six to 12 months after the initial diagnosis is recommended. ## Agents/Circumstances to Avoid Although immunizations have been known to precede and possibly trigger attacks, it is still recommended that they be given on the usual recommended schedule because the risk of immunization precipitating an attack is probably low [based on expert opinion]. Patients with persistent weakness and especially scapular instability should be cautioned to avoid overexerting the affected limb. ## Evaluation of Relatives at Risk See ## Pregnancy Management Women with HNA should be monitored in the post-partum interval for the development of symptoms. Prompt treatment with corticosteroids or similar agents may ameliorate an HNA attack. ## Therapies Under Investigation In an open-label study of oral prednisone in adults with INA or HNA (60 mg/day for one week, followed by a one week taper by 10 mg/day with a last dose of 5 mg) the only statistically significant finding was a reduction in the time for paresis recovery [ An additional review of the Dutch experience revealed the following: Relative to the untreated patients, a significantly higher proportion of the patients receiving oral prednisolone recovered early from their pareses. Taken in the first month, prednisolone tended to decrease the average duration of the initial pain, although this finding was not statistically significant. Functional recovery set in earlier, with significantly more treated patients achieving full recovery within a year or reporting a ‘‘good’’ outcome within six months. Side effects occurred in 20% of patients, but did not result in discontinuation of treatment [ A randomized placebo-controlled trial of oral prednisone conducted in the Netherlands was terminated after three years because of insufficient recruitment within the specified time frame. No treatment effect could be demonstrated in the 13 persons in the primary treatment and placebo arm; however, the small number of participants precluded any definite conclusions. Experimental immunosuppressive therapies that have been used in other inflammatory polyneuropathies, but for which there are limited data available for treatment of attacks in HNA, include the following: Methylprednisolone, intravenous 30 mg/kg (or 1.0 g in adults) every 24 hours for three days [ Intravenous immune globulin, 0.4 g/kg/day for five days [ Search • Relative to the untreated patients, a significantly higher proportion of the patients receiving oral prednisolone recovered early from their pareses. • Taken in the first month, prednisolone tended to decrease the average duration of the initial pain, although this finding was not statistically significant. • Functional recovery set in earlier, with significantly more treated patients achieving full recovery within a year or reporting a ‘‘good’’ outcome within six months. • Side effects occurred in 20% of patients, but did not result in discontinuation of treatment [ • Methylprednisolone, intravenous 30 mg/kg (or 1.0 g in adults) every 24 hours for three days [ • Intravenous immune globulin, 0.4 g/kg/day for five days [ ## Genetic Counseling Hereditary neuralgic amyotrophy is inherited in an autosomal dominant manner. Most individuals diagnosed with hereditary neuralgic amyotrophy have an affected parent. A proband with hereditary neuralgic amyotrophy 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 germline mosaicism in a parent or a Recommendations for parents of a proband with an apparent Note: (1) Although most individuals diagnosed with hereditary neuralgic amyotrophy have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. (2) If the parent is the individual in whom the pathogenic variant first occurred s/he may have somatic mosaicism for the variant and may be mildly/minimally affected. If a parent of the proband is affected, the risk to the sibs is 50%. When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. If the pathogenic variant found in the proband cannot be detected in the DNA of either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism. 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. Testing for the pathogenic variant in the absence of definite symptoms of the disease is predictive testing. At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Others may have different motivations including simply the "need to know." Testing of asymptomatic at-risk adult family members usually involves pre-test interviews in which the motives for requesting the test, the individual's knowledge of hereditary neuralgic amyotrophy, the possible impact of positive and negative test results, and neurologic status are assessed. Those seeking testing should be counseled regarding possible problems that they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Other issues to consider are implications for the at-risk status of other family members. Informed consent should be procured and records kept confidential. Individuals with a positive test result need arrangements for long-term follow up and evaluations. Individuals younger than age 18 years who are symptomatic usually benefit from having a specific diagnosis established. See also the National Society of Genetic Counselors 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 hereditary neuralgic amyotrophy have an affected parent. • A proband with hereditary neuralgic amyotrophy 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 germline mosaicism in a parent or a • Recommendations for parents of a proband with an apparent • If a parent of the proband is affected, the risk to the sibs is 50%. • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. • If the pathogenic variant found in the proband cannot be detected in the DNA of either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism. • 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 Hereditary neuralgic amyotrophy is inherited in an autosomal dominant manner. ## Risk to Family Members Most individuals diagnosed with hereditary neuralgic amyotrophy have an affected parent. A proband with hereditary neuralgic amyotrophy 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 germline mosaicism in a parent or a Recommendations for parents of a proband with an apparent Note: (1) Although most individuals diagnosed with hereditary neuralgic amyotrophy have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. (2) If the parent is the individual in whom the pathogenic variant first occurred s/he may have somatic mosaicism for the variant and may be mildly/minimally affected. If a parent of the proband is affected, the risk to the sibs is 50%. When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. If the pathogenic variant found in the proband cannot be detected in the DNA of either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism. • Most individuals diagnosed with hereditary neuralgic amyotrophy have an affected parent. • A proband with hereditary neuralgic amyotrophy 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 germline mosaicism in a parent or a • Recommendations for parents of a proband with an apparent • If a parent of the proband is affected, the risk to the sibs is 50%. • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. • If the pathogenic variant found in the proband cannot be detected in the DNA of either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism. ## 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. Testing for the pathogenic variant in the absence of definite symptoms of the disease is predictive testing. At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Others may have different motivations including simply the "need to know." Testing of asymptomatic at-risk adult family members usually involves pre-test interviews in which the motives for requesting the test, the individual's knowledge of hereditary neuralgic amyotrophy, the possible impact of positive and negative test results, and neurologic status are assessed. Those seeking testing should be counseled regarding possible problems that they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Other issues to consider are implications for the at-risk status of other family members. Informed consent should be procured and records kept confidential. Individuals with a positive test result need arrangements for long-term follow up and evaluations. Individuals younger than age 18 years who are symptomatic usually benefit from having a specific diagnosis established. See also the National Society of Genetic Counselors • 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 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 61A Great Suffolk Street London SE1 0BU United Kingdom • • • • 61A Great Suffolk Street • London SE1 0BU • United Kingdom • ## Molecular Genetics Hereditary Neuralgic Amyotrophy: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Hereditary Neuralgic Amyotrophy ( Six intragenic duplications and one whole-gene duplication have been identified in families with HNA [ Note: Human Mar. 2006 (NCBI36/hg18) Browser Sequences are available at Selected Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions For more information, see ## References ## Published Guidelines / Consensus Statements ## Literature Cited ## Chapter Notes 29 August 2019 (ma) Retired chapter: rarely genetic 6 December 2012 (me) Comprehensive update posted live 27 February 2008 (me) Review posted live 11 June 2007 (mch) Original submission • 29 August 2019 (ma) Retired chapter: rarely genetic • 6 December 2012 (me) Comprehensive update posted live • 27 February 2008 (me) Review posted live • 11 June 2007 (mch) Original submission ## Revision History 29 August 2019 (ma) Retired chapter: rarely genetic 6 December 2012 (me) Comprehensive update posted live 27 February 2008 (me) Review posted live 11 June 2007 (mch) Original submission • 29 August 2019 (ma) Retired chapter: rarely genetic • 6 December 2012 (me) Comprehensive update posted live • 27 February 2008 (me) Review posted live • 11 June 2007 (mch) Original submission Different presentations of upper-extremity atrophy and paresis A. On the left: atrophy of supraspinatus and infraspinatus muscles and rhomboid muscles (white arrow); on the right: scapular tilting and rotation caused by serratus anterior muscle weakness (white arrow with ) B. On the right: severe scapular winging caused by serratus anterior paralysis (white arrow) C. On the left: atrophy of supraspinatus and infraspinatus muscles (white arrow), and trapezius muscle (white arrow with ) showing underlying rhomboid muscles D. Severe atrophy of the deltoid muscle (white arrow) and moderate atrophy of the biceps brachii muscle (white arrow with *)	[]	27/2/2008	6/12/2012		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
hnpcc	hnpcc	[ "Hereditary Non-Polyposis Colorectal Cancer (HNPCC)", "DNA mismatch repair protein Mlh1", "DNA mismatch repair protein Msh2", "DNA mismatch repair protein Msh6", "Epithelial cell adhesion molecule", "Mismatch repair endonuclease PMS2", "EPCAM", "MLH1", "MSH2", "MSH6", "PMS2", "Lynch Syndrome" ]	Lynch Syndrome	Gregory Idos, Laura Valle	Summary Lynch syndrome is characterized by an increased risk for colorectal cancer (CRC) and cancers of the endometrium, ovary, stomach, small bowel, urinary tract, biliary tract, brain (usually glioblastoma), skin (sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas), pancreas, and prostate. Cancer risks and age of onset vary depending on the associated gene. Several other cancer types have been reported to occur in individuals with Lynch syndrome (e.g., breast, sarcomas, adrenocortical carcinoma). However, the data are not sufficient to demonstrate that the risk of developing these cancers is increased in individuals with Lynch syndrome. The diagnosis of Lynch syndrome is established in a proband by identification on molecular genetic testing of a germline heterozygous pathogenic variant in Lynch syndrome caused by a heterozygous germline pathogenic variant in	## Diagnosis No consensus clinical diagnostic criteria for Lynch syndrome have been published. A diagnosis of Lynch syndrome A diagnosis of a tumor of the Lynch syndrome spectrum (e.g., colorectal, endometrial, ovarian, stomach, small bowel, urinary tract [urothelial], biliary tract, prostate, brain [usually glioblastoma], skin [sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas], and pancreas) with one of the following on Microsatellite instability (MSI) testing showing that tumor tissue is MSI high. (For information on MSI testing, including advantages and disadvantages, click Immunohistochemistry (IHC) demonstrating loss of expression of one or more of the mismatch repair (MMR) gene products: MLH1, MSH2, MSH6, and/or PMS2. (For information on advantages and disadvantages of IHC testing, click Next-generation sequencing in tumor tissue revealing MSI Identification of a pathogenic variant in tumor tissue in an MMR gene A diagnosis of colorectal cancer (CRC) or endometrial cancer and Colorectal or endometrial cancer diagnosed before age 50 years Synchronous or metachronous Lynch syndrome-related cancers (e.g., colorectal, endometrial, ovarian, stomach, small bowel, urinary tract, biliary tract, prostate, brain, sebaceous adenomas, sebaceous carcinomas, keratoacanthomas, pancreatic) Colorectal tumor tissue with MSI-high histology (e.g., poor differentiation, tumor-infiltrating lymphocytes, Crohn-like lymphocytic reaction, mucinous/signet-ring differentiation, medullary growth pattern) At least one first-degree relative with any Lynch syndrome-related cancer diagnosed before age 50 years At least two first-degree relatives with any Lynch syndrome-related cancers regardless of age of cancer diagnosis A family member with colorectal or endometrial cancer who meets one of the above criteria Note: Molecular genetic testing ideally begins with a person who has had a Lynch syndrome-related cancer. However, in some families there may be no affected individual who is alive or willing to be tested. A family member with a confirmed diagnosis of Lynch syndrome (pathogenic variant in one of the genes listed in A ≥5% probability of having a pathogenic variant in one of the genes listed in Note: Several risk assessment models including PREMM5 [ * Adapted from revised Bethesda Guidelines and National Comprehensive Cancer Network Guidelines; click Screening approaches include: Screen all CRC and endometrial cancers with MSI or IHC testing. This was shown to be a cost-effective approach for identifying individuals who should be offered germline molecular genetic testing for Lynch syndrome [ Use age of onset, familial cancer history, and pathologic features to predict which individuals are more likely to have a germline MMR pathogenic variant [ Tumor tissue sequence analysis for a pathogenic variant in one of the genes listed in Note: Lynch syndrome-related cancers do not have hypermethylation of the Note: (1) Somatic The diagnosis of Lynch syndrome can be Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include a For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Lynch Syndrome See Data obtained from universal Lynch syndrome screening for colorectal and endometrial cancers See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants. Detection of exon or whole-gene deletions/duplications require specific sequencing data analysis or use of alternative molecular methods (see footnote 7). For issues to consider in interpretation of sequence analysis results, click Alteration of the proportions may occur in populations with over-representation of specific founder variants. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include specific data analysis of gene panels, quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Constitutional inactivation of Due to the high level of homology between Methods to sequence and identify large rearrangements in Although Germline deletions of Tumor Tissue Test Results, Interpretation, and Additional Testing Options Sporadic cancer Cancer due to other hereditary cancer syndrome Sporadic cancer Germline MMR gene pathogenic variant Germline MMR gene testing or paired germline/tumor tissue MMR gene testing If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing. Sporadic cancer Germline MMR gene pathogenic variant IHC If IHC not available, consider germline MMR gene testing or paired germline/tumor tissue MMR gene testing. If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing. Sporadic cancer Germline Germline Targeted If If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing. Sporadic cancer Germline Constitutional If early-onset cancer (< age 50 yrs) or significant family history of cancer: germline MMR gene testing If not: no additional testing For early onset only: constitutional Sporadic cancer Germline Constitutional Germline Germline Sporadic cancer Germline MMR testing or paired germline/tumor tissue MMR gene testing If germline testing negative & paired germline/tumor tissue not done: consider tumor tissue MMR gene testing. Germline Germline Sporadic cancer Germline Germline Sporadic cancer Germline Sporadic cancer Germline Germline Sporadic cancer w/treatment effect Germline MMR gene testing or germline/tumor tissue MMR gene testing If germline testing negative & paired germline/tumor tissue not done: consider tumor tissue MMR gene testing. If applicable, consider MSI analysis or repeat IHC on nontreated tumor. Sporadic cancer: MLH1 promoter methylation or somatic Germline Germline Targeted If If germline testing negative & paired germline/tumor tissue not done: consider tumor tissue MMR gene testing. Germline MMR gene path var Sporadic cancer Targeted If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing Adapted from Empty cells indicate either that testing was not done or that results may not influence testing strategy. – = absent staining of protein; + = normal staining of protein; IHC = immunohistochemistry; MMR = mismatch repair; MSI = microsatellite instability; MSS = microsatellite stability; Neg = negative; path var = pathogenic variant; Pos = positive Tumor testing strategies apply to colorectal and endometrial cancers. Limited data exist regarding the efficacy of tumor testing in other types of Lynch syndrome tumors. 45%-68% of tumors with evidence of MMR deficiency have biallelic somatic pathogenic variants. If biallelic somatic pathogenic variants are identified, the affected individual and their relatives should be managed based on the family cancer history and NOT as if they had Lynch syndrome. Prior to germline genetic testing, proper pre-test counseling should be done. For information on testing for germline pathogenic variants, see In the presence of a strong family history (e.g., Amsterdam criteria are met), or if additional features of a hereditary cancer syndrome are present, additional testing may be warranted in the proband or tumor testing in another affected family member because of the possibility that the original tumor selected for testing was a sporadic colorectal cancer (phenocopy). Constitutional Absent MSH6 IHC staining in rectal tumors may be due to treatment effect (neoadjuvant chemoradiotherapy). • A diagnosis of a tumor of the Lynch syndrome spectrum (e.g., colorectal, endometrial, ovarian, stomach, small bowel, urinary tract [urothelial], biliary tract, prostate, brain [usually glioblastoma], skin [sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas], and pancreas) with one of the following on • Microsatellite instability (MSI) testing showing that tumor tissue is MSI high. (For information on MSI testing, including advantages and disadvantages, click • Immunohistochemistry (IHC) demonstrating loss of expression of one or more of the mismatch repair (MMR) gene products: MLH1, MSH2, MSH6, and/or PMS2. (For information on advantages and disadvantages of IHC testing, click • Next-generation sequencing in tumor tissue revealing MSI • Identification of a pathogenic variant in tumor tissue in an MMR gene • Microsatellite instability (MSI) testing showing that tumor tissue is MSI high. (For information on MSI testing, including advantages and disadvantages, click • Immunohistochemistry (IHC) demonstrating loss of expression of one or more of the mismatch repair (MMR) gene products: MLH1, MSH2, MSH6, and/or PMS2. (For information on advantages and disadvantages of IHC testing, click • Next-generation sequencing in tumor tissue revealing MSI • Identification of a pathogenic variant in tumor tissue in an MMR gene • A diagnosis of colorectal cancer (CRC) or endometrial cancer and • Colorectal or endometrial cancer diagnosed before age 50 years • Synchronous or metachronous Lynch syndrome-related cancers (e.g., colorectal, endometrial, ovarian, stomach, small bowel, urinary tract, biliary tract, prostate, brain, sebaceous adenomas, sebaceous carcinomas, keratoacanthomas, pancreatic) • Colorectal tumor tissue with MSI-high histology (e.g., poor differentiation, tumor-infiltrating lymphocytes, Crohn-like lymphocytic reaction, mucinous/signet-ring differentiation, medullary growth pattern) • At least one first-degree relative with any Lynch syndrome-related cancer diagnosed before age 50 years • At least two first-degree relatives with any Lynch syndrome-related cancers regardless of age of cancer diagnosis • Colorectal or endometrial cancer diagnosed before age 50 years • Synchronous or metachronous Lynch syndrome-related cancers (e.g., colorectal, endometrial, ovarian, stomach, small bowel, urinary tract, biliary tract, prostate, brain, sebaceous adenomas, sebaceous carcinomas, keratoacanthomas, pancreatic) • Colorectal tumor tissue with MSI-high histology (e.g., poor differentiation, tumor-infiltrating lymphocytes, Crohn-like lymphocytic reaction, mucinous/signet-ring differentiation, medullary growth pattern) • At least one first-degree relative with any Lynch syndrome-related cancer diagnosed before age 50 years • At least two first-degree relatives with any Lynch syndrome-related cancers regardless of age of cancer diagnosis • A family member with colorectal or endometrial cancer who meets one of the above criteria • Note: Molecular genetic testing ideally begins with a person who has had a Lynch syndrome-related cancer. However, in some families there may be no affected individual who is alive or willing to be tested. • A family member with a confirmed diagnosis of Lynch syndrome (pathogenic variant in one of the genes listed in • A ≥5% probability of having a pathogenic variant in one of the genes listed in • Note: Several risk assessment models including PREMM5 [ • Microsatellite instability (MSI) testing showing that tumor tissue is MSI high. (For information on MSI testing, including advantages and disadvantages, click • Immunohistochemistry (IHC) demonstrating loss of expression of one or more of the mismatch repair (MMR) gene products: MLH1, MSH2, MSH6, and/or PMS2. (For information on advantages and disadvantages of IHC testing, click • Next-generation sequencing in tumor tissue revealing MSI • Identification of a pathogenic variant in tumor tissue in an MMR gene • Colorectal or endometrial cancer diagnosed before age 50 years • Synchronous or metachronous Lynch syndrome-related cancers (e.g., colorectal, endometrial, ovarian, stomach, small bowel, urinary tract, biliary tract, prostate, brain, sebaceous adenomas, sebaceous carcinomas, keratoacanthomas, pancreatic) • Colorectal tumor tissue with MSI-high histology (e.g., poor differentiation, tumor-infiltrating lymphocytes, Crohn-like lymphocytic reaction, mucinous/signet-ring differentiation, medullary growth pattern) • At least one first-degree relative with any Lynch syndrome-related cancer diagnosed before age 50 years • At least two first-degree relatives with any Lynch syndrome-related cancers regardless of age of cancer diagnosis • Screen all CRC and endometrial cancers with MSI or IHC testing. This was shown to be a cost-effective approach for identifying individuals who should be offered germline molecular genetic testing for Lynch syndrome [ • Use age of onset, familial cancer history, and pathologic features to predict which individuals are more likely to have a germline MMR pathogenic variant [ • Tumor tissue sequence analysis for a pathogenic variant in one of the genes listed in • Note: Lynch syndrome-related cancers do not have hypermethylation of the • • Note: (1) Somatic • Sporadic cancer • Cancer due to other hereditary cancer syndrome • Sporadic cancer • Germline MMR gene pathogenic variant • Germline MMR gene testing or paired germline/tumor tissue MMR gene testing • If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing. • Sporadic cancer • Germline MMR gene pathogenic variant • IHC • If IHC not available, consider germline MMR gene testing or paired germline/tumor tissue MMR gene testing. • If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing. • Sporadic cancer • Germline • Germline • Targeted • If • If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing. • Sporadic cancer • Germline • Constitutional • If early-onset cancer (< age 50 yrs) or significant family history of cancer: germline MMR gene testing • If not: no additional testing • For early onset only: constitutional • Sporadic cancer • Germline • Constitutional • Germline • Germline • Sporadic cancer • Germline MMR testing or paired germline/tumor tissue MMR gene testing • If germline testing negative & paired germline/tumor tissue not done: consider tumor tissue MMR gene testing. • Germline • Germline • Sporadic cancer • Germline • Germline • Sporadic cancer • Germline • Sporadic cancer • Germline • Germline • Sporadic cancer w/treatment effect • Germline MMR gene testing or germline/tumor tissue MMR gene testing • If germline testing negative & paired germline/tumor tissue not done: consider tumor tissue MMR gene testing. • If applicable, consider MSI analysis or repeat IHC on nontreated tumor. • Sporadic cancer: MLH1 promoter methylation or somatic • Germline • Germline • Targeted • If • If germline testing negative & paired germline/tumor tissue not done: consider tumor tissue MMR gene testing. • Germline MMR gene path var • Sporadic cancer • Targeted • If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing ## Suggestive Findings A diagnosis of Lynch syndrome A diagnosis of a tumor of the Lynch syndrome spectrum (e.g., colorectal, endometrial, ovarian, stomach, small bowel, urinary tract [urothelial], biliary tract, prostate, brain [usually glioblastoma], skin [sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas], and pancreas) with one of the following on Microsatellite instability (MSI) testing showing that tumor tissue is MSI high. (For information on MSI testing, including advantages and disadvantages, click Immunohistochemistry (IHC) demonstrating loss of expression of one or more of the mismatch repair (MMR) gene products: MLH1, MSH2, MSH6, and/or PMS2. (For information on advantages and disadvantages of IHC testing, click Next-generation sequencing in tumor tissue revealing MSI Identification of a pathogenic variant in tumor tissue in an MMR gene A diagnosis of colorectal cancer (CRC) or endometrial cancer and Colorectal or endometrial cancer diagnosed before age 50 years Synchronous or metachronous Lynch syndrome-related cancers (e.g., colorectal, endometrial, ovarian, stomach, small bowel, urinary tract, biliary tract, prostate, brain, sebaceous adenomas, sebaceous carcinomas, keratoacanthomas, pancreatic) Colorectal tumor tissue with MSI-high histology (e.g., poor differentiation, tumor-infiltrating lymphocytes, Crohn-like lymphocytic reaction, mucinous/signet-ring differentiation, medullary growth pattern) At least one first-degree relative with any Lynch syndrome-related cancer diagnosed before age 50 years At least two first-degree relatives with any Lynch syndrome-related cancers regardless of age of cancer diagnosis A family member with colorectal or endometrial cancer who meets one of the above criteria Note: Molecular genetic testing ideally begins with a person who has had a Lynch syndrome-related cancer. However, in some families there may be no affected individual who is alive or willing to be tested. A family member with a confirmed diagnosis of Lynch syndrome (pathogenic variant in one of the genes listed in A ≥5% probability of having a pathogenic variant in one of the genes listed in Note: Several risk assessment models including PREMM5 [ * Adapted from revised Bethesda Guidelines and National Comprehensive Cancer Network Guidelines; click Screening approaches include: Screen all CRC and endometrial cancers with MSI or IHC testing. This was shown to be a cost-effective approach for identifying individuals who should be offered germline molecular genetic testing for Lynch syndrome [ Use age of onset, familial cancer history, and pathologic features to predict which individuals are more likely to have a germline MMR pathogenic variant [ Tumor tissue sequence analysis for a pathogenic variant in one of the genes listed in Note: Lynch syndrome-related cancers do not have hypermethylation of the Note: (1) Somatic • A diagnosis of a tumor of the Lynch syndrome spectrum (e.g., colorectal, endometrial, ovarian, stomach, small bowel, urinary tract [urothelial], biliary tract, prostate, brain [usually glioblastoma], skin [sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas], and pancreas) with one of the following on • Microsatellite instability (MSI) testing showing that tumor tissue is MSI high. (For information on MSI testing, including advantages and disadvantages, click • Immunohistochemistry (IHC) demonstrating loss of expression of one or more of the mismatch repair (MMR) gene products: MLH1, MSH2, MSH6, and/or PMS2. (For information on advantages and disadvantages of IHC testing, click • Next-generation sequencing in tumor tissue revealing MSI • Identification of a pathogenic variant in tumor tissue in an MMR gene • Microsatellite instability (MSI) testing showing that tumor tissue is MSI high. (For information on MSI testing, including advantages and disadvantages, click • Immunohistochemistry (IHC) demonstrating loss of expression of one or more of the mismatch repair (MMR) gene products: MLH1, MSH2, MSH6, and/or PMS2. (For information on advantages and disadvantages of IHC testing, click • Next-generation sequencing in tumor tissue revealing MSI • Identification of a pathogenic variant in tumor tissue in an MMR gene • A diagnosis of colorectal cancer (CRC) or endometrial cancer and • Colorectal or endometrial cancer diagnosed before age 50 years • Synchronous or metachronous Lynch syndrome-related cancers (e.g., colorectal, endometrial, ovarian, stomach, small bowel, urinary tract, biliary tract, prostate, brain, sebaceous adenomas, sebaceous carcinomas, keratoacanthomas, pancreatic) • Colorectal tumor tissue with MSI-high histology (e.g., poor differentiation, tumor-infiltrating lymphocytes, Crohn-like lymphocytic reaction, mucinous/signet-ring differentiation, medullary growth pattern) • At least one first-degree relative with any Lynch syndrome-related cancer diagnosed before age 50 years • At least two first-degree relatives with any Lynch syndrome-related cancers regardless of age of cancer diagnosis • Colorectal or endometrial cancer diagnosed before age 50 years • Synchronous or metachronous Lynch syndrome-related cancers (e.g., colorectal, endometrial, ovarian, stomach, small bowel, urinary tract, biliary tract, prostate, brain, sebaceous adenomas, sebaceous carcinomas, keratoacanthomas, pancreatic) • Colorectal tumor tissue with MSI-high histology (e.g., poor differentiation, tumor-infiltrating lymphocytes, Crohn-like lymphocytic reaction, mucinous/signet-ring differentiation, medullary growth pattern) • At least one first-degree relative with any Lynch syndrome-related cancer diagnosed before age 50 years • At least two first-degree relatives with any Lynch syndrome-related cancers regardless of age of cancer diagnosis • A family member with colorectal or endometrial cancer who meets one of the above criteria • Note: Molecular genetic testing ideally begins with a person who has had a Lynch syndrome-related cancer. However, in some families there may be no affected individual who is alive or willing to be tested. • A family member with a confirmed diagnosis of Lynch syndrome (pathogenic variant in one of the genes listed in • A ≥5% probability of having a pathogenic variant in one of the genes listed in • Note: Several risk assessment models including PREMM5 [ • Microsatellite instability (MSI) testing showing that tumor tissue is MSI high. (For information on MSI testing, including advantages and disadvantages, click • Immunohistochemistry (IHC) demonstrating loss of expression of one or more of the mismatch repair (MMR) gene products: MLH1, MSH2, MSH6, and/or PMS2. (For information on advantages and disadvantages of IHC testing, click • Next-generation sequencing in tumor tissue revealing MSI • Identification of a pathogenic variant in tumor tissue in an MMR gene • Colorectal or endometrial cancer diagnosed before age 50 years • Synchronous or metachronous Lynch syndrome-related cancers (e.g., colorectal, endometrial, ovarian, stomach, small bowel, urinary tract, biliary tract, prostate, brain, sebaceous adenomas, sebaceous carcinomas, keratoacanthomas, pancreatic) • Colorectal tumor tissue with MSI-high histology (e.g., poor differentiation, tumor-infiltrating lymphocytes, Crohn-like lymphocytic reaction, mucinous/signet-ring differentiation, medullary growth pattern) • At least one first-degree relative with any Lynch syndrome-related cancer diagnosed before age 50 years • At least two first-degree relatives with any Lynch syndrome-related cancers regardless of age of cancer diagnosis • Screen all CRC and endometrial cancers with MSI or IHC testing. This was shown to be a cost-effective approach for identifying individuals who should be offered germline molecular genetic testing for Lynch syndrome [ • Use age of onset, familial cancer history, and pathologic features to predict which individuals are more likely to have a germline MMR pathogenic variant [ • Tumor tissue sequence analysis for a pathogenic variant in one of the genes listed in • Note: Lynch syndrome-related cancers do not have hypermethylation of the • • Note: (1) Somatic ## Establishing the Diagnosis The diagnosis of Lynch syndrome can be Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include a For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Lynch Syndrome See Data obtained from universal Lynch syndrome screening for colorectal and endometrial cancers See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants. Detection of exon or whole-gene deletions/duplications require specific sequencing data analysis or use of alternative molecular methods (see footnote 7). For issues to consider in interpretation of sequence analysis results, click Alteration of the proportions may occur in populations with over-representation of specific founder variants. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include specific data analysis of gene panels, quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Constitutional inactivation of Due to the high level of homology between Methods to sequence and identify large rearrangements in Although Germline deletions of Tumor Tissue Test Results, Interpretation, and Additional Testing Options Sporadic cancer Cancer due to other hereditary cancer syndrome Sporadic cancer Germline MMR gene pathogenic variant Germline MMR gene testing or paired germline/tumor tissue MMR gene testing If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing. Sporadic cancer Germline MMR gene pathogenic variant IHC If IHC not available, consider germline MMR gene testing or paired germline/tumor tissue MMR gene testing. If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing. Sporadic cancer Germline Germline Targeted If If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing. Sporadic cancer Germline Constitutional If early-onset cancer (< age 50 yrs) or significant family history of cancer: germline MMR gene testing If not: no additional testing For early onset only: constitutional Sporadic cancer Germline Constitutional Germline Germline Sporadic cancer Germline MMR testing or paired germline/tumor tissue MMR gene testing If germline testing negative & paired germline/tumor tissue not done: consider tumor tissue MMR gene testing. Germline Germline Sporadic cancer Germline Germline Sporadic cancer Germline Sporadic cancer Germline Germline Sporadic cancer w/treatment effect Germline MMR gene testing or germline/tumor tissue MMR gene testing If germline testing negative & paired germline/tumor tissue not done: consider tumor tissue MMR gene testing. If applicable, consider MSI analysis or repeat IHC on nontreated tumor. Sporadic cancer: MLH1 promoter methylation or somatic Germline Germline Targeted If If germline testing negative & paired germline/tumor tissue not done: consider tumor tissue MMR gene testing. Germline MMR gene path var Sporadic cancer Targeted If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing Adapted from Empty cells indicate either that testing was not done or that results may not influence testing strategy. – = absent staining of protein; + = normal staining of protein; IHC = immunohistochemistry; MMR = mismatch repair; MSI = microsatellite instability; MSS = microsatellite stability; Neg = negative; path var = pathogenic variant; Pos = positive Tumor testing strategies apply to colorectal and endometrial cancers. Limited data exist regarding the efficacy of tumor testing in other types of Lynch syndrome tumors. 45%-68% of tumors with evidence of MMR deficiency have biallelic somatic pathogenic variants. If biallelic somatic pathogenic variants are identified, the affected individual and their relatives should be managed based on the family cancer history and NOT as if they had Lynch syndrome. Prior to germline genetic testing, proper pre-test counseling should be done. For information on testing for germline pathogenic variants, see In the presence of a strong family history (e.g., Amsterdam criteria are met), or if additional features of a hereditary cancer syndrome are present, additional testing may be warranted in the proband or tumor testing in another affected family member because of the possibility that the original tumor selected for testing was a sporadic colorectal cancer (phenocopy). Constitutional Absent MSH6 IHC staining in rectal tumors may be due to treatment effect (neoadjuvant chemoradiotherapy). • Sporadic cancer • Cancer due to other hereditary cancer syndrome • Sporadic cancer • Germline MMR gene pathogenic variant • Germline MMR gene testing or paired germline/tumor tissue MMR gene testing • If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing. • Sporadic cancer • Germline MMR gene pathogenic variant • IHC • If IHC not available, consider germline MMR gene testing or paired germline/tumor tissue MMR gene testing. • If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing. • Sporadic cancer • Germline • Germline • Targeted • If • If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing. • Sporadic cancer • Germline • Constitutional • If early-onset cancer (< age 50 yrs) or significant family history of cancer: germline MMR gene testing • If not: no additional testing • For early onset only: constitutional • Sporadic cancer • Germline • Constitutional • Germline • Germline • Sporadic cancer • Germline MMR testing or paired germline/tumor tissue MMR gene testing • If germline testing negative & paired germline/tumor tissue not done: consider tumor tissue MMR gene testing. • Germline • Germline • Sporadic cancer • Germline • Germline • Sporadic cancer • Germline • Sporadic cancer • Germline • Germline • Sporadic cancer w/treatment effect • Germline MMR gene testing or germline/tumor tissue MMR gene testing • If germline testing negative & paired germline/tumor tissue not done: consider tumor tissue MMR gene testing. • If applicable, consider MSI analysis or repeat IHC on nontreated tumor. • Sporadic cancer: MLH1 promoter methylation or somatic • Germline • Germline • Targeted • If • If germline testing negative & paired germline/tumor tissue not done: consider tumor tissue MMR gene testing. • Germline MMR gene path var • Sporadic cancer • Targeted • If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing ## Option 1 (recommended) For an introduction to multigene panels click ## Option 2 (not often recommended) ## Option 3 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Lynch Syndrome See Data obtained from universal Lynch syndrome screening for colorectal and endometrial cancers See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants. Detection of exon or whole-gene deletions/duplications require specific sequencing data analysis or use of alternative molecular methods (see footnote 7). For issues to consider in interpretation of sequence analysis results, click Alteration of the proportions may occur in populations with over-representation of specific founder variants. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include specific data analysis of gene panels, quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Constitutional inactivation of Due to the high level of homology between Methods to sequence and identify large rearrangements in Although Germline deletions of Tumor Tissue Test Results, Interpretation, and Additional Testing Options Sporadic cancer Cancer due to other hereditary cancer syndrome Sporadic cancer Germline MMR gene pathogenic variant Germline MMR gene testing or paired germline/tumor tissue MMR gene testing If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing. Sporadic cancer Germline MMR gene pathogenic variant IHC If IHC not available, consider germline MMR gene testing or paired germline/tumor tissue MMR gene testing. If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing. Sporadic cancer Germline Germline Targeted If If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing. Sporadic cancer Germline Constitutional If early-onset cancer (< age 50 yrs) or significant family history of cancer: germline MMR gene testing If not: no additional testing For early onset only: constitutional Sporadic cancer Germline Constitutional Germline Germline Sporadic cancer Germline MMR testing or paired germline/tumor tissue MMR gene testing If germline testing negative & paired germline/tumor tissue not done: consider tumor tissue MMR gene testing. Germline Germline Sporadic cancer Germline Germline Sporadic cancer Germline Sporadic cancer Germline Germline Sporadic cancer w/treatment effect Germline MMR gene testing or germline/tumor tissue MMR gene testing If germline testing negative & paired germline/tumor tissue not done: consider tumor tissue MMR gene testing. If applicable, consider MSI analysis or repeat IHC on nontreated tumor. Sporadic cancer: MLH1 promoter methylation or somatic Germline Germline Targeted If If germline testing negative & paired germline/tumor tissue not done: consider tumor tissue MMR gene testing. Germline MMR gene path var Sporadic cancer Targeted If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing Adapted from Empty cells indicate either that testing was not done or that results may not influence testing strategy. – = absent staining of protein; + = normal staining of protein; IHC = immunohistochemistry; MMR = mismatch repair; MSI = microsatellite instability; MSS = microsatellite stability; Neg = negative; path var = pathogenic variant; Pos = positive Tumor testing strategies apply to colorectal and endometrial cancers. Limited data exist regarding the efficacy of tumor testing in other types of Lynch syndrome tumors. 45%-68% of tumors with evidence of MMR deficiency have biallelic somatic pathogenic variants. If biallelic somatic pathogenic variants are identified, the affected individual and their relatives should be managed based on the family cancer history and NOT as if they had Lynch syndrome. Prior to germline genetic testing, proper pre-test counseling should be done. For information on testing for germline pathogenic variants, see In the presence of a strong family history (e.g., Amsterdam criteria are met), or if additional features of a hereditary cancer syndrome are present, additional testing may be warranted in the proband or tumor testing in another affected family member because of the possibility that the original tumor selected for testing was a sporadic colorectal cancer (phenocopy). Constitutional Absent MSH6 IHC staining in rectal tumors may be due to treatment effect (neoadjuvant chemoradiotherapy). • Sporadic cancer • Cancer due to other hereditary cancer syndrome • Sporadic cancer • Germline MMR gene pathogenic variant • Germline MMR gene testing or paired germline/tumor tissue MMR gene testing • If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing. • Sporadic cancer • Germline MMR gene pathogenic variant • IHC • If IHC not available, consider germline MMR gene testing or paired germline/tumor tissue MMR gene testing. • If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing. • Sporadic cancer • Germline • Germline • Targeted • If • If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing. • Sporadic cancer • Germline • Constitutional • If early-onset cancer (< age 50 yrs) or significant family history of cancer: germline MMR gene testing • If not: no additional testing • For early onset only: constitutional • Sporadic cancer • Germline • Constitutional • Germline • Germline • Sporadic cancer • Germline MMR testing or paired germline/tumor tissue MMR gene testing • If germline testing negative & paired germline/tumor tissue not done: consider tumor tissue MMR gene testing. • Germline • Germline • Sporadic cancer • Germline • Germline • Sporadic cancer • Germline • Sporadic cancer • Germline • Germline • Sporadic cancer w/treatment effect • Germline MMR gene testing or germline/tumor tissue MMR gene testing • If germline testing negative & paired germline/tumor tissue not done: consider tumor tissue MMR gene testing. • If applicable, consider MSI analysis or repeat IHC on nontreated tumor. • Sporadic cancer: MLH1 promoter methylation or somatic • Germline • Germline • Targeted • If • If germline testing negative & paired germline/tumor tissue not done: consider tumor tissue MMR gene testing. • Germline MMR gene path var • Sporadic cancer • Targeted • If germline testing negative & paired germline/tumor tissue not done, consider tumor tissue MMR gene testing ## Clinical Characteristics Individuals with Lynch syndrome are at increased risk for colorectal cancer (CRC) and other cancers including those of the endometrium, ovary, stomach, small bowel, urinary tract, biliary tract, brain (usually glioblastoma), skin (sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas), pancreas, and prostate ( Cancer Risks by Gene in Individuals with Lynch Syndrome by Age 70 Years Compared to the General Population F = female; M = male Cumulative risk (age: 0-74) for both sexes estimated from worldwide data [ Organ-specific cancer risks calculated based on an international multicenter prospective observational study ( Data on cancer risks for those with an Lifetime (birth to death) cumulative cancer risks for colorectal, endometrial, and breast cancers have been estimated to be 4%, 3%, and 13%, respectively, for the US population [ As of December 2020 there are no data from the CRCs with MSI tend to have a better prognosis in a stage-wise comparison than MSS tumors, potentially reflecting active anti-tumor immune responses. Moreover, treatments supporting the anti-tumoral immune response, such as the immune checkpoint blockade therapy, showed great success in MSI-high tumors [ The risk of recurrent CRC is increased in individuals with Lynch syndrome. A meta-analysis of six studies including a total of 871 individuals found that based on an average of 91 months' follow up, the rate of metachronous cancers was 23% among those individuals who had a segmental colectomy, compared to 6% among individuals who had a colectomy (colectomy defined as subtotal or colectomy with ileosigmoid anastomosis) [ The mean age at endometrial cancer diagnosis is between 47 and 50 years for The duodenum and jejunum are the most common sites for cancer of the small bowel, with approximately 50% in reach of upper endoscopy [ Several types of sarcomas have been reported in individuals with an MMR pathogenic variant, including fibrous histiocytomas, rhabdomyosarcomas, leiomyosarcoma, and liposarcoma [ Adrenocortical carcinoma (ACC) has also been reported in families with Lynch syndrome. The most extensive study of this association, performed through a hereditary cancer clinic at the University of Michigan, found that two (1.7%) of 114 individuals presenting with ACC had a family history consistent with Lynch syndrome and had a pathogenic variant in an MMR gene identified. This association was further evaluated by case review of 135 individuals with pathogenic variants in an MMR gene, which identified two (1.4%) individuals who also had ACC [ Features in the family history that increase suspicion of CMMRD include a family history of Lynch syndrome, consanguineous parents, and/or at least one parent with clinical findings of Lynch syndrome. However, this diagnosis should not be excluded if the family history is negative, as a significant number of children with CMMRD will not have a family history consistent with Lynch syndrome [ Cancer risks vary among the genes associated with Lynch syndrome (see Germline pathogenic variants in Penetrance of CRCs and extracolonic cancers associated with pathogenic variants in an MMR gene or Lynch syndrome may also be referred to as hereditary non-polyposis colorectal cancer (HNPCC). However, HNPCC currently encompasses Lynch syndrome and all other forms of MMR-deficient and MMR-proficient hereditary nonpolyposis colorectal cancer (even those where a genetic cause has not been identified), whereas the diagnosis of Lynch syndrome requires identification of a pathogenic variant in an MMR gene or The population prevalence of Lynch syndrome has been estimated at 1:279 (1 in 1,946 for Lynch syndrome accounts for approximately 3% of CRCs and 3% of endometrial cancers [ • Several types of sarcomas have been reported in individuals with an MMR pathogenic variant, including fibrous histiocytomas, rhabdomyosarcomas, leiomyosarcoma, and liposarcoma [ • Adrenocortical carcinoma (ACC) has also been reported in families with Lynch syndrome. The most extensive study of this association, performed through a hereditary cancer clinic at the University of Michigan, found that two (1.7%) of 114 individuals presenting with ACC had a family history consistent with Lynch syndrome and had a pathogenic variant in an MMR gene identified. This association was further evaluated by case review of 135 individuals with pathogenic variants in an MMR gene, which identified two (1.4%) individuals who also had ACC [ ## Clinical Description Individuals with Lynch syndrome are at increased risk for colorectal cancer (CRC) and other cancers including those of the endometrium, ovary, stomach, small bowel, urinary tract, biliary tract, brain (usually glioblastoma), skin (sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas), pancreas, and prostate ( Cancer Risks by Gene in Individuals with Lynch Syndrome by Age 70 Years Compared to the General Population F = female; M = male Cumulative risk (age: 0-74) for both sexes estimated from worldwide data [ Organ-specific cancer risks calculated based on an international multicenter prospective observational study ( Data on cancer risks for those with an Lifetime (birth to death) cumulative cancer risks for colorectal, endometrial, and breast cancers have been estimated to be 4%, 3%, and 13%, respectively, for the US population [ As of December 2020 there are no data from the CRCs with MSI tend to have a better prognosis in a stage-wise comparison than MSS tumors, potentially reflecting active anti-tumor immune responses. Moreover, treatments supporting the anti-tumoral immune response, such as the immune checkpoint blockade therapy, showed great success in MSI-high tumors [ The risk of recurrent CRC is increased in individuals with Lynch syndrome. A meta-analysis of six studies including a total of 871 individuals found that based on an average of 91 months' follow up, the rate of metachronous cancers was 23% among those individuals who had a segmental colectomy, compared to 6% among individuals who had a colectomy (colectomy defined as subtotal or colectomy with ileosigmoid anastomosis) [ The mean age at endometrial cancer diagnosis is between 47 and 50 years for The duodenum and jejunum are the most common sites for cancer of the small bowel, with approximately 50% in reach of upper endoscopy [ Several types of sarcomas have been reported in individuals with an MMR pathogenic variant, including fibrous histiocytomas, rhabdomyosarcomas, leiomyosarcoma, and liposarcoma [ Adrenocortical carcinoma (ACC) has also been reported in families with Lynch syndrome. The most extensive study of this association, performed through a hereditary cancer clinic at the University of Michigan, found that two (1.7%) of 114 individuals presenting with ACC had a family history consistent with Lynch syndrome and had a pathogenic variant in an MMR gene identified. This association was further evaluated by case review of 135 individuals with pathogenic variants in an MMR gene, which identified two (1.4%) individuals who also had ACC [ Features in the family history that increase suspicion of CMMRD include a family history of Lynch syndrome, consanguineous parents, and/or at least one parent with clinical findings of Lynch syndrome. However, this diagnosis should not be excluded if the family history is negative, as a significant number of children with CMMRD will not have a family history consistent with Lynch syndrome [ • Several types of sarcomas have been reported in individuals with an MMR pathogenic variant, including fibrous histiocytomas, rhabdomyosarcomas, leiomyosarcoma, and liposarcoma [ • Adrenocortical carcinoma (ACC) has also been reported in families with Lynch syndrome. The most extensive study of this association, performed through a hereditary cancer clinic at the University of Michigan, found that two (1.7%) of 114 individuals presenting with ACC had a family history consistent with Lynch syndrome and had a pathogenic variant in an MMR gene identified. This association was further evaluated by case review of 135 individuals with pathogenic variants in an MMR gene, which identified two (1.4%) individuals who also had ACC [ ## Other Cancers Several types of sarcomas have been reported in individuals with an MMR pathogenic variant, including fibrous histiocytomas, rhabdomyosarcomas, leiomyosarcoma, and liposarcoma [ Adrenocortical carcinoma (ACC) has also been reported in families with Lynch syndrome. The most extensive study of this association, performed through a hereditary cancer clinic at the University of Michigan, found that two (1.7%) of 114 individuals presenting with ACC had a family history consistent with Lynch syndrome and had a pathogenic variant in an MMR gene identified. This association was further evaluated by case review of 135 individuals with pathogenic variants in an MMR gene, which identified two (1.4%) individuals who also had ACC [ • Several types of sarcomas have been reported in individuals with an MMR pathogenic variant, including fibrous histiocytomas, rhabdomyosarcomas, leiomyosarcoma, and liposarcoma [ • Adrenocortical carcinoma (ACC) has also been reported in families with Lynch syndrome. The most extensive study of this association, performed through a hereditary cancer clinic at the University of Michigan, found that two (1.7%) of 114 individuals presenting with ACC had a family history consistent with Lynch syndrome and had a pathogenic variant in an MMR gene identified. This association was further evaluated by case review of 135 individuals with pathogenic variants in an MMR gene, which identified two (1.4%) individuals who also had ACC [ ## Lynch Syndrome Variants Features in the family history that increase suspicion of CMMRD include a family history of Lynch syndrome, consanguineous parents, and/or at least one parent with clinical findings of Lynch syndrome. However, this diagnosis should not be excluded if the family history is negative, as a significant number of children with CMMRD will not have a family history consistent with Lynch syndrome [ ## Phenotype Correlations by Gene Cancer risks vary among the genes associated with Lynch syndrome (see Germline pathogenic variants in ## Genotype-Phenotype Correlations ## Penetrance Penetrance of CRCs and extracolonic cancers associated with pathogenic variants in an MMR gene or ## Nomenclature Lynch syndrome may also be referred to as hereditary non-polyposis colorectal cancer (HNPCC). However, HNPCC currently encompasses Lynch syndrome and all other forms of MMR-deficient and MMR-proficient hereditary nonpolyposis colorectal cancer (even those where a genetic cause has not been identified), whereas the diagnosis of Lynch syndrome requires identification of a pathogenic variant in an MMR gene or ## Prevalence The population prevalence of Lynch syndrome has been estimated at 1:279 (1 in 1,946 for Lynch syndrome accounts for approximately 3% of CRCs and 3% of endometrial cancers [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this Pathogenic variants in Sporadic tumors (including colorectal and endometrial cancers) found to have mismatch repair (MMR) deficiency (based on MSI and/or IHC analysis) may be due to methylation or biallelic somatic pathogenic variants in ## Differential Diagnosis Hereditary Cancer Syndromes with Increased Risk of Colorectal Cancer in the Differential Diagnosis of Lynch Syndrome 39 (range: 34-43) Polyp diagnosis: 16 (range: 7-36) CHRPE Osteomas, supernumerary teeth, odontomas Desmoids, epidermoid cysts ↑ risk of medulloblastoma, thyroid papillary carcinoma, hepatoblastoma, & pancreatic, gastric & duodenal cancers Upper GI findings & thyroid & duodenal cancer risks are similar to FAP. Other extraintestinal manifestations are unusual. Desmoid tumors assoc w/3' APC variants 30%-40% by age 70 yrs CRC may develop in absence of polyposis. Note: Most CRCs are MSS; some are MSI high. ↑ risk of cancers of endometrium, ovary, brain, breast, & other tumor types Adenomas in upper GI tract 50%-60% by age 70 yrs CRC may develop in absence of polyposis. Note: Most CRCs are MSS; some are MSI high. ↑ risk of cancers of endometrium, ovary, brain, breast, & other tumor types Adenomas in upper GI tract Colonic adenomas (10->100 cumulative polyps) Hyperplastic &/or serrated polyps may occur. Duodenal adenomas 43%-63% by age 60 yrs 80%-90% lifetime risk if untreated CRC may develop in absence of polyposis Note: Most CRCs are MSS; a minority are MSI high. Duodenal adenomas are common w/↑ risk of duodenal cancer. ↑ risk of ovarian & bladder malignancies Additional features: thyroid nodules, benign adrenal lesions, jawbone cysts, & CHRPE Colonic adenomas (1-100 cumulative polyps) Hyperplastic &/or serrated polyps may occur. Duodenal adenomas High risk of multiple primary tumors ~35%-78% risk of extracolonic cancer by age 60 yrs ↑ risk of breast & endometrial cancers & other tumors types: cervical, urothelial carcinoma of the bladder, meningiomas, unspecified brain tumors, basal cell carcinomas, head & neck squamous cell carcinomas, & hematologic malignancies Colonic adenomas (10-100 cumulative polyps) Duodenal adenomas ↑ risk of cancers of upper GI tract & pancreas Some Peutz-Jeghers-type hamartomatous polyps can occur in extraintestinal sites incl renal pelvis, bronchus, gall bladder, nasal passages, urinary bladder, & ureters. Mucocutaneous pigmentation (melanocytic macules) Gonadal tumors ↑ risk of GI cancers, & cancers of the breast, ovary, cervix, endometrium, pancreas, & testis 40s Polyp diagnosis: late 20s or later (also reported in adolescence) AD = autosomal dominant; AR = autosomal recessive; CHRPE = congenital hypertrophy of the retinal pigment epithelium; CRC = colorectal cancer; FAP = familial adenomatous polyposis; GI = gastrointestinal; MOI = mode of inheritance; MSI = microsatellite instability; MSS = microstatellite stable Multigene panels may include testing for genes and/or variants associated with moderate risk of CRC. For many of these variants there are no clear guidelines for the clinical management of heterozygotes. In many cases, the information from testing for variants associated with moderate penetrance does not change the risk management based on family history alone. Variants associated with moderate risk can confer a roughly twofold increased CRC risk – similar to that associated with having a first-degree relative with CRC [ The most prevalent known variants associated with moderate risk for CRC are listed in Most Prevalent Known Variants Associated with Moderate Risk for CRC Present in ~7% of individuals with Ashkenazi Jewish ancestry. Individuals with this variant do not have polyposis. Germline heterozygous The CRC risk estimates for monoallelic Sporadic MMR-deficient tumors commonly occur in older individuals (predominantly in females). These tumors show lack of MLH1 protein expression due to Despite its rarity, analysis for constitutional Individuals in whom a Lynch syndrome-associated germline pathogenic variant is not identified and who have somatic • 39 (range: 34-43) • Polyp diagnosis: 16 (range: 7-36) • CHRPE • Osteomas, supernumerary teeth, odontomas • Desmoids, epidermoid cysts • ↑ risk of medulloblastoma, thyroid papillary carcinoma, hepatoblastoma, & pancreatic, gastric & duodenal cancers • Upper GI findings & thyroid & duodenal cancer risks are similar to FAP. • Other extraintestinal manifestations are unusual. • Desmoid tumors assoc w/3' APC variants • 30%-40% by age 70 yrs • CRC may develop in absence of polyposis. • Note: Most CRCs are MSS; some are MSI high. • ↑ risk of cancers of endometrium, ovary, brain, breast, & other tumor types • Adenomas in upper GI tract • 50%-60% by age 70 yrs • CRC may develop in absence of polyposis. • Note: Most CRCs are MSS; some are MSI high. • ↑ risk of cancers of endometrium, ovary, brain, breast, & other tumor types • Adenomas in upper GI tract • Colonic adenomas (10->100 cumulative polyps) • Hyperplastic &/or serrated polyps may occur. • Duodenal adenomas • 43%-63% by age 60 yrs • 80%-90% lifetime risk if untreated • CRC may develop in absence of polyposis • Note: Most CRCs are MSS; a minority are MSI high. • Duodenal adenomas are common w/↑ risk of duodenal cancer. • ↑ risk of ovarian & bladder malignancies • Additional features: thyroid nodules, benign adrenal lesions, jawbone cysts, & CHRPE • Colonic adenomas (1-100 cumulative polyps) • Hyperplastic &/or serrated polyps may occur. • Duodenal adenomas • High risk of multiple primary tumors • ~35%-78% risk of extracolonic cancer by age 60 yrs • ↑ risk of breast & endometrial cancers & other tumors types: cervical, urothelial carcinoma of the bladder, meningiomas, unspecified brain tumors, basal cell carcinomas, head & neck squamous cell carcinomas, & hematologic malignancies • Colonic adenomas (10-100 cumulative polyps) • Duodenal adenomas • ↑ risk of cancers of upper GI tract & pancreas • Some • Peutz-Jeghers-type hamartomatous polyps can occur in extraintestinal sites incl renal pelvis, bronchus, gall bladder, nasal passages, urinary bladder, & ureters. • Mucocutaneous pigmentation (melanocytic macules) • Gonadal tumors • ↑ risk of GI cancers, & cancers of the breast, ovary, cervix, endometrium, pancreas, & testis • 40s • Polyp diagnosis: late 20s or later (also reported in adolescence) • Despite its rarity, analysis for constitutional • Individuals in whom a Lynch syndrome-associated germline pathogenic variant is not identified and who have somatic ## Hereditary Cancer Syndromes Hereditary Cancer Syndromes with Increased Risk of Colorectal Cancer in the Differential Diagnosis of Lynch Syndrome 39 (range: 34-43) Polyp diagnosis: 16 (range: 7-36) CHRPE Osteomas, supernumerary teeth, odontomas Desmoids, epidermoid cysts ↑ risk of medulloblastoma, thyroid papillary carcinoma, hepatoblastoma, & pancreatic, gastric & duodenal cancers Upper GI findings & thyroid & duodenal cancer risks are similar to FAP. Other extraintestinal manifestations are unusual. Desmoid tumors assoc w/3' APC variants 30%-40% by age 70 yrs CRC may develop in absence of polyposis. Note: Most CRCs are MSS; some are MSI high. ↑ risk of cancers of endometrium, ovary, brain, breast, & other tumor types Adenomas in upper GI tract 50%-60% by age 70 yrs CRC may develop in absence of polyposis. Note: Most CRCs are MSS; some are MSI high. ↑ risk of cancers of endometrium, ovary, brain, breast, & other tumor types Adenomas in upper GI tract Colonic adenomas (10->100 cumulative polyps) Hyperplastic &/or serrated polyps may occur. Duodenal adenomas 43%-63% by age 60 yrs 80%-90% lifetime risk if untreated CRC may develop in absence of polyposis Note: Most CRCs are MSS; a minority are MSI high. Duodenal adenomas are common w/↑ risk of duodenal cancer. ↑ risk of ovarian & bladder malignancies Additional features: thyroid nodules, benign adrenal lesions, jawbone cysts, & CHRPE Colonic adenomas (1-100 cumulative polyps) Hyperplastic &/or serrated polyps may occur. Duodenal adenomas High risk of multiple primary tumors ~35%-78% risk of extracolonic cancer by age 60 yrs ↑ risk of breast & endometrial cancers & other tumors types: cervical, urothelial carcinoma of the bladder, meningiomas, unspecified brain tumors, basal cell carcinomas, head & neck squamous cell carcinomas, & hematologic malignancies Colonic adenomas (10-100 cumulative polyps) Duodenal adenomas ↑ risk of cancers of upper GI tract & pancreas Some Peutz-Jeghers-type hamartomatous polyps can occur in extraintestinal sites incl renal pelvis, bronchus, gall bladder, nasal passages, urinary bladder, & ureters. Mucocutaneous pigmentation (melanocytic macules) Gonadal tumors ↑ risk of GI cancers, & cancers of the breast, ovary, cervix, endometrium, pancreas, & testis 40s Polyp diagnosis: late 20s or later (also reported in adolescence) AD = autosomal dominant; AR = autosomal recessive; CHRPE = congenital hypertrophy of the retinal pigment epithelium; CRC = colorectal cancer; FAP = familial adenomatous polyposis; GI = gastrointestinal; MOI = mode of inheritance; MSI = microsatellite instability; MSS = microstatellite stable • 39 (range: 34-43) • Polyp diagnosis: 16 (range: 7-36) • CHRPE • Osteomas, supernumerary teeth, odontomas • Desmoids, epidermoid cysts • ↑ risk of medulloblastoma, thyroid papillary carcinoma, hepatoblastoma, & pancreatic, gastric & duodenal cancers • Upper GI findings & thyroid & duodenal cancer risks are similar to FAP. • Other extraintestinal manifestations are unusual. • Desmoid tumors assoc w/3' APC variants • 30%-40% by age 70 yrs • CRC may develop in absence of polyposis. • Note: Most CRCs are MSS; some are MSI high. • ↑ risk of cancers of endometrium, ovary, brain, breast, & other tumor types • Adenomas in upper GI tract • 50%-60% by age 70 yrs • CRC may develop in absence of polyposis. • Note: Most CRCs are MSS; some are MSI high. • ↑ risk of cancers of endometrium, ovary, brain, breast, & other tumor types • Adenomas in upper GI tract • Colonic adenomas (10->100 cumulative polyps) • Hyperplastic &/or serrated polyps may occur. • Duodenal adenomas • 43%-63% by age 60 yrs • 80%-90% lifetime risk if untreated • CRC may develop in absence of polyposis • Note: Most CRCs are MSS; a minority are MSI high. • Duodenal adenomas are common w/↑ risk of duodenal cancer. • ↑ risk of ovarian & bladder malignancies • Additional features: thyroid nodules, benign adrenal lesions, jawbone cysts, & CHRPE • Colonic adenomas (1-100 cumulative polyps) • Hyperplastic &/or serrated polyps may occur. • Duodenal adenomas • High risk of multiple primary tumors • ~35%-78% risk of extracolonic cancer by age 60 yrs • ↑ risk of breast & endometrial cancers & other tumors types: cervical, urothelial carcinoma of the bladder, meningiomas, unspecified brain tumors, basal cell carcinomas, head & neck squamous cell carcinomas, & hematologic malignancies • Colonic adenomas (10-100 cumulative polyps) • Duodenal adenomas • ↑ risk of cancers of upper GI tract & pancreas • Some • Peutz-Jeghers-type hamartomatous polyps can occur in extraintestinal sites incl renal pelvis, bronchus, gall bladder, nasal passages, urinary bladder, & ureters. • Mucocutaneous pigmentation (melanocytic macules) • Gonadal tumors • ↑ risk of GI cancers, & cancers of the breast, ovary, cervix, endometrium, pancreas, & testis • 40s • Polyp diagnosis: late 20s or later (also reported in adolescence) ## Moderate-Risk Colorectal Cancer (CRC) Predisposition Multigene panels may include testing for genes and/or variants associated with moderate risk of CRC. For many of these variants there are no clear guidelines for the clinical management of heterozygotes. In many cases, the information from testing for variants associated with moderate penetrance does not change the risk management based on family history alone. Variants associated with moderate risk can confer a roughly twofold increased CRC risk – similar to that associated with having a first-degree relative with CRC [ The most prevalent known variants associated with moderate risk for CRC are listed in Most Prevalent Known Variants Associated with Moderate Risk for CRC Present in ~7% of individuals with Ashkenazi Jewish ancestry. Individuals with this variant do not have polyposis. Germline heterozygous The CRC risk estimates for monoallelic ## Sporadic Colorectal Cancer Sporadic MMR-deficient tumors commonly occur in older individuals (predominantly in females). These tumors show lack of MLH1 protein expression due to Despite its rarity, analysis for constitutional Individuals in whom a Lynch syndrome-associated germline pathogenic variant is not identified and who have somatic • Despite its rarity, analysis for constitutional • Individuals in whom a Lynch syndrome-associated germline pathogenic variant is not identified and who have somatic ## Management To establish the extent of disease and needs in an individual diagnosed with Lynch syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Lynch Syndrome Consider upper endoscopy exam esp for those w/family history of gastric cancer & those of Asian ancestry. Biopsies should be evaluated for CRC = colorectal cancer; EUS = endoscopic ultrasound; MOI = mode of inheritance; MRCP = magnetic resonance cholangiopancreatography Colonoscopy is recommended rather than flexible sigmoidoscopy because of the predominance of proximal colon cancers in Lynch syndrome. Studies on the effectiveness of transvaginal ultrasound and endometrial biopsy have not shown them to reduce endometrial cancer mortality. In a systematic review of cost effectiveness of early detection and prevention strategies for endometrial cancer, prophylactic surgery was more effective and less costly than screening with transvaginal ultrasound, CA-125, or endometrial biopsy [ Studies have not supported that surveillance for gastric and duodenal cancers improve early detection or outcomes of these cancers, but because the stomach and duodenum are the most common extracolonic non-gynecologic cancer in Lynch syndrome, periodic upper endoscopy exams have been included in guidelines. There is no clear evidence to support surveillance of urothelial cancers in Lynch syndrome. Surveillance may be considered in selected individuals with a family history of urothelial cancer. Begin surveillance at 50 years old (or 10 years younger than the earliest exocrine pancreatic cancer diagnosis in the family) for individuals with pancreatic cancer in first- or second-degree relatives from the same side of the family as the identified pathogenic germline variant. Medical geneticist, certified genetic counselor, or certified advanced genetic nurse Treatment of Manifestations in Individuals with Lynch Syndrome Prophylactic hysterectomy and bilateral salpingo-oophorectomy can be considered after childbearing is completed. Because screening colonoscopy with polypectomy is an effective preventive measure for colorectal cancer, prophylactic colectomy (removal of the colon prior to the development of cancer) is generally not recommended for individuals with Lynch syndrome. Aspirin therapy has been shown to decrease the risk for CRC in individuals with Lynch syndrome. Based on combined experience, several consensus statements and expert reviews including the NCCN, the Mallorca guidelines, and the US Multi-Society Task Force on CRC suggest that aspirin can be considered, taking into account an individual's personal health and comorbidities, in the management of individuals with Lynch syndrome [ Recommended Surveillance for Individuals with Lynch Syndrome Consider upper endoscopy exam esp for those w/family history of gastric cancer & those of Asian ancestry. Biopsies should be evaluated for No additional specific screening recommendations for other Lynch syndrome-assoc cancers Follow general population screening guidelines & seek prompt medical attention for changes in health or persistent symptoms. CRC = colorectal cancer; EUS = endoscopic ultrasound; MRCP = magnetic resonance cholangiopancreatography Colonoscopy is recommended rather than flexible sigmoidoscopy because of the predominance of proximal colon cancers in Lynch syndrome. Studies on the effectiveness of transvaginal ultrasound and endometrial biopsy have not shown them to reduce endometrial cancer mortality. In a systematic review of cost effectiveness of early detection and prevention strategies for endometrial cancer, prophylactic surgery was more effective and less costly than screening with transvaginal ultrasound, CA-125, or endometrial biopsy [ Upper gastrointestinal endoscopy has recently been recommended for surveillance in individuals with Lynch syndrome [ Limited data exist to advocate for surveillance for urothelial cancers in Lynch syndrome. Surveillance may be considered in individuals with a family history of urothelial cancer. There is accumulating evidence that a high body mass, cigarette smoking, type 2 diabetes, and high cholesterol increase the risk of CRC in Lynch syndrome. The direction and strength of observed associations are similar to those for the general population [ It is appropriate to clarify the genetic status of all first-degree relatives (parents, sibs, and children) of an affected individual by molecular genetic testing for the Lynch syndrome-related 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. Early recognition of cancers associated with Lynch syndrome may allow for timely intervention and improved final outcome. Sibs should be considered at risk even if the parents have not had cancer because most Lynch syndrome results from an inherited (not If clinical history and family history cannot identify the parent from whom the proband inherited the Lynch syndrome-related pathogenic variant, molecular genetic testing should be offered to both parents to determine which has the pathogenic variant. In general, molecular genetic testing for Lynch syndrome is not recommended for at-risk individuals younger than age 18 years. However, predictive testing should be considered if there is a history of early-onset cancer in the family. For unaffected individuals with a Lynch syndrome-related pathogenic variant, screening should begin between ages 20 and 25 years, or two to five years earlier than the earliest diagnosis in the family [ See Ideally cancer screening exams would be planned around a pregnancy. An affected female would be encouraged to be current on her cancer screening before attempting to become pregnant. If an affected female is diagnosed with cancer during pregnancy, she should be counseled about cancer treatment options and their potential implications for the fetus. Search • Consider upper endoscopy exam esp for those w/family history of gastric cancer & those of Asian ancestry. • Biopsies should be evaluated for • Consider upper endoscopy exam esp for those w/family history of gastric cancer & those of Asian ancestry. • Biopsies should be evaluated for • No additional specific screening recommendations for other Lynch syndrome-assoc cancers • Follow general population screening guidelines & seek prompt medical attention for changes in health or persistent symptoms. • Sibs should be considered at risk even if the parents have not had cancer because most Lynch syndrome results from an inherited (not • If clinical history and family history cannot identify the parent from whom the proband inherited the Lynch syndrome-related pathogenic variant, molecular genetic testing should be offered to both parents to determine which has the pathogenic variant. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Lynch syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Lynch Syndrome Consider upper endoscopy exam esp for those w/family history of gastric cancer & those of Asian ancestry. Biopsies should be evaluated for CRC = colorectal cancer; EUS = endoscopic ultrasound; MOI = mode of inheritance; MRCP = magnetic resonance cholangiopancreatography Colonoscopy is recommended rather than flexible sigmoidoscopy because of the predominance of proximal colon cancers in Lynch syndrome. Studies on the effectiveness of transvaginal ultrasound and endometrial biopsy have not shown them to reduce endometrial cancer mortality. In a systematic review of cost effectiveness of early detection and prevention strategies for endometrial cancer, prophylactic surgery was more effective and less costly than screening with transvaginal ultrasound, CA-125, or endometrial biopsy [ Studies have not supported that surveillance for gastric and duodenal cancers improve early detection or outcomes of these cancers, but because the stomach and duodenum are the most common extracolonic non-gynecologic cancer in Lynch syndrome, periodic upper endoscopy exams have been included in guidelines. There is no clear evidence to support surveillance of urothelial cancers in Lynch syndrome. Surveillance may be considered in selected individuals with a family history of urothelial cancer. Begin surveillance at 50 years old (or 10 years younger than the earliest exocrine pancreatic cancer diagnosis in the family) for individuals with pancreatic cancer in first- or second-degree relatives from the same side of the family as the identified pathogenic germline variant. Medical geneticist, certified genetic counselor, or certified advanced genetic nurse • Consider upper endoscopy exam esp for those w/family history of gastric cancer & those of Asian ancestry. • Biopsies should be evaluated for ## Treatment of Manifestations Treatment of Manifestations in Individuals with Lynch Syndrome ## Prevention of Primary Manifestations Prophylactic hysterectomy and bilateral salpingo-oophorectomy can be considered after childbearing is completed. Because screening colonoscopy with polypectomy is an effective preventive measure for colorectal cancer, prophylactic colectomy (removal of the colon prior to the development of cancer) is generally not recommended for individuals with Lynch syndrome. Aspirin therapy has been shown to decrease the risk for CRC in individuals with Lynch syndrome. Based on combined experience, several consensus statements and expert reviews including the NCCN, the Mallorca guidelines, and the US Multi-Society Task Force on CRC suggest that aspirin can be considered, taking into account an individual's personal health and comorbidities, in the management of individuals with Lynch syndrome [ ## Surveillance Recommended Surveillance for Individuals with Lynch Syndrome Consider upper endoscopy exam esp for those w/family history of gastric cancer & those of Asian ancestry. Biopsies should be evaluated for No additional specific screening recommendations for other Lynch syndrome-assoc cancers Follow general population screening guidelines & seek prompt medical attention for changes in health or persistent symptoms. CRC = colorectal cancer; EUS = endoscopic ultrasound; MRCP = magnetic resonance cholangiopancreatography Colonoscopy is recommended rather than flexible sigmoidoscopy because of the predominance of proximal colon cancers in Lynch syndrome. Studies on the effectiveness of transvaginal ultrasound and endometrial biopsy have not shown them to reduce endometrial cancer mortality. In a systematic review of cost effectiveness of early detection and prevention strategies for endometrial cancer, prophylactic surgery was more effective and less costly than screening with transvaginal ultrasound, CA-125, or endometrial biopsy [ Upper gastrointestinal endoscopy has recently been recommended for surveillance in individuals with Lynch syndrome [ Limited data exist to advocate for surveillance for urothelial cancers in Lynch syndrome. Surveillance may be considered in individuals with a family history of urothelial cancer. • Consider upper endoscopy exam esp for those w/family history of gastric cancer & those of Asian ancestry. • Biopsies should be evaluated for • No additional specific screening recommendations for other Lynch syndrome-assoc cancers • Follow general population screening guidelines & seek prompt medical attention for changes in health or persistent symptoms. ## Agents/Circumstances to Avoid There is accumulating evidence that a high body mass, cigarette smoking, type 2 diabetes, and high cholesterol increase the risk of CRC in Lynch syndrome. The direction and strength of observed associations are similar to those for the general population [ ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of all first-degree relatives (parents, sibs, and children) of an affected individual by molecular genetic testing for the Lynch syndrome-related 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. Early recognition of cancers associated with Lynch syndrome may allow for timely intervention and improved final outcome. Sibs should be considered at risk even if the parents have not had cancer because most Lynch syndrome results from an inherited (not If clinical history and family history cannot identify the parent from whom the proband inherited the Lynch syndrome-related pathogenic variant, molecular genetic testing should be offered to both parents to determine which has the pathogenic variant. In general, molecular genetic testing for Lynch syndrome is not recommended for at-risk individuals younger than age 18 years. However, predictive testing should be considered if there is a history of early-onset cancer in the family. For unaffected individuals with a Lynch syndrome-related pathogenic variant, screening should begin between ages 20 and 25 years, or two to five years earlier than the earliest diagnosis in the family [ See • Sibs should be considered at risk even if the parents have not had cancer because most Lynch syndrome results from an inherited (not • If clinical history and family history cannot identify the parent from whom the proband inherited the Lynch syndrome-related pathogenic variant, molecular genetic testing should be offered to both parents to determine which has the pathogenic variant. ## Pregnancy Management Ideally cancer screening exams would be planned around a pregnancy. An affected female would be encouraged to be current on her cancer screening before attempting to become pregnant. If an affected female is diagnosed with cancer during pregnancy, she should be counseled about cancer treatment options and their potential implications for the fetus. ## Therapies Under Investigation Search ## Genetic Counseling In most individuals, Lynch syndrome is caused by a heterozygous germline pathogenic variant in Individuals with Lynch syndrome caused by constitutional inactivation of Note: Several factors (in addition to the possibility of a constitutional The majority of individuals diagnosed with Lynch syndrome inherited a pathogenic variant from a parent who may or may not have had cancer. If clinical and family history cannot identify the parent from whom the proband inherited the pathogenic variant, molecular genetic testing should be offered to both parents to determine which parent is heterozygous for the pathogenic variant identified in the proband. In the rare event that the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent (and parental identity testing has confirmed biological maternity and paternity), possible explanations include the following: A Germline mosaicism in a parent (Though theoretically possible, no instances of a proband inheriting a Lynch syndrome-related pathogenic variant from a parent with germline mosaicism have been reported to date.) A parent who is heterozygous for a Lynch syndrome-related pathogenic variant may not have had cancer because of incomplete penetrance, variable age of cancer development, cancer risk reduction resulting from screening or prophylactic surgery, or early death. Therefore, an apparently negative family history cannot be confirmed without appropriate molecular genetic testing to establish that neither parent is heterozygous for the pathogenic variant identified in the proband. If a parent of the proband has the pathogenic variant identified in the proband, the risk to the sibs is 50%. Note: Molecular genetic testing for the familial Lynch syndrome-related variant should be offered to all sibs (see If the proband has a known Lynch 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 genetic status of the parents is unknown, sibs should be considered at risk for cancers associated with Lynch syndrome (regardless of whether parents have had cancer) and offered molecular genetic testing. 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. Predictive testing for at-risk relatives is possible once the Lynch syndrome-related pathogenic variant has been identified in an affected family member. Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. In general, genetic testing for Lynch syndrome is not recommended for at-risk individuals younger than age 18 years. However, predictive testing should be considered if there is a history of early-onset cancer in the family. In unaffected individuals with a Lynch syndrome-related pathogenic variant, screening is recommended beginning at age 20 to 25 years, or two to five years prior to the earliest diagnosis in the family [ For more information, see the National Society of Genetic Counselors In a family with an established diagnosis of Lynch syndrome, it is appropriate to consider testing of symptomatic individuals regardless of age. Once a germline heterozygous Lynch syndrome-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The majority of individuals diagnosed with Lynch syndrome inherited a pathogenic variant from a parent who may or may not have had cancer. • If clinical and family history cannot identify the parent from whom the proband inherited the pathogenic variant, molecular genetic testing should be offered to both parents to determine which parent is heterozygous for the pathogenic variant identified in the proband. • In the rare event that the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent (and parental identity testing has confirmed biological maternity and paternity), possible explanations include the following: • A • Germline mosaicism in a parent (Though theoretically possible, no instances of a proband inheriting a Lynch syndrome-related pathogenic variant from a parent with germline mosaicism have been reported to date.) • A • Germline mosaicism in a parent (Though theoretically possible, no instances of a proband inheriting a Lynch syndrome-related pathogenic variant from a parent with germline mosaicism have been reported to date.) • A parent who is heterozygous for a Lynch syndrome-related pathogenic variant may not have had cancer because of incomplete penetrance, variable age of cancer development, cancer risk reduction resulting from screening or prophylactic surgery, or early death. Therefore, an apparently negative family history cannot be confirmed without appropriate molecular genetic testing to establish that neither parent is heterozygous for the pathogenic variant identified in the proband. • A • Germline mosaicism in a parent (Though theoretically possible, no instances of a proband inheriting a Lynch syndrome-related pathogenic variant from a parent with germline mosaicism have been reported to date.) • If a parent of the proband has the pathogenic variant identified in the proband, the risk to the sibs is 50%. Note: Molecular genetic testing for the familial Lynch syndrome-related variant should be offered to all sibs (see • If the proband has a known Lynch 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 genetic status of the parents is unknown, sibs should be considered at risk for cancers associated with Lynch syndrome (regardless of whether parents have had cancer) and offered molecular genetic testing. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • Predictive testing for at-risk relatives is possible once the Lynch syndrome-related pathogenic variant has been identified in an affected family member. • Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. • In general, genetic testing for Lynch syndrome is not recommended for at-risk individuals younger than age 18 years. However, predictive testing should be considered if there is a history of early-onset cancer in the family. In unaffected individuals with a Lynch syndrome-related pathogenic variant, screening is recommended beginning at age 20 to 25 years, or two to five years prior to the earliest diagnosis in the family [ • For more information, see the National Society of Genetic Counselors ## Mode of Inheritance In most individuals, Lynch syndrome is caused by a heterozygous germline pathogenic variant in Individuals with Lynch syndrome caused by constitutional inactivation of Note: Several factors (in addition to the possibility of a constitutional ## Risk to Family Members The majority of individuals diagnosed with Lynch syndrome inherited a pathogenic variant from a parent who may or may not have had cancer. If clinical and family history cannot identify the parent from whom the proband inherited the pathogenic variant, molecular genetic testing should be offered to both parents to determine which parent is heterozygous for the pathogenic variant identified in the proband. In the rare event that the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent (and parental identity testing has confirmed biological maternity and paternity), possible explanations include the following: A Germline mosaicism in a parent (Though theoretically possible, no instances of a proband inheriting a Lynch syndrome-related pathogenic variant from a parent with germline mosaicism have been reported to date.) A parent who is heterozygous for a Lynch syndrome-related pathogenic variant may not have had cancer because of incomplete penetrance, variable age of cancer development, cancer risk reduction resulting from screening or prophylactic surgery, or early death. Therefore, an apparently negative family history cannot be confirmed without appropriate molecular genetic testing to establish that neither parent is heterozygous for the pathogenic variant identified in the proband. If a parent of the proband has the pathogenic variant identified in the proband, the risk to the sibs is 50%. Note: Molecular genetic testing for the familial Lynch syndrome-related variant should be offered to all sibs (see If the proband has a known Lynch 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 genetic status of the parents is unknown, sibs should be considered at risk for cancers associated with Lynch syndrome (regardless of whether parents have had cancer) and offered molecular genetic testing. • The majority of individuals diagnosed with Lynch syndrome inherited a pathogenic variant from a parent who may or may not have had cancer. • If clinical and family history cannot identify the parent from whom the proband inherited the pathogenic variant, molecular genetic testing should be offered to both parents to determine which parent is heterozygous for the pathogenic variant identified in the proband. • In the rare event that the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent (and parental identity testing has confirmed biological maternity and paternity), possible explanations include the following: • A • Germline mosaicism in a parent (Though theoretically possible, no instances of a proband inheriting a Lynch syndrome-related pathogenic variant from a parent with germline mosaicism have been reported to date.) • A • Germline mosaicism in a parent (Though theoretically possible, no instances of a proband inheriting a Lynch syndrome-related pathogenic variant from a parent with germline mosaicism have been reported to date.) • A parent who is heterozygous for a Lynch syndrome-related pathogenic variant may not have had cancer because of incomplete penetrance, variable age of cancer development, cancer risk reduction resulting from screening or prophylactic surgery, or early death. Therefore, an apparently negative family history cannot be confirmed without appropriate molecular genetic testing to establish that neither parent is heterozygous for the pathogenic variant identified in the proband. • A • Germline mosaicism in a parent (Though theoretically possible, no instances of a proband inheriting a Lynch syndrome-related pathogenic variant from a parent with germline mosaicism have been reported to date.) • If a parent of the proband has the pathogenic variant identified in the proband, the risk to the sibs is 50%. Note: Molecular genetic testing for the familial Lynch syndrome-related variant should be offered to all sibs (see • If the proband has a known Lynch 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 genetic status of the parents is unknown, sibs should be considered at risk for cancers associated with Lynch syndrome (regardless of whether parents have had cancer) and offered molecular genetic testing. ## 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. Predictive testing for at-risk relatives is possible once the Lynch syndrome-related pathogenic variant has been identified in an affected family member. Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. In general, genetic testing for Lynch syndrome is not recommended for at-risk individuals younger than age 18 years. However, predictive testing should be considered if there is a history of early-onset cancer in the family. In unaffected individuals with a Lynch syndrome-related pathogenic variant, screening is recommended beginning at age 20 to 25 years, or two to five years prior to the earliest diagnosis in the family [ For more information, see the National Society of Genetic Counselors In a family with an established diagnosis of Lynch syndrome, it is appropriate to consider testing of symptomatic individuals regardless of age. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • Predictive testing for at-risk relatives is possible once the Lynch syndrome-related pathogenic variant has been identified in an affected family member. • Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. • In general, genetic testing for Lynch syndrome is not recommended for at-risk individuals younger than age 18 years. However, predictive testing should be considered if there is a history of early-onset cancer in the family. In unaffected individuals with a Lynch syndrome-related pathogenic variant, screening is recommended beginning at age 20 to 25 years, or two to five years prior to the earliest diagnosis in the family [ • For more information, see the National Society of Genetic Counselors ## Prenatal Testing and Preimplantation Genetic Testing Once a germline heterozygous Lynch syndrome-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources P.O. Box 5456 Vacaville CA 95688 • • • • P.O. Box 5456 • Vacaville CA 95688 • • • • • • • • • • • ## Molecular Genetics Lynch Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Lynch Syndrome ( Lynch syndrome is caused by pathogenic variants in genes involved with the mismatch repair (MMR) pathway. This pathway functions to identify and remove single-nucleotide mismatches or insertions and deletion loops. Pathogenic variants in four of the MMR genes can cause Lynch syndrome [ Lynch Syndrome: Gene-Specific Laboratory Considerations Genes in alphabetic order Lynch Syndrome: Notable Pathogenic Variants by Gene Variants listed in the table have been provided by the authors. Genes from Information obtained from ## Molecular Pathogenesis Lynch syndrome is caused by pathogenic variants in genes involved with the mismatch repair (MMR) pathway. This pathway functions to identify and remove single-nucleotide mismatches or insertions and deletion loops. Pathogenic variants in four of the MMR genes can cause Lynch syndrome [ Lynch Syndrome: Gene-Specific Laboratory Considerations Genes in alphabetic order Lynch Syndrome: Notable Pathogenic Variants by Gene Variants listed in the table have been provided by the authors. Genes from Information obtained from ## Chapter Notes Stephen B Gruber, MD, PhD; USC Norris Comprehensive Cancer Center (2004-2021)Gregory Idos, MD, MS (2021-present)Wendy Kohlmann, MS; University of Utah Huntsman Cancer Institute (2004-2021)Laura Valle, PhD (2021-present) 4 February 2021 (sw) Comprehensive update posted live 12 April 2018 (sw) Revision: Tumor testing table added ( 1 February 2018 (sw) Comprehensive update posted live 22 May 2014 (me) Comprehensive update posted live 20 September 2012 (cd) Revision: Multigene panels for Lynch syndrome (hereditary non-polyposis colon cancer) available clinically 11 August 2011 (me) Comprehensive update posted live 29 November 2006 (me) Comprehensive update posted live 5 February 2004 (me) Review posted live 18 April 2003 (sg) Original submission • 4 February 2021 (sw) Comprehensive update posted live • 12 April 2018 (sw) Revision: Tumor testing table added ( • 1 February 2018 (sw) Comprehensive update posted live • 22 May 2014 (me) Comprehensive update posted live • 20 September 2012 (cd) Revision: Multigene panels for Lynch syndrome (hereditary non-polyposis colon cancer) available clinically • 11 August 2011 (me) Comprehensive update posted live • 29 November 2006 (me) Comprehensive update posted live • 5 February 2004 (me) Review posted live • 18 April 2003 (sg) Original submission ## Author History Stephen B Gruber, MD, PhD; USC Norris Comprehensive Cancer Center (2004-2021)Gregory Idos, MD, MS (2021-present)Wendy Kohlmann, MS; University of Utah Huntsman Cancer Institute (2004-2021)Laura Valle, PhD (2021-present) ## Revision History 4 February 2021 (sw) Comprehensive update posted live 12 April 2018 (sw) Revision: Tumor testing table added ( 1 February 2018 (sw) Comprehensive update posted live 22 May 2014 (me) Comprehensive update posted live 20 September 2012 (cd) Revision: Multigene panels for Lynch syndrome (hereditary non-polyposis colon cancer) available clinically 11 August 2011 (me) Comprehensive update posted live 29 November 2006 (me) Comprehensive update posted live 5 February 2004 (me) Review posted live 18 April 2003 (sg) Original submission • 4 February 2021 (sw) Comprehensive update posted live • 12 April 2018 (sw) Revision: Tumor testing table added ( • 1 February 2018 (sw) Comprehensive update posted live • 22 May 2014 (me) Comprehensive update posted live • 20 September 2012 (cd) Revision: Multigene panels for Lynch syndrome (hereditary non-polyposis colon cancer) available clinically • 11 August 2011 (me) Comprehensive update posted live • 29 November 2006 (me) Comprehensive update posted live • 5 February 2004 (me) Review posted live • 18 April 2003 (sg) Original submission ## References American College of Medical Genetics technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). Available American College of Medical Genetics/American Society of Human Genetics. Joint statement on genetic testing for colon cancer (pdf). Available American Gastroenterological Association. Medical position statement: hereditary colorectal cancer and genetic testing (pdf). Available American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available American Society of Colon and Rectal Surgeons. Practice parameters for the treatment of patients with dominantly inherited colorectal cancer (FAP and HNPCC). 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 Giardiello FM, Brensinger JD, Petersen GM. American Gastroenterological Association technical review on hereditary colorectal cancer and genetic testing. Gastroenterology. 2001;121:198-213. [ Lu KH, Wood ME, Daniels M, Burke C, Ford J, Kauff ND, Kohlmann W, Lindor NM, Mulvey TM, Robinson L, Rubinstein WS, Stoffel EM, Snyder C, Syngal S, Merrill JK, Wollins DS, Hughes KS, et al. American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. J Clin Oncol. 2014;32:833-40. [ National Comprehensive Cancer Network. Genetic/familial high-risk assessment: colorectal cancer. 2020. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available Weissman SM, Burt R, Church J, Erdman S, Hampel H, Holter S, Jasperson K, Kalady MF, Haidle JL, Lynch HT, Palaniappan S, Wise PE, Senter L. Identification of individuals at risk for Lynch syndrome using targeted evaluations and genetic testing: National Society of Genetic Counselors and the Collaborative Group of the Americas on Inherited Colorectal Cancer joint practice guideline. J Genet Couns. 2012;21:484-93. [ • American College of Medical Genetics technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). Available • American College of Medical Genetics/American Society of Human Genetics. Joint statement on genetic testing for colon cancer (pdf). Available • American Gastroenterological Association. Medical position statement: hereditary colorectal cancer and genetic testing (pdf). Available • American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available • American Society of Colon and Rectal Surgeons. Practice parameters for the treatment of patients with dominantly inherited colorectal cancer (FAP and HNPCC). 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 • Giardiello FM, Brensinger JD, Petersen GM. American Gastroenterological Association technical review on hereditary colorectal cancer and genetic testing. Gastroenterology. 2001;121:198-213. [ • Lu KH, Wood ME, Daniels M, Burke C, Ford J, Kauff ND, Kohlmann W, Lindor NM, Mulvey TM, Robinson L, Rubinstein WS, Stoffel EM, Snyder C, Syngal S, Merrill JK, Wollins DS, Hughes KS, et al. American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. J Clin Oncol. 2014;32:833-40. [ • National Comprehensive Cancer Network. Genetic/familial high-risk assessment: colorectal cancer. 2020. • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available • Weissman SM, Burt R, Church J, Erdman S, Hampel H, Holter S, Jasperson K, Kalady MF, Haidle JL, Lynch HT, Palaniappan S, Wise PE, Senter L. Identification of individuals at risk for Lynch syndrome using targeted evaluations and genetic testing: National Society of Genetic Counselors and the Collaborative Group of the Americas on Inherited Colorectal Cancer joint practice guideline. J Genet Couns. 2012;21:484-93. [ ## Published Guidelines / Consensus Statements American College of Medical Genetics technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). Available American College of Medical Genetics/American Society of Human Genetics. Joint statement on genetic testing for colon cancer (pdf). Available American Gastroenterological Association. Medical position statement: hereditary colorectal cancer and genetic testing (pdf). Available American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available American Society of Colon and Rectal Surgeons. Practice parameters for the treatment of patients with dominantly inherited colorectal cancer (FAP and HNPCC). 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 Giardiello FM, Brensinger JD, Petersen GM. American Gastroenterological Association technical review on hereditary colorectal cancer and genetic testing. Gastroenterology. 2001;121:198-213. [ Lu KH, Wood ME, Daniels M, Burke C, Ford J, Kauff ND, Kohlmann W, Lindor NM, Mulvey TM, Robinson L, Rubinstein WS, Stoffel EM, Snyder C, Syngal S, Merrill JK, Wollins DS, Hughes KS, et al. American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. J Clin Oncol. 2014;32:833-40. [ National Comprehensive Cancer Network. Genetic/familial high-risk assessment: colorectal cancer. 2020. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available Weissman SM, Burt R, Church J, Erdman S, Hampel H, Holter S, Jasperson K, Kalady MF, Haidle JL, Lynch HT, Palaniappan S, Wise PE, Senter L. Identification of individuals at risk for Lynch syndrome using targeted evaluations and genetic testing: National Society of Genetic Counselors and the Collaborative Group of the Americas on Inherited Colorectal Cancer joint practice guideline. J Genet Couns. 2012;21:484-93. [ • American College of Medical Genetics technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). Available • American College of Medical Genetics/American Society of Human Genetics. Joint statement on genetic testing for colon cancer (pdf). Available • American Gastroenterological Association. Medical position statement: hereditary colorectal cancer and genetic testing (pdf). Available • American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available • American Society of Colon and Rectal Surgeons. Practice parameters for the treatment of patients with dominantly inherited colorectal cancer (FAP and HNPCC). 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 • Giardiello FM, Brensinger JD, Petersen GM. American Gastroenterological Association technical review on hereditary colorectal cancer and genetic testing. Gastroenterology. 2001;121:198-213. [ • Lu KH, Wood ME, Daniels M, Burke C, Ford J, Kauff ND, Kohlmann W, Lindor NM, Mulvey TM, Robinson L, Rubinstein WS, Stoffel EM, Snyder C, Syngal S, Merrill JK, Wollins DS, Hughes KS, et al. American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. J Clin Oncol. 2014;32:833-40. [ • National Comprehensive Cancer Network. Genetic/familial high-risk assessment: colorectal cancer. 2020. • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available • Weissman SM, Burt R, Church J, Erdman S, Hampel H, Holter S, Jasperson K, Kalady MF, Haidle JL, Lynch HT, Palaniappan S, Wise PE, Senter L. Identification of individuals at risk for Lynch syndrome using targeted evaluations and genetic testing: National Society of Genetic Counselors and the Collaborative Group of the Americas on Inherited Colorectal Cancer joint practice guideline. J Genet Couns. 2012;21:484-93. [ ## Literature Cited	[ "M Aarnio, R Salovaara, LA Aaltonen, JP Mecklin, HJ Jarvinen. Features of gastric cancer in hereditary non-polyposis colorectal cancer syndrome.. Int J Cancer 1997;74:551-5", "R Adam, I Spier, B Zhao, M Kloth, J Marquez, I Hinrichsen, J Kirfel, A Tafazzoli, S Horpaopan, S Uhlhaas, D Stienen, N Friedrichs, J Altmüller, A Laner, S Holzapfel, S Peters, K Kayser, H Thiele, E Holinski-Feder, G Marra, G Kristiansen, MM Nöthen, R Büttner, G Möslein, RC Betz, A Brieger, RP Lifton, S Aretz. Exome sequencing identifies biallelic MSH3 germline mutations as a recessive subtype of colorectal adenomatous polyposis.. Am J Hum Genet. 2016;99:337-51", "CC Anele, SO Adegbola, A Askari, A Rajendran, SK Clark, A Latchford, OD Faiz. Risk of metachronous colorectal cancer following colectomy in Lynch syndrome: a systematic review and meta-analysis.. Colorectal Dis. 2017;19:528-36", "AM Arnold, M Morak, A Benet-Pagès, A Laner, D Frishman, E Holinski-Feder. Targeted deep-intronic sequencing in a cohort of unexplained cases of suspected Lynch syndrome.. Eur J Hum Genet. 2020;28:597-608", "D Bakry, M Aronson, C Durno, H Rimawi, R Farah, QK Alharbi, M Alharbi, A Shamvil, S Ben-Shachar, M Mistry, S Constantini, R Dvir, I Qaddoumi, S Gallinger, J Lerner-Ellis, A Pollett, D Stephens, S Kelies, E Chao, D Malkin, E Bouffet, C Hawkins, U Tabori. Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: report from the constitutional mismatch repair deficiency consortium.. Eur J Cancer. 2014;50:987-96", "RA Barnetson, A Tenesa, SM Farrington, ID Nicholl, R Cetnarskyj, ME Porteous, H Campbell, MG Dunlop. Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer.. N Engl J Med. 2006;354:2751-63", "AS Bercow, EL Eisenhauer. Screening and surgical prophylaxis for hereditary cancer syndromes with high risk of endometrial and ovarian cancer.. J Surg Oncol. 2019;120:864-72", "H Bläker, S Haupt, M Morak, E Holinski-Feder, A Arnold, D Horst, J Sieber-Frank, F Seidler, M von Winterfeld, E Alwers, J Chang-Claude, H Brenner, W Roth, C Engel, M Löffler, G Möslein, HK Schackert, J Weitz, C Perne, S Aretz, R Hüneburg, W Schmiegel, D Vangala, N Rahner, V Steinke-Lange, V Heuveline, M von Knebel Doeberitz, A Ahadova, M Hoffmeister, M Kloor. Age-dependent performance of BRAF mutation testing in Lynch syndrome diagnostics.. Int J Cancer. 2020;147:2801-10", "F Bray, J Ferlay, I Soerjomataram, RL Siegel, LA Torre, A Jemal. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.. CA Cancer J Clin. 2018;68:394-424", "DD Buchanan, JR Stewart, M Clendenning, C Rosty, K Mahmood, BJ Pope, MA Jenkins, JL Hopper, MC Southey, FA Macrae, IM Winship, AK Win. Risk of colorectal cancer for carriers of a germ-line mutation in POLE or POLD1.. Genet Med. 2018;20:890-5", "J Burn, AM Gerdes, F Macrae, JP Mecklin, G Moeslein, S Olschwang, D Eccles, DG Evans, ER Maher, L Bertario, ML Bisgaard, MG Dunlop, JW Ho, SV Hodgson, A Lindblom, J Lubinski, PJ Morrison, V Murday, R Ramesar, L Side, RJ Scott, HJ Thomas, HF Vasen, G Barker, G Crawford, F Elliott, M Movahedi, K Pylvanainen, JT Wijnen, R Fodde, HT Lynch, JC Mathers, DT Bishop. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial.. Lancet. 2011;378:2081-7", "J Burn, H Sheth, F Elliott, L Reed, F Macrae, JP Mecklin, G Möslein, FE McRonald, L Bertario, DG Evans, AM Gerdes, JWC Ho, A Lindblom, PJ Morrison, J Rashbass, R Ramesar, T Seppälä, HJW Thomas, K Pylvänäinen, GM Borthwick, JC Mathers, DT Bishop. Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: a double-blind, randomised, placebo-controlled trial.. Lancet. 2020;395:1855-63", "LG Capelle, NC Van Grieken, HF Lingsma, EW Steyerberg, WJ Klokman, MJ Bruno, HF Vasen, EJ Kuipers. Risk and epidemiological time trends of gastric cancer in Lynch syndrome carriers in the Netherlands.. Gastroenterology. 2010;138:487-92", "C Cellier, G Perrod, C Colas, M Dhooge, JC Saurin, T Lecomte, E Coron, G Rahmi, C Savale, S Chaussade, J Bellanger, X Dray, N Benech, M Le Rhun, JP Barbieux, H Pereira, G Chatellier, E Samaha. Back-to-back comparison of colonoscopy with virtual chromoendoscopy using a third-generation narrow-band imaging system to chromoendoscopy with indigo carmine in patients with Lynch syndrome.. Am J Gastroenterol. 2019;114:1665-70", "S Chen, W Wang, S Lee, K Nafa, J Lee, K Romans, P Watson, SB Gruber, D Euhus, KW Kinzler, J Jass, S Gallinger, NM Lindor, G Casey, N Ellis, FM Giardiello, K Offit, G Parmigiani. Prediction of germline mutations and cancer risk in the Lynch syndrome.. JAMA 2006;296:1479-87", "G Cini, M Quaia, V Canzonieri, M Fornasarig, R Maestro, A Morabito, AV D'Elia, ED Urso, I Mammi, A Viel. Toward a better definition of EPCAM deletions in Lynch syndrome: report of new variants in Italy and the associated molecular phenotype.. Mol Genet Genomic Med. 2019;7", "EJ Crosbie, NAJ Ryan, RJ McVey, F Lalloo, N Bowers, K Green, ER Woodward, T Clancy, J Bolton, AJ Wallace, RF McMahon, DG Evans. Assessment of mismatch repair deficiency in ovarian cancer.. J Med Genet. 2021;58:687-91", "SG Dashti, R Chau, DA Ouakrim, DD Buchanan, M Clendenning, JP Young, IM Winship, J Arnold, DJ Ahnen, RW Haile, G Casey, S Gallinger, SN Thibodeau, NM Lindor, L Le Marchand, PA Newcomb, JD Potter, JA Baron, JL Hopper, MA Jenkins, AK Win. Female hormonal factors and the risk of endometrial cancer in Lynch syndrome.. JAMA 2015;314:61-71", "SG Dashti, WY Li, DD Buchanan, M Clendenning, C Rosty, IM Winship, FA Macrae, GG Giles, S Hardikar, X Hua, SN Thibodeau, JC Figueiredo, G Casey, RW Haile, S Gallinger, L Le Marchand, PA Newcomb, JD Potter, NM Lindor, JL Hopper, MA Jenkins, AK Win. Type 2 diabetes mellitus, blood cholesterol, triglyceride and colorectal cancer risk in Lynch syndrome.. Br J Cancer. 2019;121:869-76", "MA den Bakker, C Seynaeve, M Kliffen, WN Dinjens. Microsatellite instability in a pleomorphic rhabdomyosarcoma in a patient with hereditary non-polyposis colorectal cancer.. Histopathology. 2003;43:297-9", "M Dominguez-Valentin, JR Sampson, TT Seppälä, SW Ten Broeke, JP Plazzer, S Nakken, C Engel, S Aretz, MA Jenkins, L Sunde, I Bernstein, G Capella, F Balaguer, H Thomas, DG Evans, J Burn, M Greenblatt, E Hovig, WH de Vos Tot Nederveen Cappel, RH Sijmons, L Bertario, MG Tibiletti, GM Cavestro, A Lindblom, A Della Valle, F Lopez-Köstner, N Gluck, LH Katz, K Heinimann, CA Vaccaro, R Büttner, H Görgens, E Holinski-Feder, M Morak, S Holzapfel, R Hüneburg, MV Knebel Doeberitz, M Loeffler, N Rahner, HK Schackert, V Steinke-Lange, W Schmiegel, D Vangala, K Pylvänäinen, L Renkonen-Sinisalo, JL Hopper, AK Win, RW Haile, NM Lindor, S Gallinger, L Le Marchand, PA Newcomb, JC Figueiredo, SN Thibodeau, K Wadt, C Therkildsen, H Okkels, Z Ketabi, L Moreira, A Sánchez, M Serra-Burriel, M Pineda, M Navarro, I Blanco, K Green, F Lalloo, EJ Crosbie, J Hill, OG Denton, IM Frayling, EA Rødland, H Vasen, M Mints, F Neffa, P Esperon, K Alvarez, R Kariv, G Rosner, TA Pinero, ML Gonzalez, P Kalfayan, D Tjandra, IM Winship, F Macrae, G Möslein, JP Mecklin, M Nielsen, P Møller. Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database.. Genet Med. 2020;22:15-25", "L Dong, X Jin, W Wang. Distinct clinical phenotype and genetic testing strategy for Lynch syndrome in China based on a large colorectal cancer cohort.. Int J Cancer. 2020;146:3077-86", "JG Dowty, AK Win, DD Buchanan, NM Lindor, FA Macrae, M Clendenning, YC Antill, SN Thibodeau, G Casey, S Gallinger, LL Marchand, PA Newcomb, RW Haile, GP Young, PA James, GG Giles, SR Gunawardena, BA Leggett, M Gattas, A Boussioutas, DJ Ahnen, JA Baron, S Parry, J Goldblatt, JP Young, JL Hopper, MA Jenkins. Cancer risks for MLH1 and MSH2 mutation carriers.. Hum Mutat. 2013;34:490-7", "CA Durno, S Holter, PM Sherman, S Gallinger. The gastrointestinal phenotype of germline biallelic mismatch repair gene mutations.. Am J Gastroenterol. 2010;105:2449-56", "D Dymerska, K Gołębiewska, M Kuświk, H Rudnicka, RJ Scott, R Billings, A Pławski, P Boruń, M Siołek, B Kozak-Klonowska, M Szwiec, E Kilar, T Huzarski, T Byrski, J Lubiński, G Kurzawski. New EPCAM founder deletion in Polish population.. Clin Genet. 2017;92:649-53", "Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives.. Genet Med. 2009;11:35-41", "MM Entius, JJ Keller, P Drillenburg, KC Kuypers, FM Giardiello, GJ Offerhaus. Microsatellite instability and expression of hMLH-1 and hMSH-2 in sebaceous gland carcinomas as markers for Muir-Torre syndrome.. Clin Cancer Res 2000;6:1784-9", "JN Everett, VM Raymond, M Dandapani, M Marvin, W Kohlmann, A Chittenden, E Koeppe, SL Gustafson, T Else, DR Fullen, TM Johnson, S Syngal, SB Gruber, EM Stoffel. Screening for germline mismatch repair mutations following diagnosis of sebaceous neoplasm.. JAMA Dermatol. 2014;150:1315-21", "I Ferreira, K Wiedemeyer, P Demetter, DJ Adams, MJ Arends, T Brenn. Update on the pathology, genetics and somatic landscape of sebaceous tumours.. Histopathology. 2020;76:640-9", "FM Giardiello, JI Allen, JE Axilbund, CR Boland, CA Burke, RW Burt, JM Church, JA Dominitz, DA Johnson, T Kaltenbach, TR Levin, DA Lieberman, DJ Robertson, S Syngal, DK Rex. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-society Task Force on colorectal cancer.. Am J Gastroenterol. 2014;109:1159-79", "A Goel, TP Nguyen, HC Leung, T Nagasaka, J Rhees, E Hotchkiss, M Arnold, P Banerji, M Koi, CT Kwok, D Packham, L Lipton, CR Boland, RL Ward, MP Hitchins. De novo constitutional MLH1 epimutations confer early-onset colorectal cancer in two new sporadic Lynch syndrome cases, with derivation of the epimutation on the paternal allele in one.. Int J Cancer. 2011;128:869-78", "ML Goodenberger, BC Thomas, D Riegert-Johnson, CR Boland, SE Plon, M Clendenning, AK Win, L Senter, SM Lipkin, ZK Stadler, FA Macrae, HT Lynch, JN Weitzel, A de la Chapelle, S Syngal, P Lynch, S Parry, MA Jenkins, S Gallinger, S Holter, M Aronson, PA Newcomb, T Burnett. Le Marchan d L, Pichurin P, Hampel H, Terdiman JP, Lu KH, Thibodeau S, Lindor NM. PMS2 monoallelic mutation carriers: the known unknown.. Genet Med. 2016;18:13-9", "RC Grant, I Selander, AA Connor, S Selvarajah, A Borgida, L Briollais, GM Petersen, J Lerner-Ellis, S Holter, S Gallinger. Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer.. Gastroenterology. 2015;148:556-64", "JE Grolleman, RM de Voer, FA Elsayed, M Nielsen, RDA Weren, C Palles, MJL Ligtenberg, JR Vos, SW Ten Broeke, NFCC de Miranda, RA Kuiper, EJ Kamping, EAM Jansen, ME Vink-Börger, I Popp, A Lang, I Spier, R Hüneburg, PA James, N Li, M Staninova, H Lindsay, D Cockburn, O Spasic-Boskovic, M Clendenning, K Sweet, G Capellá, W Sjursen, H Høberg-Vetti, MC Jongmans, K Neveling, A Geurts van Kessel, H Morreau, FJ Hes, RH Sijmons, HK Schackert, C Ruiz-Ponte, D Dymerska, J Lubinski, B Rivera, WD Foulkes, IP Tomlinson, L Valle, DD Buchanan, S Kenwrick, J Adlard, AJ Dimovski, IG Campbell, S Aretz, D Schindler, T van Wezel, N Hoogerbrugge, RP Kuiper. Mutational signature analysis reveals NTHL1 deficiency to cause a multi-tumor phenotype.. Cancer Cell. 2019;35:256-66.e5", "PJ Guilford, JB Hopkins, WM Grady, SD Markowitz, J Willis, H Lynch, A Rajput, GL Wiesner, NM Lindor, LJ Burgart, TT Toro, D Lee, JM Limacher, DW Shaw, MP Findlay, AE Reeve. E-cadherin germline mutations define an inherited cancer syndrome dominated by diffuse gastric cancer.. Hum Mutat 1999;14:249-55", "S Gupta, D Provenzale, X Llor, AL Halverson, W Grady, DC Chung, S Haraldsdottir, AJ Markowitz, TP Slavin, H Hampel. CGC, Ness RM, Weiss JM, Ahnen DJ, Chen LM, Cooper G, Early DS, Giardiello FM, Hall MJ, Hamilton SR, Kanth P, Klapman JB, Lazenby AJ, Lynch PM, Mayer RJ, Mikkelson J; CGC, Peter S, Regenbogen SE, Dwyer MA; CGC, Ogba N. NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 2.2019.. J Natl Compr Canc Netw. 2019;17:1032-41", "JF Haanstra, A Al-Toma, E Dekker, SA Vanhoutvin, FM Nagengast, EM Mathus-Vliegen, ME van Leerdam. de Vos tot Nederveen Cappel WH, Sanduleanu S, Veenendaal RA, Cats A, Vasen HF, Kleibeuker JH, Koornstra JJ. Prevalence of small-bowel neoplasia in Lynch syndrome assessed by video capsule endoscopy.. Gut. 2015;64:1578-83", "S Haraldsdottir, H Hampel, L Wei, C Wu, W Frankel, T Bekaii-Saab, A de la Chapelle, RM Goldberg. Prostate cancer incidence in males with Lynch syndrome.. Genet Med. 2014;16:553-7", "S Haraldsdottir, T Rafnar, WL Frankel. Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2.. Nat Commun. 2017;8:14755", "B Heald, H Hampel, J Church, B Dudley, MJ Hall, ME Mork, A Singh, E Stoffel, J Stoll, YN You, MB Yurgelun, SS Kupfer. Collaborative Group of the Americas on Inherited Gastrointestinal Cancer Position statement on multigene panel testing for patients with colorectal cancer and/or polyposis.. Fam Cancer. 2020;19:223-39", "M Hegde, M Ferber, R Mao, W Samowitz, A Ganguly. ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis).. Genet Med. 2014;16:101-16", "MP Hitchins, RW Rapkins, CT Kwok, S Srivastava, JJ Wong, LM Khachigian, P Polly, J Goldblatt, RL Ward. Dominantly inherited constitutional epigenetic silencing of MLH1 in a cancer-affected family is linked to a single nucleotide variant within the 5'UTR.. Cancer Cell. 2011;20:200-13", "MP Hitchins. Constitutional epimutation as a mechanism for cancer causality and heritability?. Nat Rev Cancer. 2015;15:625-34", "GE Idos, AW Kurian, C Ricker, D Sturgeon, JO Culver, KE Kingham, R Koff, NM Chun, C Rowe-Teeter, AP Lebensohn, P Levonian. Multicenter prospective cohort study of the diagnostic yield and patient experience of multiplex gene panel testing for hereditary cancer risk.. JCO Precision Oncology. 2019;3:1-2", "AML Jansen, CMJ Tops, D Ruano, R van Eijk, JT Wijnen, S Ten Broeke, M Nielsen, FJ Hes, T van Wezel, H Morreau. The complexity of screening PMS2 in DNA isolated from formalin-fixed paraffin-embedded material.. Eur J Hum Genet. 2020;28:333-8", "CJ Jessup, M Redston, E Tilton, JD Reimann. Importance of universal mismatch repair protein immunohistochemistry in patients with sebaceous neoplasia as an initial screening tool for Muir-Torre syndrome.. Hum Pathol. 2016;49:1-9", "AM John, RA Schwartz. Muir-Torre syndrome (MTS): an update and approach to diagnosis and management.. J Am Acad Dermatol. 2016;74:558-66", "W Jiang, MY Cai, SY Li, JX Bei, F Wang, H Hampel, YH Ling, IM Frayling, FA Sinicrope, MA Rodriguez-Bigas, JJ Dignam, DJ Kerr, R Rosell, M Mao, JB Li, YM Guo, XY Wu, LH Kong, JH Tang, XD Wu, CF Li, JR Chen, QJ Ou, MZ Ye, FM Guo, P Han, QW Wang, DS Wan, L Li, RH Xu, ZZ Pan, PR Ding. Universal screening for Lynch syndrome in a large consecutive cohort of Chinese colorectal cancer patients: high prevalence and unique molecular features.. Int J Cancer. 2019;144:2161-8", "RM Kahn, S Gordhandas, BP Maddy, B Baltich Nelson, G Askin, PJ Christos, TA Caputo, E Chapman-Davis, K Holcomb, MK Frey. Universal endometrial cancer tumor typing: How much has immunohistochemistry, microsatellite instability, and MLH1 methylation improved the diagnosis of Lynch syndrome across the population?. Cancer. 2019;125:3172-83", "F Kastrinos, H Uno, C Ukaegbu, C Alvero, A McFarland, MB Yurgelun, MH Kulke, D Schrag, JA Meyerhardt, CS Fuchs, RJ Mayer, K Ng, EW Steyerberg, S Syngal. Development and validation of the PREMM5 model for comprehensive risk assessment of Lynch syndrome.. J Clin Oncol. 2017;35:2165-72", "BW Katona, MB Yurgelun, JE Garber, K Offit, SM Domchek, ME Robson, ZK Stadler. A counseling framework for moderate-penetrance colorectal cancer susceptibility genes.. Genet Med. 2018;20:1324-7", "MJ Kempers, RP Kuiper, CW Ockeloen, PO Chappuis, P Hutter, N Rahner, HK Schackert, V Steinke, E Holinski-Feder, M Morak, M Kloor, R Büttner, ET Verwiel, JH van Krieken, ID Nagtegaal, M Goossens, RS van der Post, RC Niessen, RH Sijmons, I Kluijt, FB Hogervorst, EM Leter, JJ Gille, CM Aalfs, EJ Redeker, FJ Hes, CM Tops, BP van Nesselrooij, ME van Gijn, EB Gómez García, DM Eccles, DJ Bunyan, S Syngal, EM Stoffel, JO Culver, MR Palomares, T Graham, L Velsher, J Papp, E Oláh, TL Chan, SY Leung, AG van Kessel, LA Kiemeney, N Hoogerbrugge, MJ Ligtenberg. Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study.. Lancet Oncol. 2011;12:49-55", "RP Kuiper, LE Vissers, R Venkatachalam, D Bodmer, E Hoenselaar, M Goossens, A Haufe, E Kamping, RC Niessen, FB Hogervorst, JJ Gille, B Redeker, CM Tops, ME van Gijn, AM van den Ouweland, N Rahner, V Steinke, P Kahl, E Holinski-Feder, M Morak, M Kloor, S Stemmler, B Betz, P Hutter, DJ Bunyan, S Syngal, JO Culver, T Graham, TL Chan, ID Nagtegaal, JH van Krieken, HK Schackert, N Hoogerbrugge, AG van Kessel, MJ Ligtenberg. Recurrence and variability of germline EPCAM deletions in Lynch syndrome.. Hum Mutat. 2011;32:407-14", "S Kumar, CM Dudzik, M Reed, JM Long, KJ Wangensteen, BW Katona. Upper endoscopy surveillance in Lynch syndrome detects gastric and duodenal adenocarcinomas.. Cancer Prev Res (Phila) 2020;13:1047-54", "U Ladabaum, G Wang, J Terdiman, A Blanco, M Kuppermann, CR Boland, J Ford, E Elkin, KA Phillips. Strategies to identify Lynch syndrome among patients with colorectal cancer: a cost-effectiveness analysis.. Ann Intern Med. 2011;155:69-79", "S Ladigan-Badura, DB Vangala, C Engel, K Bucksch, R Hueneburg, C Perne, J Nattermann, V Steinke-Lange, N Rahner, HK Schackert, J Weitz, M Kloor, J Kuhlkamp, HP Nguyen, G Moeslein, C Strassburg, M Morak, E Holinski-Feder, R Buettner, S Aretz, M Loeffler, W Schmiegel, C Pox, K Schulmann. Value of upper GI endoscopy for gastric cancer surveillance in patients with Lynch syndrome.. Int J Cancer. 2021;148:106-14", "AR Lamba, AY Moore, T Moore, J Rhees, MA Arnold, CR Boland. Defective DNA mismatch repair activity is common in sebaceous neoplasms, and may be an ineffective approach to screen for Lynch syndrome.. Fam Cancer. 2015;14:259-64", "DT Le, JN Uram, H Wang, BR Bartlett, H Kemberling, AD Eyring, AD Skora, BS Luber, NS Azad, D Laheru, B Biedrzycki, RC Donehower, A Zaheer, GA Fisher, TS Crocenzi, JJ Lee, SM Duffy, RM Goldberg, A de la Chapelle, M Koshiji, F Bhaijee, T Huebner, RH Hruban, LD Wood, N Cuka, DM Pardoll, N Papadopoulos, KW Kinzler, S Zhou, TC Cornish, JM Taube, RA Anders, JR Eshleman, B Vogelstein, LA Diaz. PD-1 blockade in tumors with mismatch-repair deficiency.. N Engl J Med. 2015;372:2509-20", "DT Le, JN Durham, KN Smith, H Wang, BR Bartlett, LK Aulakh, S Lu, H Kemberling, C Wilt, BS Luber, F Wong, NS Azad, AA Rucki, D Laheru, R Donehower, A Zaheer, GA Fisher, TS Crocenzi, JJ Lee, TF Greten, AG Duffy, KK Ciombor, AD Eyring, BH Lam, A Joe, SP Kang, M Holdhoff, L Danilova, L Cope, C Meyer, S Zhou, RM Goldberg, DK Armstrong, KM Bever, AN Fader, J Taube, F Housseau, D Spetzler, N Xiao, DM Pardoll, N Papadopoulos, KW Kinzler, JR Eshleman, B Vogelstein, RA Anders, LA Diaz. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.. Science. 2017;357:409-13", "CY Lee, HY Yen, AW Zhong, H Gao. Resolving misalignment interference for NGS-based clinical diagnostics.. Hum Genet. 2021;140:477-92", "J Li, H Dai, Y Feng, J Tang, S Chen, X Tian, E Gorman, ES Schmitt, TA Hansen, J Wang, SE Plon, VW Zhang, LJ Wong. A comprehensive strategy for accurate mutation detection of the highly homologous PMS2.. J Mol Diagn. 2015a;17:545-53", "L Li, N Hamel, K Baker, MJ McGuffin, M Couillard, A Gologan, VA Marcus, B Chodirker, A Chudley, C Stefanovici, A Durandy, RA Hegele, BJ Feng, DE Goldgar, J Zhu, M De Rosa, SB Gruber, K Wimmer, B Young, G Chong, MD Tischkowitz, WD Foulkes. A homozygous PMS2 founder mutation with an attenuated constitutional mismatch repair deficiency phenotype.. J Med Genet. 2015b;52:348-52", "S Lieberman, T Walsh, M Schechter, T Adar, E Goldin, R Beeri, N Sharon, H Baris, L Ben Avi, E Half, I Lerer, BH Shirts, CC Pritchard, I Tomlinson, MC King, E Levy-Lahad, T Peretz, Y Goldberg. Features of patients with hereditary mixed polyposis syndrome caused by duplication of GREM1 and implications for screening and surveillance.. Gastroenterology. 2017;152:1876-80.e1", "KH Lu, DS Loose, MS Yates, GM Nogueras-Gonzalez, MF Munsell, LM Chen, H Lynch, T Cornelison, S Boyd-Rogers, M Rubin, MS Daniels, P Conrad, A Milbourne, DM Gershenson, RR Broaddus. Prospective multicenter randomized intermediate biomarker study of oral contraceptive versus depo-provera for prevention of endometrial cancer in women with Lynch syndrome.. Cancer Prev Res (Phila) 2013;6:774-81", "X Ma, B Zhang, W Zheng. Genetic variants associated with colorectal cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence.. Gut. 2014;63:326-36", "P Machin, L Catasus, C Pons, J Munoz, JM Conde-Zurita, J Balmana, M Barnadas, RM Marti, J Prat, X Matias-Guiu. Microsatellite instability and immunostaining for MSH-2 and MLH-1 in cutaneous and internal tumors from patients with the Muir-Torre syndrome.. J Cutan Pathol 2002;29:415-20", "S Mange, C Bellcross, D Cragun, D Duquette, L Gorman, H Hampel, J Jasperson. Creation of a network to promote universal screening for Lynch syndrome: the Lynch syndrome screening network.. J Genet Couns. 2015;24:421-7", "L Moreira, F Balaguer, N Lindor, A de la Chapelle, H Hampel, LA Aaltonen, JL Hopper, L Le Marchand, S Gallinger, PA Newcomb, R Haile, SN Thibodeau, S Gunawardena, MA Jenkins, DD Buchanan, JD Potter, JA Baron, DJ Ahnen, V Moreno, M Andreu, M Ponz de Leon, AK Rustgi, A Castells. Identification of Lynch syndrome among patients with colorectal cancer.. JAMA 2012;308:1555-65", "P Mur, M Pineda, A Romero, J Del Valle, E Borràs, A Canal, M Navarro, J Brunet, D Rueda, Y Ramón, T Cajal, C Lázaro, T Caldés, I Blanco, JL Soto, G. Capellá. Identification of a founder EPCAM deletion in Spanish Lynch syndrome families.. Clin Genet. 2014;85:260-6", "K Newton, NM Jorgensen, AJ Wallace, DD Buchanan, F Lalloo, RF McMahon, J Hill, DG Evans. Tumour MLH1 promoter region methylation testing is an effective prescreen for Lynch Syndrome (HNPCC).. J Med Genet. 2014;51:789-96", "RC Niessen, RM Hofstra, H Westers, MJ Ligtenberg, K Kooi, PO Jager, ML de Groote, T Dijkhuizen, MJ Olderode-Berends, H Hollema, JH Kleibeuker, RH Sijmons. Germline hypermethylation of MLH1 and EPCAM deletions are a frequent cause of Lynch syndrome.. Genes Chromosomes Cancer. 2009;48:737-44", "TT Nieminen, MF O'Donohue, Y Wu, H Lohi, SW Scherer, AD Paterson, P Ellonen, WM Abdel-Rahman, S Valo, JP Mecklin, HJ Järvinen, PE Gleizes, P Peltomäki. Germline mutation of RPS20, encoding a ribosomal protein, causes predisposition to hereditary nonpolyposis colorectal carcinoma without DNA mismatch repair deficiency.. Gastroenterology. 2014;147:595-598.e5", "M Nilbert, C Therkildsen, A Nissen, M Akerman, I Bernstein. Sarcomas associated with hereditary nonpolyposis colorectal cancer: broad anatomical and morphological spectrum.. Fam Cancer. 2009;8:209-13", "A Obermair, DR Youlden, JP Young, NM Lindor, JA Baron, P Newcomb, S Parry, JL Hopper, R Haile, MA Jenkins. Risk of endometrial cancer for women diagnosed with HNPCC-related colorectal carcinoma.. Int J Cancer. 2010;127:2678-84", "A Olkinuora, TT Nieminen, E Mårtensson, A Rohlin, A Ristimäki, L Koskenvuo, A Lepistö. Gebre-Medhin S, Nordling M, Peltomäki P. Biallelic germline nonsense variant of MLH3 underlies polyposis predisposition.. Genet Med. 2019;21:1868-73", "MJ Overman, R McDermott, JL Leach, S Lonardi, HJ Lenz, MA Morse, J Desai, A Hill, M Axelson, RA Moss, MV Goldberg, ZA Cao, JM Ledeine, GA Maglinte, S Kopetz, T André. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study.. Lancet Oncol. 2017;18:1182-91", "P Peltomäki. Role of DNA mismatch repair defects in the pathogenesis of human cancer.. J Clin Oncol 2003;21:1174-9", "L Pérez-Carbonell, C Ruiz-Ponte, C Guarinos, C Alenda, A Payá, A Brea, CM Egoavil, A Castillejo, VM Barberá, X Bessa, RM Xicola, M Rodríguez-Soler, C Sánchez-Fortún, N Acame, S Castellví-Bel, V Piñol, F Balaguer, L Bujanda, ML De-Castro, X Llor, M Andreu, A Carracedo, JL Soto, A Castells, R Jover. Comparison between universal molecular screening for Lynch syndrome and revised Bethesda guidelines in a large population-based cohort of patients with colorectal cancer.. Gut. 2012;61:865-72", "M Pinheiro, I Francisco, C Pinto, A Peixoto, I Veiga, B Filipe, C Santos, S Maia, J Silva, P Pinto, R Santos, I Claro, P Lage, P Lopes, S Ferreira, I Rosa, R Fonseca, P Rodrigues, R Henrique, P Chaves, AD Pereira, C Brandão, C Albuquerque, MR Teixeira. The nonsense mutation MSH2 c.2152C>T shows a founder effect in Portuguese Lynch syndrome families.. Genes Chromosomes Cancer. 2019;58:657-64", "D Pinto, C Pinto, J Guerra, M Pinheiro, R Santos, HM Vedeld, Z Yohannes, A Peixoto, C Santos, P Pinto, P Lopes, R Lothe, GE Lind, R Henrique, MR Teixeira. Contribution of MLH1 constitutional methylation for Lynch syndrome diagnosis in patients with tumor MLH1 downregulation.. Cancer Med. 2018;7:433-44", "G Ponti, E Castellsagué, C Ruini, A Percesepe, A Tomasi. Mismatch repair genes founder mutations and cancer susceptibility in Lynch syndrome.. Clin Genet. 2015;87:507-16", "G Ponti, L Losi, M Pedroni, E Lucci-Cordisco, C Di Gregorio, G Pellancani, S. Seidenari. Value of MLH1 and MSH2 mutations in the appearance of Muir-Torre syndrome phenotype in HNPCC patients presenting sebaceous gland tumors or keratoacanthomas.. J Invest Dermatol. 2006;126:2302-7", "JM Powers, JE Ebrahimzadeh, BW Katona. Genetic testing for hereditary gastrointestinal cancer syndromes: Interpreting results in today's practice.. Curr Treat Options Gastroenterol. 2019;17:636-49", "CC Pritchard, J Mateo, MF Walsh, N De Sarkar, W Abida, H Beltran, A Garofalo, R Gulati, S Carreira, R Eeles, O Elemento, MA Rubin, D Robinson, R Lonigro, M Hussain, A Chinnaiyan, J Vinson, J Filipenko, L Garraway, ME Taplin, S AlDubayan, GC Han, M Beightol, C Morrissey, B Nghiem, HH Cheng, B Montgomery, T Walsh, S Casadei, M Berger, L Zhang, A Zehir, J Vijai, HI Scher, C Sawyers, N Schultz, PW Kantoff, D Solit, M Robson, EM Van Allen, K Offit, J de Bono, PS Nelson. Inherited DNA-repair gene mutations in men with metastatic prostate cancer.. N Engl J Med. 2016;375:443-53", "M Pritzlaff, Y Tian, P Reineke, AJ Stuenkel, K Allen, S Gutierrez, M Jackson, JS Dolinsky, H LaDuca, J Xu, MH Black, BT Helfand. Diagnosing hereditary cancer predisposition in men with prostate cancer.. Genet Med. 2020;22:1517-23", "JT Rabban, SM Calkins, AN Karnezis, JP Grenert, A Blanco, B Crawford, LM Chen. Association of tumor morphology with mismatch-repair protein status in older endometrial cancer patients: implications for universal versus selective screening strategies for Lynch syndrome.. Am J Surg Pathol. 2014;38:793-800", "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", "NC Ramchander, NAJ Ryan, TDJ Walker, L Harries, J Bolton, T Bosse, DG Evans, EJ Crosbie. Distinct immunological landscapes characterize inherited and sporadic mismatch repair deficient endometrial cancer.. Front Immunol. 2020;10:3023", "VM Raymond, JN Everett, LV Furtado, SL Gustafson, CR Jungbluth, SB Gruber, GD Hammer, EM Stoffel, JK Greenson, TJ Giordano, T Else. Adrenocortical carcinoma is a lynch syndrome-associated cancer.. J Clin Oncol. 2013;31:3012-8", "L Renkonen-Sinisalo, P Sipponen, M Aarnio, R Julkunen, LA Aaltonen, S Sarna, HJ Jarvinen, JP Mecklin. No support for endoscopic surveillance for gastric cancer in hereditary non-polyposis colorectal cancer.. Scand J Gastroenterol 2002;37:574-7", "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", "L Rivero-Sánchez, C Arnau-Collell, J Herrero, D Remedios, J Cubiella, M García-Cougil, V Alvarez, E Albéniz, P Calvo, J Gordillo, I Puig, J López-Vicente, A Huerta, M López-Cerón, I Salces, B Peñas, S Parejo, E Rodriguez de Santiago, M Herraiz, C Carretero, AZ Gimeno-Garcia, E Saperas, C Alvarez-Urturi, R Moreira, C Rodriguez de Miguel, T Ocaña, L Moreira, S Carballal, A Sánchez, G Jung, A Castells, J Llach, F Balaguer, M Pellisé. White-light endoscopy is adequate for Lynch syndrome surveillance in a randomized and noninferiority study.. Gastroenterology. 2020;158:895-904.e1", "MA Rodriguez-Bigas, HF Vasen, HT Lynch, P Watson, T Myrhoj, HJ Jarvinen, JP Mecklin, F Macrae, DJ St John, L Bertario, P Fidalgo, L Madlensky, P Rozen. Characteristics of small bowel carcinoma in hereditary nonpolyposis colorectal carcinoma. International Collaborative Group on HNPCC.. Cancer 1998;83:240-4", "BM Rossi, EI Palmero, F López-Kostner, C Sarroca, CA Vaccaro, F Spirandelli, P Ashton-Prolla, Y Rodriguez, H de Campos Reis Galvão, RM Reis, A Escremim de Paula, LG Capochin Romagnolo, K Alvarez, A Della Valle, F Neffa, PG Kalfayan, E Spirandelli, S Chialina, M Gutiérrez Angulo, MDC Castro-Mujica, J Sanchez de Monte, R Quispe, SD da Silva, NT Rossi, C Barletta-Carrillo, S Revollo, X Taborga, LL Morillas, H Tubeuf, EM Monteiro-Santos, TA Piñero, C Dominguez-Barrera, P Wernhoff, A Martins, E Hovig, P Møller, M Dominguez-Valentin. A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America.. BMC Cancer. 2017;17:623", "EE Salo-Mullen, EM O'Reilly, DP Kelsen, AM Ashraf, MA Lowery, KH Yu, DL Reidy, AS Epstein, A Lincoln, A Saldia, LM Jacobs, R Rau-Murthy, L Zhang, RC Kurtz, L Saltz, K Offit, ME Robson, ZK Stadler. Identification of germline genetic mutations in patients with pancreatic cancer.. Cancer. 2015;121:4382-8", "MU Salvador, MRF Truelson, C Mason, B Souders, H LaDuca, B Dougall, MH Black, K Fulk, J Profato, S Gutierrez, K Jasperson, B Tippin-Davis, HM Lu, P Gray, S Shah, EC Chao, N Ghahramani, M Landsverk, CL Gau, D Chen, M Pronold. Comprehensive paired tumor/germline testing for Lynch syndrome: bringing resolution to the diagnostic process.. J Clin Oncol. 2019;37:647-57", "K Schulmann, FE Brasch, E Kunstmann, C Engel, C Pagenstecher, H Vogelsang, S Kruger, T Vogel, HP Knaebel, J Ruschoff, SA Hahn, MV Knebel-Doeberitz, G Moeslein, SJ Meltzer, HK Schackert, C Tympner, E Mangold, W Schmiegel. HNPCC-associated small bowel cancer: clinical and molecular characteristics.. Gastroenterology 2005;128:590-9", "RL Siegel, KD Miller, A Jemal. Cancer statistics, 2020.. CA Cancer J Clin. 2020;70:7-30", "R Sijmons, R Hofstra, H Hollema, R Mensink, A van der Hout, H Hoekstra, J Kleibeuker, W Molenaar, J Wijnen, R Fodde, H Vasen, C Buys. Inclusion of malignant fibrous histiocytoma in the tumour spectrum associated with hereditary non-polyposis colorectal cancer.. Genes Chromosomes Cancer. 2000;29:353-5", "MJ Smith, JE Urquhart, EF Harkness, EK Miles, NL Bowers, HJ Byers, M Bulman, C Gokhale, AJ Wallace, WG Newman, DG Evans. The contribution of whole gene deletions and large rearrangements to the mutation spectrum in inherited tumor predisposing syndromes.. Hum Mutat. 2016;37:250-6", "CD South, H Hampel, I Comeras, JA Westman, WL Frankel, A de la Chapelle. The frequency of Muir-Torre syndrome among Lynch syndrome families.. J Natl Cancer Inst. 2008;100:277-81", "G Sroczynski, A Gogollari, A Conrads-Frank, LR Hallsson, N Pashayan, M Widschwendter, U Siebert. Cost-effectiveness of early detection and prevention strategies for endometrial cancer-a systematic review.. Cancers (Basel) 2020;12:1874", "M Suerink, K Wimmer, L Brugieres, C Colas, R Gallon, T Ripperger, PR Benusiglio, EMA Bleiker, Z Ghorbanoghli, Y Goldberg, JCH Hardwick, M Kloor, M le Mentec, M Muleris, M Pineda, C Ruiz-Ponte, HFA Vasen. Report of the fifth meeting of the European Consortium 'Care for CMMRD' (C4CMMRD), Leiden, The Netherlands, July 6th 2019.. Fam Cancer. 2021;20:67-73", "S Takeuchi, M Doi, N Ikari, M Yamamoto, T. Furukawa. Mutations in BRCA1, BRCA2, and PALB2, and a panel of 50 cancer-associated genes in pancreatic ductal adenocarcinoma.. Sci Rep. 2018;8:8105", "C Therkildsen, S Ladelund, E Rambech, A Persson, A Petersen, M Nilbert. Glioblastomas, astrocytomas and oligodendrogliomas linked to Lynch syndrome.. Eur J Neurol. 2015;22:717-24", "J Tomsic, L Senter, S Liyanarachchi, M Clendenning, CP Vaughn, MA Jenkins, JL Hopper, J Young, W Samowitz, A de la Chapelle. Recurrent and founder mutations in the PMS2 gene.. Clin Genet. 2013;83:238-43", "K Tutlewska, J Lubinski, G Kurzawski. Germlie deletions in the EPCAM gene as a cause of Lynch syndrome.. Hered Cancer Clin Pract. 2013;11:9", "HM van der Klift, CM Tops, EC Bik, MW Boogaard, AM Borgstein, KB Hansson, MG Ausems, E Gomez Garcia, A Green, FJ Hes, L Izatt, LP van Hest, AM Alonso, AH Vriends, A Wagner, WA van Zelst-Stams, HF Vasen, H Morreau, P Devilee, JT Wijnen. Quantification of sequence exchange events between PMS2 and PMS2CL provides a basis for improved mutation scanning of Lynch syndrome patients.. Hum Mutat. 2010;31:578-87", "HM van der Klift, AR Mensenkamp, M Drost, EC Bik, YJ Vos, HJ Gille, BE Redeker, Y Tiersma, JB Zonneveld, EG García, TG Letteboer, MJ Olderode-Berends, LP van Hest, TA van Os, S Verhoef, A Wagner, CJ van Asperen, SW Ten Broeke, FJ Hes, N de Wind, M Nielsen, P Devilee, MJ Ligtenberg, JT Wijnen, CM Tops. Comprehensive mutation analysis of PMS2 in a large cohort of probands suspected of Lynch syndrome or constitutional mismatch repair deficiency syndrome.. Hum Mutat. 2016;37:1162-79", "HF Vasen, I Blanco, K Aktan-Collan, JP Gopie, A Alonso, S Aretz, I Bernstein, L Bertario, J Burn, G Capella, C Colas, C Engel, IM Frayling, M Genuardi, K Heinimann, FJ Hes, SV Hodgson, JA Karagiannis, F Lalloo, A Lindblom, JP Mecklin, P Møller, T Myrhoj, FM Nagengast, Y Parc, M Ponz de Leon, L Renkonen-Sinisalo, JR Sampson, A Stormorken, RH Sijmons, S Tejpar, HJ Thomas, N Rahner, JT Wijnen, HJ Järvinen, G Möslein. Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts.. Gut. 2013;62:812-23", "CP Vaughn, J Robles, JJ Swensen, CE Miller, E Lyon, R Mao, P Bayrak-Toydemir, WS Samowitz. Clinical analysis of PMS2: mutation detection and avoidance of pseudogenes.. Hum Mutat. 2010;31:588-93", "P Watson, R Butzow, HT Lynch, JP Mecklin, HJ Jarvinen, HF Vasen, L Madlensky, P Fidalgo, I Bernstein. The clinical features of ovarian cancer in hereditary nonpolyposis colorectal cancer.. Gynecol Oncol 2001;82:223-8", "K Wimmer, J Etzler. Constitutional mismatch repair-deficiency syndrome: have we so far seen only the tip of an iceberg?. Hum Genet. 2008;124:105-22", "K Wimmer, CP Kratz, HF Vasen, O Caron, C Colas, N Entz-Werle, AM Gerdes, Y Goldberg, D Ilencikova, M Muleris, A Duval, N Lavoine, C Ruiz-Ponte, I Slavc, B Burkhardt, L Brugieres. Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium 'care for CMMRD' (C4CMMRD).. J Med Genet. 2014;51:355-65", "AK Win, MA Jenkins, DD Buchanan, M Clendenning, JP Young, GG Giles, J Goldblatt, BA Leggett, JL Hopper, SN Thibodeau, NM Lindor. Determining the frequency of de novo germline mutations in DNA mismatch repair genes.. J Med Genet. 2011;48:530-4", "AK Win, MA Jenkins, JG Dowty, AC Antoniou, A Lee, GG Giles, DD Buchanan, M Clendenning, C Rosty, DJ Ahnen, SN Thibodeau, G Casey, S Gallinger, L Le Marchand, RW Haile, JD Potter, Y Zheng, NM Lindor, PA Newcomb, JL Hopper, RJ MacInnis. Prevalence and penetrance of major genes and polygenes for colorectal cancer.. Cancer Epidemiol Biomarkers Prev. 2017;26:404-12", "AK Win, NM Lindor, MA Jenkins. Risk of breast cancer in Lynch syndrome: a systematic review.. Breast Cancer Research. 2013;15:R27", "MB Yurgelun, AB Chittenden, V Morales-Oyarvide, DA Rubinson, RF Dunne, MM Kozak, ZR Qian, MW Welch, LK Brais, A Da Silva, JL Bui, C Yuan, T Li, W Li, A Masuda, M Gu, AJ Bullock, DT Chang, TE Clancy, DC Linehan, JJ Findeis-Hosey, LA Doyle, AR Thorner, MD Ducar, BM Wollison, N Khalaf, K Perez, S Syngal, AJ Aguirre, WC Hahn, ML Meyerson, CS Fuchs, S Ogino, JL Hornick, AF Hezel, AC Koong, JA Nowak, BM Wolpin. Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer.. Genet Med. 2019;21:213-23", "MB Yurgelun, MH Kulke, CS Fuchs, BA Allen, H Uno, JL Hornick, CI Ukaegbu, LK Brais, PG McNamara, RJ Mayer, D Schrag, JA Meyerhardt, K Ng, J Kidd, N Singh, AR Hartman, RJ Wenstrup, S Syngal. Cancer susceptibility gene mutations in individuals with colorectal cancer.. J Clin Oncol 2017;35:1086-95" ]	5/2/2004	4/2/2021	12/4/2018	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
hnpp	hnpp	[ "HNPP", "HNPP", "Peripheral myelin protein 22", "PMP22", "Hereditary Neuropathy with Liability to Pressure Palsies" ]	Hereditary Neuropathy with Liability to Pressure Palsies	Nicolas Chrestian	Summary Hereditary neuropathy with liability to pressure palsies (HNPP) is characterized by recurrent acute sensory and motor neuropathy in a single or multiple nerves. The most common initial manifestation is the acute onset of a non-painful focal sensory and motor neuropathy in a single nerve (mononeuropathy). The first attack usually occurs in the second or third decade but earlier onset is possible. Neuropathic pain is increasingly recognized as a common manifestation. Recovery from acute neuropathy is usually complete; when recovery is not complete, the resulting disability is mild. Some affected individuals also demonstrate a mild-to-moderate peripheral neuropathy. The diagnosis of HNPP is established in a proband with suggestive clinical and electrophysiologic findings and either the 1.5-Mb recurrent deletion or a novel deletion involving HNPP is inherited in an autosomal dominant manner. Approximately 20% of individuals with HNPP have the disorder as the result of a	## Diagnosis Hereditary neuropathy with liability to pressure palsies (HNPP) Recurrent acute focal sensory and motor neuropathies mainly at entrapment sites Painless nerve palsy after minor trauma or compression Evidence on physical examination of previous nerve palsy such as focal weakness, atrophy, or sensory loss Complete spontaneous recovery from neuropathies (in 50% of occurrences) within weeks Mild-to-moderate Prolongation of distal nerve conduction latencies (e.g., of the median nerve at the wrist and of common peroneal nerve at fibular head) is observed in most individuals, whether symptomatic or asymptomatic. Electrophysiologic criteria to consider in the diagnosis of HNPP include bilateral increase in median nerve motor and distal sensory latencies with at least one additional abnormal motor conduction finding in one peroneal nerve (89%) [ Absent or reduced sural responses are observed in one third of affected individuals [ Nerve conduction velocity may be delayed at the site of compression even with conduction block [ Ultrasonography shows multifocal increase in nerve cross-sectional area at and outside entrapment sites [ MRI may show increased nerve caliber and asymmetric swelling and hyperintensities of fascicules at entrapment sites [ The diagnosis of HNPP 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 single-gene testing and a multigene panel or comprehensive genomic testing. Individuals with the distinctive findings described in Sequence analysis of For an introduction to multigene panels click 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 HNPP See See Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click • Recurrent acute focal sensory and motor neuropathies mainly at entrapment sites • Painless nerve palsy after minor trauma or compression • Evidence on physical examination of previous nerve palsy such as focal weakness, atrophy, or sensory loss • Complete spontaneous recovery from neuropathies (in 50% of occurrences) within weeks • Mild-to-moderate • Prolongation of distal nerve conduction latencies (e.g., of the median nerve at the wrist and of common peroneal nerve at fibular head) is observed in most individuals, whether symptomatic or asymptomatic. • Electrophysiologic criteria to consider in the diagnosis of HNPP include bilateral increase in median nerve motor and distal sensory latencies with at least one additional abnormal motor conduction finding in one peroneal nerve (89%) [ • Absent or reduced sural responses are observed in one third of affected individuals [ • Nerve conduction velocity may be delayed at the site of compression even with conduction block [ • Ultrasonography shows multifocal increase in nerve cross-sectional area at and outside entrapment sites [ • MRI may show increased nerve caliber and asymmetric swelling and hyperintensities of fascicules at entrapment sites [ ## Suggestive Findings Hereditary neuropathy with liability to pressure palsies (HNPP) Recurrent acute focal sensory and motor neuropathies mainly at entrapment sites Painless nerve palsy after minor trauma or compression Evidence on physical examination of previous nerve palsy such as focal weakness, atrophy, or sensory loss Complete spontaneous recovery from neuropathies (in 50% of occurrences) within weeks Mild-to-moderate Prolongation of distal nerve conduction latencies (e.g., of the median nerve at the wrist and of common peroneal nerve at fibular head) is observed in most individuals, whether symptomatic or asymptomatic. Electrophysiologic criteria to consider in the diagnosis of HNPP include bilateral increase in median nerve motor and distal sensory latencies with at least one additional abnormal motor conduction finding in one peroneal nerve (89%) [ Absent or reduced sural responses are observed in one third of affected individuals [ Nerve conduction velocity may be delayed at the site of compression even with conduction block [ Ultrasonography shows multifocal increase in nerve cross-sectional area at and outside entrapment sites [ MRI may show increased nerve caliber and asymmetric swelling and hyperintensities of fascicules at entrapment sites [ • Recurrent acute focal sensory and motor neuropathies mainly at entrapment sites • Painless nerve palsy after minor trauma or compression • Evidence on physical examination of previous nerve palsy such as focal weakness, atrophy, or sensory loss • Complete spontaneous recovery from neuropathies (in 50% of occurrences) within weeks • Mild-to-moderate • Prolongation of distal nerve conduction latencies (e.g., of the median nerve at the wrist and of common peroneal nerve at fibular head) is observed in most individuals, whether symptomatic or asymptomatic. • Electrophysiologic criteria to consider in the diagnosis of HNPP include bilateral increase in median nerve motor and distal sensory latencies with at least one additional abnormal motor conduction finding in one peroneal nerve (89%) [ • Absent or reduced sural responses are observed in one third of affected individuals [ • Nerve conduction velocity may be delayed at the site of compression even with conduction block [ • Ultrasonography shows multifocal increase in nerve cross-sectional area at and outside entrapment sites [ • MRI may show increased nerve caliber and asymmetric swelling and hyperintensities of fascicules at entrapment sites [ ## Establishing the Diagnosis The diagnosis of HNPP 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 single-gene testing and a multigene panel or comprehensive genomic testing. Individuals with the distinctive findings described in Sequence analysis of For an introduction to multigene panels click 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 HNPP See See Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click ## Option 1 Sequence analysis of ## Option 2 For an introduction to multigene panels click 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 HNPP See See Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click ## Clinical Characteristics Hereditary neuropathy with liability to pressure palsies (HNPP) is characterized by recurrent acute sensory and motor neuropathy in a single or multiple nerves. The most common initial manifestation is the acute onset of a non-painful focal sensory and motor neuropathy in a single nerve (mononeuropathy) [ The first attack generally occurs in the second or third decade (age range: 2-70 years; mean 37 years) but could be at any age. With the widespread availability of molecular genetic testing, reports of early onset have become increasingly common [ While the nerve palsies often recur over a period of many years, some individuals have a single episode and some individuals with molecularly confirmed HNPP remain asymptomatic. Even within the same family extreme variability is seen. Nerve palsies and electrophysiologic abnormalities are more frequent in men than women [ The most common sites of focal neuropathy (in decreasing order of frequency) are the following: Peroneal nerve at the fibular head causing foot drop Ulnar nerve at the elbow, causing hypothenar and interossei muscle weakness and atrophy with sensory loss over the lateral aspect of the hand Median nerve at the wrist causing carpal tunnel syndrome with thenar muscle weakness and atrophy and sensory loss over the thumb and index finger [ Brachial plexus and radial nerve, causing transient sensory symptoms and hand pain [ Involvement of other less commonly affected nerves includes the following: Motor brachial plexopathy [ Hypoglossal nerve paralysis affecting the tongue, including after carotid endarterectomy [ Scapuloperoneal syndrome [ Sciatic neuropathy [ Laryngeal and phrenic nerve involvement [ Facial nerve involvement [ Pain is increasingly recognized as a common manifestation. In one study, 74% individuals had persistent pain lasting more than a week; of these, three quarters developed neuropathic pain and almost 90% were likely to have central sensitization (i.e., development and maintenance of chronic pain) [ Other manifestations can include: Rapid onset and progression of neuropathy early in military physical training [ Multifocal presentation Progressive muscular atrophy [ Charcot-Marie-Tooth hereditary neuropathy-like pattern [ Chronic inflammatory demyelinating polyneuropathy-like disorders [ Central nervous system white matter lesions compatible with demyelination (usually asymptomatic) [ More than 26 single Of note, six families with the Penetrance is 100% but expressivity is highly variable even within the same family. For an unknown reason men typically have more severe clinical nerve palsies and electrophysiologic studies. Hereditary neuropathy with liability to pressure palsies was previously referred to as hereditary pressure-sensitive neuropathy, tomaculous neuropathy,* recurrent pressure-sensitive neuropathy, and "tulip-bulb digger's palsy" or "potato-grubbing palsy" [ * Sural nerve biopsy often shows evidence of demyelination and "tomaculous" change (focal, sausage-like enlargement of the nerve), a nonspecific finding noted occasionally in other neuropathies. The prevalence of HNPP is unknown; it is estimated at 7:100,000-16:100,000 population. The actual prevalence may be higher because of under-diagnosis. The types of pathogenic variants and phenotypic spectrum are quite homogenous across different populations [ • Peroneal nerve at the fibular head causing foot drop • Ulnar nerve at the elbow, causing hypothenar and interossei muscle weakness and atrophy with sensory loss over the lateral aspect of the hand • Median nerve at the wrist causing carpal tunnel syndrome with thenar muscle weakness and atrophy and sensory loss over the thumb and index finger [ • Brachial plexus and radial nerve, causing transient sensory symptoms and hand pain [ • Motor brachial plexopathy [ • Hypoglossal nerve paralysis affecting the tongue, including after carotid endarterectomy [ • Scapuloperoneal syndrome [ • Sciatic neuropathy [ • Laryngeal and phrenic nerve involvement [ • Facial nerve involvement [ • Rapid onset and progression of neuropathy early in military physical training [ • Multifocal presentation • Progressive muscular atrophy [ • Charcot-Marie-Tooth hereditary neuropathy-like pattern [ • Progressive muscular atrophy [ • Charcot-Marie-Tooth hereditary neuropathy-like pattern [ • Chronic inflammatory demyelinating polyneuropathy-like disorders [ • Central nervous system white matter lesions compatible with demyelination (usually asymptomatic) [ • Progressive muscular atrophy [ • Charcot-Marie-Tooth hereditary neuropathy-like pattern [ ## Clinical Description Hereditary neuropathy with liability to pressure palsies (HNPP) is characterized by recurrent acute sensory and motor neuropathy in a single or multiple nerves. The most common initial manifestation is the acute onset of a non-painful focal sensory and motor neuropathy in a single nerve (mononeuropathy) [ The first attack generally occurs in the second or third decade (age range: 2-70 years; mean 37 years) but could be at any age. With the widespread availability of molecular genetic testing, reports of early onset have become increasingly common [ While the nerve palsies often recur over a period of many years, some individuals have a single episode and some individuals with molecularly confirmed HNPP remain asymptomatic. Even within the same family extreme variability is seen. Nerve palsies and electrophysiologic abnormalities are more frequent in men than women [ The most common sites of focal neuropathy (in decreasing order of frequency) are the following: Peroneal nerve at the fibular head causing foot drop Ulnar nerve at the elbow, causing hypothenar and interossei muscle weakness and atrophy with sensory loss over the lateral aspect of the hand Median nerve at the wrist causing carpal tunnel syndrome with thenar muscle weakness and atrophy and sensory loss over the thumb and index finger [ Brachial plexus and radial nerve, causing transient sensory symptoms and hand pain [ Involvement of other less commonly affected nerves includes the following: Motor brachial plexopathy [ Hypoglossal nerve paralysis affecting the tongue, including after carotid endarterectomy [ Scapuloperoneal syndrome [ Sciatic neuropathy [ Laryngeal and phrenic nerve involvement [ Facial nerve involvement [ Pain is increasingly recognized as a common manifestation. In one study, 74% individuals had persistent pain lasting more than a week; of these, three quarters developed neuropathic pain and almost 90% were likely to have central sensitization (i.e., development and maintenance of chronic pain) [ Other manifestations can include: Rapid onset and progression of neuropathy early in military physical training [ Multifocal presentation Progressive muscular atrophy [ Charcot-Marie-Tooth hereditary neuropathy-like pattern [ Chronic inflammatory demyelinating polyneuropathy-like disorders [ Central nervous system white matter lesions compatible with demyelination (usually asymptomatic) [ • Peroneal nerve at the fibular head causing foot drop • Ulnar nerve at the elbow, causing hypothenar and interossei muscle weakness and atrophy with sensory loss over the lateral aspect of the hand • Median nerve at the wrist causing carpal tunnel syndrome with thenar muscle weakness and atrophy and sensory loss over the thumb and index finger [ • Brachial plexus and radial nerve, causing transient sensory symptoms and hand pain [ • Motor brachial plexopathy [ • Hypoglossal nerve paralysis affecting the tongue, including after carotid endarterectomy [ • Scapuloperoneal syndrome [ • Sciatic neuropathy [ • Laryngeal and phrenic nerve involvement [ • Facial nerve involvement [ • Rapid onset and progression of neuropathy early in military physical training [ • Multifocal presentation • Progressive muscular atrophy [ • Charcot-Marie-Tooth hereditary neuropathy-like pattern [ • Progressive muscular atrophy [ • Charcot-Marie-Tooth hereditary neuropathy-like pattern [ • Chronic inflammatory demyelinating polyneuropathy-like disorders [ • Central nervous system white matter lesions compatible with demyelination (usually asymptomatic) [ • Progressive muscular atrophy [ • Charcot-Marie-Tooth hereditary neuropathy-like pattern [ ## Genotype-Phenotype Correlations More than 26 single Of note, six families with the ## Penetrance Penetrance is 100% but expressivity is highly variable even within the same family. For an unknown reason men typically have more severe clinical nerve palsies and electrophysiologic studies. ## Nomenclature Hereditary neuropathy with liability to pressure palsies was previously referred to as hereditary pressure-sensitive neuropathy, tomaculous neuropathy,* recurrent pressure-sensitive neuropathy, and "tulip-bulb digger's palsy" or "potato-grubbing palsy" [ * Sural nerve biopsy often shows evidence of demyelination and "tomaculous" change (focal, sausage-like enlargement of the nerve), a nonspecific finding noted occasionally in other neuropathies. ## Prevalence The prevalence of HNPP is unknown; it is estimated at 7:100,000-16:100,000 population. The actual prevalence may be higher because of under-diagnosis. The types of pathogenic variants and phenotypic spectrum are quite homogenous across different populations [ ## Genetically Related (Allelic) Disorders The other phenotypes associated with heterozygous pathogenic variants in A severe CMT phenotype was reported in two children who were compound heterozygotes for two different ## Differential Diagnosis The signs and symptoms of compression neuropathy in hereditary neuropathy with liability to pressure palsies (HNPP) are the same as those of the acquired type. Thus, HNPP is part of the broad differential diagnosis of both compression neuropathies and general peripheral neuropathies, including the hereditary neuropathies and Charcot-Marie-Tooth (CMT) syndrome (see * HNPP is not a common cause of isolated idiopathic carpal tunnel syndrome [ ## Acquired Disorders * HNPP is not a common cause of isolated idiopathic carpal tunnel syndrome [ ## Hereditary Disorders ## Management To establish the extent of disease and needs in an individual diagnosed with hereditary neuropathy with liability to pressure palsies (HNPP), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with HNPP Extent of weakness & atrophy, If there are assoc manifestations (e.g., focal atrophy or sensory loss in less common sites of entrapment) If affected person &/or a family member has had episodes of acute transient nerve palsy Gross motor & fine motor skills & need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Feet for evidence of Mobility, ADL, & need for adaptive devices Need for handicapped parking Community resources & Social work involvement for parental support. ADL = activities of daily living; AFO = ankle-foot orthosis; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Medical geneticist, certified genetic counselor, or certified advanced genetic nurse No specific treatment for the underlying genetic or biochemical defect exists, and no special diet or vitamin regimen is known to alter the natural course of HNPP. Treatment is symptomatic and involves the following. Occupational therapy and physical therapy may be needed to address issues with fine motor and gross motor skills, including activities of daily living. Transient bracing, such as with a wrist splint or ankle-foot orthosis (AFO), may be useful. Special shoes, including those with good ankle support, may be needed. Some individuals with residual foot drop may permanently use an AFO. Protective pads at elbows or knees may prevent pressure and trauma to local nerves. Recommended Surveillance for Individuals with HNPP ADL = activities of daily living; OT = occupational therapy; PT = physical therapy Activities that are risk factors for pressure palsies include the following [ Prolonged sitting with legs crossed Prolonged leaning on elbows Occupations requiring repetitive movements of the wrist Rapid weight loss Wearing a heavy backpack on shoulders Particular care must be taken in positioning during surgery (particularly knee surgery) to avoid nerve compression [ Vincristine, commonly used in the chemotherapy of lymphoma, has been reported to exacerbate HNPP, as other potential neurotoxic chemotherapy or agents [ Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association Asymptomatic relatives at risk may wish to clarify their genetic status by undergoing molecular genetic testing for the See Search • Extent of weakness & atrophy, • If there are assoc manifestations (e.g., focal atrophy or sensory loss in less common sites of entrapment) • If affected person &/or a family member has had episodes of acute transient nerve palsy • Gross motor & fine motor skills & need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Feet for evidence of • Mobility, ADL, & need for adaptive devices • Need for handicapped parking • Community resources & • Social work involvement for parental support. • Occupational therapy and physical therapy may be needed to address issues with fine motor and gross motor skills, including activities of daily living. • Transient bracing, such as with a wrist splint or ankle-foot orthosis (AFO), may be useful. Special shoes, including those with good ankle support, may be needed. • Some individuals with residual foot drop may permanently use an AFO. • Protective pads at elbows or knees may prevent pressure and trauma to local nerves. • Prolonged sitting with legs crossed • Prolonged leaning on elbows • Occupations requiring repetitive movements of the wrist • Rapid weight loss • Wearing a heavy backpack on shoulders ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with hereditary neuropathy with liability to pressure palsies (HNPP), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with HNPP Extent of weakness & atrophy, If there are assoc manifestations (e.g., focal atrophy or sensory loss in less common sites of entrapment) If affected person &/or a family member has had episodes of acute transient nerve palsy Gross motor & fine motor skills & need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Feet for evidence of Mobility, ADL, & need for adaptive devices Need for handicapped parking Community resources & Social work involvement for parental support. ADL = activities of daily living; AFO = ankle-foot orthosis; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Medical geneticist, certified genetic counselor, or certified advanced genetic nurse • Extent of weakness & atrophy, • If there are assoc manifestations (e.g., focal atrophy or sensory loss in less common sites of entrapment) • If affected person &/or a family member has had episodes of acute transient nerve palsy • Gross motor & fine motor skills & need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Feet for evidence of • Mobility, ADL, & need for adaptive devices • Need for handicapped parking • Community resources & • Social work involvement for parental support. ## Treatment of Manifestations No specific treatment for the underlying genetic or biochemical defect exists, and no special diet or vitamin regimen is known to alter the natural course of HNPP. Treatment is symptomatic and involves the following. Occupational therapy and physical therapy may be needed to address issues with fine motor and gross motor skills, including activities of daily living. Transient bracing, such as with a wrist splint or ankle-foot orthosis (AFO), may be useful. Special shoes, including those with good ankle support, may be needed. Some individuals with residual foot drop may permanently use an AFO. Protective pads at elbows or knees may prevent pressure and trauma to local nerves. • Occupational therapy and physical therapy may be needed to address issues with fine motor and gross motor skills, including activities of daily living. • Transient bracing, such as with a wrist splint or ankle-foot orthosis (AFO), may be useful. Special shoes, including those with good ankle support, may be needed. • Some individuals with residual foot drop may permanently use an AFO. • Protective pads at elbows or knees may prevent pressure and trauma to local nerves. ## Surveillance Recommended Surveillance for Individuals with HNPP ADL = activities of daily living; OT = occupational therapy; PT = physical therapy ## Agents/Circumstances to Avoid Activities that are risk factors for pressure palsies include the following [ Prolonged sitting with legs crossed Prolonged leaning on elbows Occupations requiring repetitive movements of the wrist Rapid weight loss Wearing a heavy backpack on shoulders Particular care must be taken in positioning during surgery (particularly knee surgery) to avoid nerve compression [ Vincristine, commonly used in the chemotherapy of lymphoma, has been reported to exacerbate HNPP, as other potential neurotoxic chemotherapy or agents [ Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association • Prolonged sitting with legs crossed • Prolonged leaning on elbows • Occupations requiring repetitive movements of the wrist • Rapid weight loss • Wearing a heavy backpack on shoulders ## Evaluation of Relatives at Risk Asymptomatic relatives at risk may wish to clarify their genetic status by undergoing molecular genetic testing for the See ## Therapies Under Investigation Search ## Genetic Counseling Hereditary neuropathy with liability to pressure palsies (HNPP) is inherited in an autosomal dominant manner. Approximately 6% to 23% of individuals diagnosed with HNPP have an asymptomatic affected parent [ Approximately 20% of individuals diagnosed with HNPP 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 * Misattributed parentage can also be explored as an alternative explanation for an apparent 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%; however, intrafamilial variability is considerable [ If the proband has a known HNPP-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, Predictive testing for at-risk relatives is possible once the HNPP-related pathogenic variant has been identified in an affected family member. Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. For more information, see the National Society of Genetic Counselors In a family with an established diagnosis of HNPP, it is appropriate to consider testing of symptomatic individuals regardless of age. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • Approximately 6% to 23% of individuals diagnosed with HNPP have an asymptomatic affected parent [ • Approximately 20% of individuals diagnosed with HNPP 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 • * Misattributed parentage can also be explored as an alternative explanation for an apparent • 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%; however, intrafamilial variability is considerable [ • If the proband has a known HNPP-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 • Predictive testing for at-risk relatives is possible once the HNPP-related pathogenic variant has been identified in an affected family member. • Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. • For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. • For more information, see the National Society of Genetic Counselors • 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 Hereditary neuropathy with liability to pressure palsies (HNPP) is inherited in an autosomal dominant manner. ## Risk to Family Members Approximately 6% to 23% of individuals diagnosed with HNPP have an asymptomatic affected parent [ Approximately 20% of individuals diagnosed with HNPP 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 * Misattributed parentage can also be explored as an alternative explanation for an apparent 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%; however, intrafamilial variability is considerable [ If the proband has a known HNPP-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 • Approximately 6% to 23% of individuals diagnosed with HNPP have an asymptomatic affected parent [ • Approximately 20% of individuals diagnosed with HNPP 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 • * Misattributed parentage can also be explored as an alternative explanation for an apparent • 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%; however, intrafamilial variability is considerable [ • If the proband has a known HNPP-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, Predictive testing for at-risk relatives is possible once the HNPP-related pathogenic variant has been identified in an affected family member. Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. For more information, see the National Society of Genetic Counselors In a family with an established diagnosis of HNPP, it is appropriate to consider testing of symptomatic individuals regardless of age. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. 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 HNPP-related pathogenic variant has been identified in an affected family member. • Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. • For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. • For more information, see the National Society of Genetic Counselors • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources Department of Molecular Genetics University of Antwerp Antwerp Antwerpen B-2610 Belgium • • • • • • • • Department of Molecular Genetics • University of Antwerp • Antwerp Antwerpen B-2610 • Belgium ## Molecular Genetics Hereditary Neuropathy with Liability to Pressure Palsies: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Hereditary Neuropathy with Liability to Pressure Palsies ( HNPP is associated with decreased mRNA message for The HNPP recurrent 1.5-Mb deletion is a submicroscopic DNA rearrangement. Although many genes are deleted, only Notable Variants listed in the table have been provided by the author. Associated with painful neuropathy without recurrent nerve palsies in one family [ Reported as a benign polymorphism, as an autosomal recessive inherited variant, or as an autosomal dominant variant with the HNPP phenotype. Detailed in National Center for Biotechnology Information, ClinVar ( ## Molecular Pathogenesis HNPP is associated with decreased mRNA message for The HNPP recurrent 1.5-Mb deletion is a submicroscopic DNA rearrangement. Although many genes are deleted, only Notable Variants listed in the table have been provided by the author. Associated with painful neuropathy without recurrent nerve palsies in one family [ Reported as a benign polymorphism, as an autosomal recessive inherited variant, or as an autosomal dominant variant with the HNPP phenotype. Detailed in National Center for Biotechnology Information, ClinVar ( ## Chapter Notes Dr Nicolas Chrestian is a pediatric neurologist specializing in neuromuscular disorders and neurogenetics. He is currently chief of service at Centre mère-enfant CHU de Québec in Quebec City, as well as professor clinician at Laval University. He has an interest in rare neuromuscular disorders including spastic paraparesis, congenital myopathies, and hereditary neuropathies. Nicolas Chrestian, MD FRCPC Chief of service, Child Neurology CME-CHUL, CHU de Québec Université Laval 2705 Boulevard Laurier Québec, QC Canada G1V 4G2 Tel: 418-654-2787 #3 Fax: 418-654-2710 [email protected] Thomas D Bird, MD; University of Washington (1998-2020) Nicolas Chrestian, MD, FRCPC, CSCN (2020-present) 27 August 2020 (bp) Comprehensive update posted live 25 September 2014 (me) Comprehensive update posted live 11 May 2010 (me) Comprehensive update posted live 14 January 2008 (me) Comprehensive update posted live 28 September 2005 (me) Comprehensive update posted live 27 August 2003 (me) Comprehensive update posted live 7 April 2003 (tb) Author revisions 20 June 2001 (me) Comprehensive update posted live 28 September 1998 (tb) Review posted live 6 January 1998 (tb) Original submission • 27 August 2020 (bp) Comprehensive update posted live • 25 September 2014 (me) Comprehensive update posted live • 11 May 2010 (me) Comprehensive update posted live • 14 January 2008 (me) Comprehensive update posted live • 28 September 2005 (me) Comprehensive update posted live • 27 August 2003 (me) Comprehensive update posted live • 7 April 2003 (tb) Author revisions • 20 June 2001 (me) Comprehensive update posted live • 28 September 1998 (tb) Review posted live • 6 January 1998 (tb) Original submission ## Author Notes Dr Nicolas Chrestian is a pediatric neurologist specializing in neuromuscular disorders and neurogenetics. He is currently chief of service at Centre mère-enfant CHU de Québec in Quebec City, as well as professor clinician at Laval University. He has an interest in rare neuromuscular disorders including spastic paraparesis, congenital myopathies, and hereditary neuropathies. Nicolas Chrestian, MD FRCPC Chief of service, Child Neurology CME-CHUL, CHU de Québec Université Laval 2705 Boulevard Laurier Québec, QC Canada G1V 4G2 Tel: 418-654-2787 #3 Fax: 418-654-2710 [email protected] ## Author History Thomas D Bird, MD; University of Washington (1998-2020) Nicolas Chrestian, MD, FRCPC, CSCN (2020-present) ## Revision History 27 August 2020 (bp) Comprehensive update posted live 25 September 2014 (me) Comprehensive update posted live 11 May 2010 (me) Comprehensive update posted live 14 January 2008 (me) Comprehensive update posted live 28 September 2005 (me) Comprehensive update posted live 27 August 2003 (me) Comprehensive update posted live 7 April 2003 (tb) Author revisions 20 June 2001 (me) Comprehensive update posted live 28 September 1998 (tb) Review posted live 6 January 1998 (tb) Original submission • 27 August 2020 (bp) Comprehensive update posted live • 25 September 2014 (me) Comprehensive update posted live • 11 May 2010 (me) Comprehensive update posted live • 14 January 2008 (me) Comprehensive update posted live • 28 September 2005 (me) Comprehensive update posted live • 27 August 2003 (me) Comprehensive update posted live • 7 April 2003 (tb) Author revisions • 20 June 2001 (me) Comprehensive update posted live • 28 September 1998 (tb) Review posted live • 6 January 1998 (tb) Original submission ## References Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available • Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available ## Published Guidelines / Consensus Statements Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available • Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available ## Literature Cited	[]	28/9/1998	27/8/2020	7/4/2003	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
hnrnph2-ndd	hnrnph2-ndd	[ "Bain Type Syndromic Intellectual Disability", "X-Linked Syndromic Intellectual Developmental Disorder, Bain Type", "Bain Type Syndromic Intellectual Disability", "X-Linked Syndromic Intellectual Developmental Disorder, Bain Type", "Heterogeneous nuclear ribonucleoprotein H2", "HNRNPH2", "HNRNPH2-Related Neurodevelopmental Disorder" ]		Sehajvir Madhok, Jennifer Bain	Summary Most individuals with The diagnosis of	## Diagnosis For the purposes of this No consensus clinical diagnostic criteria for Developmental delay / intellectual disability, most often characterized by significant motor abnormalities with severe expressive and receptive language impairment AND Any of the following features in infancy or childhood: Developmental regression Generalized hypotonia of infancy Infant feeding difficulties Acquired microcephaly Poor growth Movement disorders, such as hand stereotypies Epilepsy, of variable semiology Behavioral problems and psychiatric issues including anxiety, attention-deficit/hyperactivity disorder, sensory issues, social communication disorder, or autism spectrum disorder Nonspecific dysmorphic features (See Ophthalmologic involvement including strabismus and cortical visual impairment 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 [ To date, all pathogenic coding variants have been missense variants [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • Developmental delay / intellectual disability, most often characterized by significant motor abnormalities with severe expressive and receptive language impairment • AND • Any of the following features in infancy or childhood: • Developmental regression • Generalized hypotonia of infancy • Infant feeding difficulties • Acquired microcephaly • Poor growth • Movement disorders, such as hand stereotypies • Epilepsy, of variable semiology • Behavioral problems and psychiatric issues including anxiety, attention-deficit/hyperactivity disorder, sensory issues, social communication disorder, or autism spectrum disorder • Nonspecific dysmorphic features (See • Ophthalmologic involvement including strabismus and cortical visual impairment • Developmental regression • Generalized hypotonia of infancy • Infant feeding difficulties • Acquired microcephaly • Poor growth • Movement disorders, such as hand stereotypies • Epilepsy, of variable semiology • Behavioral problems and psychiatric issues including anxiety, attention-deficit/hyperactivity disorder, sensory issues, social communication disorder, or autism spectrum disorder • Nonspecific dysmorphic features (See • Ophthalmologic involvement including strabismus and cortical visual impairment • Developmental regression • Generalized hypotonia of infancy • Infant feeding difficulties • Acquired microcephaly • Poor growth • Movement disorders, such as hand stereotypies • Epilepsy, of variable semiology • Behavioral problems and psychiatric issues including anxiety, attention-deficit/hyperactivity disorder, sensory issues, social communication disorder, or autism spectrum disorder • Nonspecific dysmorphic features (See • Ophthalmologic involvement including strabismus and cortical visual impairment • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings Developmental delay / intellectual disability, most often characterized by significant motor abnormalities with severe expressive and receptive language impairment AND Any of the following features in infancy or childhood: Developmental regression Generalized hypotonia of infancy Infant feeding difficulties Acquired microcephaly Poor growth Movement disorders, such as hand stereotypies Epilepsy, of variable semiology Behavioral problems and psychiatric issues including anxiety, attention-deficit/hyperactivity disorder, sensory issues, social communication disorder, or autism spectrum disorder Nonspecific dysmorphic features (See Ophthalmologic involvement including strabismus and cortical visual impairment • Developmental delay / intellectual disability, most often characterized by significant motor abnormalities with severe expressive and receptive language impairment • AND • Any of the following features in infancy or childhood: • Developmental regression • Generalized hypotonia of infancy • Infant feeding difficulties • Acquired microcephaly • Poor growth • Movement disorders, such as hand stereotypies • Epilepsy, of variable semiology • Behavioral problems and psychiatric issues including anxiety, attention-deficit/hyperactivity disorder, sensory issues, social communication disorder, or autism spectrum disorder • Nonspecific dysmorphic features (See • Ophthalmologic involvement including strabismus and cortical visual impairment • Developmental regression • Generalized hypotonia of infancy • Infant feeding difficulties • Acquired microcephaly • Poor growth • Movement disorders, such as hand stereotypies • Epilepsy, of variable semiology • Behavioral problems and psychiatric issues including anxiety, attention-deficit/hyperactivity disorder, sensory issues, social communication disorder, or autism spectrum disorder • Nonspecific dysmorphic features (See • Ophthalmologic involvement including strabismus and cortical visual impairment • Developmental regression • Generalized hypotonia of infancy • Infant feeding difficulties • Acquired microcephaly • Poor growth • Movement disorders, such as hand stereotypies • Epilepsy, of variable semiology • Behavioral problems and psychiatric issues including anxiety, attention-deficit/hyperactivity disorder, sensory issues, social communication disorder, or autism spectrum disorder • Nonspecific dysmorphic features (See • Ophthalmologic involvement including strabismus and cortical visual impairment ## 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 [ To date, all pathogenic coding variants have been missense variants [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 Most individuals with To date, 49 individuals from 45 families with pathogenic variants in At least one unaffected mother of an affected female was found to have the same ASD = autism spectrum disorder; ADHD = attention=deficit/hyperactivity disorder Speech and language is severely affected, with the majority of affected individuals being nonverbal or minimally verbal and others with speech apraxia or difficulties with articulation. In those who acquired speech, most did so between ages one and five years. Most affected individuals have delays in the acquisition of both gross and fine motor skills in infancy. Many affected individuals are nonambulatory. All affected individuals significantly benefit from intensive therapy services, and many also use orthoses in addition to other devices. Referral to a rehabilitation specialist / physiatrist and orthopedist is recommended for appropriate supports. Most individuals require significant support in daily activities. Many affected individuals have low cognitive skills and low adaptive skill sets using the Vineland Adaptive Behavior Scales. Most cognitive scales show floor effects below the first centile for many testing domains of standardized cognitive assessment. Most individuals require special education and support in daily activities into adulthood. The most common diagnoses include anxiety (68%), self-injurious behaviors (38%), and autism spectrum disorder (34%). Attention-deficit/hyperactivity disorder was diagnosed in about 15% of affected individuals, but a higher number of caregivers reported concerns regarding attention, hyperactivity, and distractibility. Some affected individuals demonstrated stereotypies and intermittent developmental regression that can be suggestive of Rett syndrome (see Electromyography done on one affected individual showed selective lower extremity denervation. Of three affected individuals who underwent muscle biopsy, two were found to have abnormalities and the third was normal. One affected individual was found to have mild type II fiber atrophy; the other affected individual had reduced activity in the respiratory chain enzymes in complexes II and III. Motor planning problems Ataxia Stereotypies Clumsiness Abnormal gait The average age of presentation of first seizure is 8.7 years (range: age 3-34 years). The semiology of clinical seizures is variable. Staring episodes (69%) are the most common seizure type. Febrile seizures are present in 23% of affected individuals. Other seizure semiologies include tonic-clonic (43%), tonic (38%), spasms (23%), clonic (15%), and myoclonic (15%). Abnormal EEG findings include diffuse slowing of the background, left-sided posterior and midline epileptic discharges, and paroxysmal activity in the right temporal lobe. Most affected individuals have reported feeding issues before age 12 months, with some having concerns immediately after birth. About 34% of affected individuals have dysphagia accompanied by aspiration. Many affected individuals have persistent feeding issues, along with poor growth, throughout life. Several have required placement of feeding tubes. Poor appetite Gastroesophageal reflux disease Swallowing difficulty (dysphagia) Pica Diarrhea Overeating, which can lead to weight gain in rare affected individuals Abdominal pain Bloating Pes planus Arachnodactyly Scoliosis, including kyphosis and lordosis, which is most frequently neuromuscular in origin Hip dysplasia Rarer findings include: Navicular bone drop with calcaneal adduction Bone, muscle, and joint pain Arthritis and stiffness of joints Almond-shaped eyes Short palpebral fissures Short philtrum Long columella Hypoplastic alae nasi Full lower lip Micrognathia No genotype-phenotype correlations have been identified. The overall prevalence remains unknown; to date, 49 individuals from 45 families have been reported with this disorder. • Speech and language is severely affected, with the majority of affected individuals being nonverbal or minimally verbal and others with speech apraxia or difficulties with articulation. In those who acquired speech, most did so between ages one and five years. • Most affected individuals have delays in the acquisition of both gross and fine motor skills in infancy. Many affected individuals are nonambulatory. All affected individuals significantly benefit from intensive therapy services, and many also use orthoses in addition to other devices. Referral to a rehabilitation specialist / physiatrist and orthopedist is recommended for appropriate supports. Most individuals require significant support in daily activities. • Many affected individuals have low cognitive skills and low adaptive skill sets using the Vineland Adaptive Behavior Scales. Most cognitive scales show floor effects below the first centile for many testing domains of standardized cognitive assessment. Most individuals require special education and support in daily activities into adulthood. • The most common diagnoses include anxiety (68%), self-injurious behaviors (38%), and autism spectrum disorder (34%). • Attention-deficit/hyperactivity disorder was diagnosed in about 15% of affected individuals, but a higher number of caregivers reported concerns regarding attention, hyperactivity, and distractibility. • Some affected individuals demonstrated stereotypies and intermittent developmental regression that can be suggestive of Rett syndrome (see • Electromyography done on one affected individual showed selective lower extremity denervation. • Of three affected individuals who underwent muscle biopsy, two were found to have abnormalities and the third was normal. One affected individual was found to have mild type II fiber atrophy; the other affected individual had reduced activity in the respiratory chain enzymes in complexes II and III. • Electromyography done on one affected individual showed selective lower extremity denervation. • Of three affected individuals who underwent muscle biopsy, two were found to have abnormalities and the third was normal. One affected individual was found to have mild type II fiber atrophy; the other affected individual had reduced activity in the respiratory chain enzymes in complexes II and III. • Motor planning problems • Ataxia • Stereotypies • Clumsiness • Abnormal gait • Motor planning problems • Ataxia • Stereotypies • Clumsiness • Abnormal gait • Electromyography done on one affected individual showed selective lower extremity denervation. • Of three affected individuals who underwent muscle biopsy, two were found to have abnormalities and the third was normal. One affected individual was found to have mild type II fiber atrophy; the other affected individual had reduced activity in the respiratory chain enzymes in complexes II and III. • Motor planning problems • Ataxia • Stereotypies • Clumsiness • Abnormal gait • The average age of presentation of first seizure is 8.7 years (range: age 3-34 years). • The semiology of clinical seizures is variable. • Staring episodes (69%) are the most common seizure type. • Febrile seizures are present in 23% of affected individuals. • Other seizure semiologies include tonic-clonic (43%), tonic (38%), spasms (23%), clonic (15%), and myoclonic (15%). • Staring episodes (69%) are the most common seizure type. • Febrile seizures are present in 23% of affected individuals. • Other seizure semiologies include tonic-clonic (43%), tonic (38%), spasms (23%), clonic (15%), and myoclonic (15%). • Abnormal EEG findings include diffuse slowing of the background, left-sided posterior and midline epileptic discharges, and paroxysmal activity in the right temporal lobe. • Staring episodes (69%) are the most common seizure type. • Febrile seizures are present in 23% of affected individuals. • Other seizure semiologies include tonic-clonic (43%), tonic (38%), spasms (23%), clonic (15%), and myoclonic (15%). • Most affected individuals have reported feeding issues before age 12 months, with some having concerns immediately after birth. • About 34% of affected individuals have dysphagia accompanied by aspiration. • Many affected individuals have persistent feeding issues, along with poor growth, throughout life. Several have required placement of feeding tubes. • Most affected individuals have reported feeding issues before age 12 months, with some having concerns immediately after birth. • About 34% of affected individuals have dysphagia accompanied by aspiration. • Many affected individuals have persistent feeding issues, along with poor growth, throughout life. Several have required placement of feeding tubes. • • Poor appetite • Gastroesophageal reflux disease • Swallowing difficulty (dysphagia) • Pica • Diarrhea • Overeating, which can lead to weight gain in rare affected individuals • Abdominal pain • Bloating • Poor appetite • Gastroesophageal reflux disease • Swallowing difficulty (dysphagia) • Pica • Diarrhea • Overeating, which can lead to weight gain in rare affected individuals • Abdominal pain • Bloating • Most affected individuals have reported feeding issues before age 12 months, with some having concerns immediately after birth. • About 34% of affected individuals have dysphagia accompanied by aspiration. • Many affected individuals have persistent feeding issues, along with poor growth, throughout life. Several have required placement of feeding tubes. • Poor appetite • Gastroesophageal reflux disease • Swallowing difficulty (dysphagia) • Pica • Diarrhea • Overeating, which can lead to weight gain in rare affected individuals • Abdominal pain • Bloating • Pes planus • Arachnodactyly • Scoliosis, including kyphosis and lordosis, which is most frequently neuromuscular in origin • Hip dysplasia • Rarer findings include: • Navicular bone drop with calcaneal adduction • Bone, muscle, and joint pain • Arthritis and stiffness of joints • Pes planus • Arachnodactyly • Scoliosis, including kyphosis and lordosis, which is most frequently neuromuscular in origin • Hip dysplasia • Navicular bone drop with calcaneal adduction • Bone, muscle, and joint pain • Arthritis and stiffness of joints • Almond-shaped eyes • Short palpebral fissures • Short philtrum • Long columella • Hypoplastic alae nasi • Full lower lip • Micrognathia • Almond-shaped eyes • Short palpebral fissures • Short philtrum • Long columella • Hypoplastic alae nasi • Full lower lip • Micrognathia • Pes planus • Arachnodactyly • Scoliosis, including kyphosis and lordosis, which is most frequently neuromuscular in origin • Hip dysplasia • Navicular bone drop with calcaneal adduction • Bone, muscle, and joint pain • Arthritis and stiffness of joints • Almond-shaped eyes • Short palpebral fissures • Short philtrum • Long columella • Hypoplastic alae nasi • Full lower lip • Micrognathia ## Clinical Description Most individuals with To date, 49 individuals from 45 families with pathogenic variants in At least one unaffected mother of an affected female was found to have the same ASD = autism spectrum disorder; ADHD = attention=deficit/hyperactivity disorder Speech and language is severely affected, with the majority of affected individuals being nonverbal or minimally verbal and others with speech apraxia or difficulties with articulation. In those who acquired speech, most did so between ages one and five years. Most affected individuals have delays in the acquisition of both gross and fine motor skills in infancy. Many affected individuals are nonambulatory. All affected individuals significantly benefit from intensive therapy services, and many also use orthoses in addition to other devices. Referral to a rehabilitation specialist / physiatrist and orthopedist is recommended for appropriate supports. Most individuals require significant support in daily activities. Many affected individuals have low cognitive skills and low adaptive skill sets using the Vineland Adaptive Behavior Scales. Most cognitive scales show floor effects below the first centile for many testing domains of standardized cognitive assessment. Most individuals require special education and support in daily activities into adulthood. The most common diagnoses include anxiety (68%), self-injurious behaviors (38%), and autism spectrum disorder (34%). Attention-deficit/hyperactivity disorder was diagnosed in about 15% of affected individuals, but a higher number of caregivers reported concerns regarding attention, hyperactivity, and distractibility. Some affected individuals demonstrated stereotypies and intermittent developmental regression that can be suggestive of Rett syndrome (see Electromyography done on one affected individual showed selective lower extremity denervation. Of three affected individuals who underwent muscle biopsy, two were found to have abnormalities and the third was normal. One affected individual was found to have mild type II fiber atrophy; the other affected individual had reduced activity in the respiratory chain enzymes in complexes II and III. Motor planning problems Ataxia Stereotypies Clumsiness Abnormal gait The average age of presentation of first seizure is 8.7 years (range: age 3-34 years). The semiology of clinical seizures is variable. Staring episodes (69%) are the most common seizure type. Febrile seizures are present in 23% of affected individuals. Other seizure semiologies include tonic-clonic (43%), tonic (38%), spasms (23%), clonic (15%), and myoclonic (15%). Abnormal EEG findings include diffuse slowing of the background, left-sided posterior and midline epileptic discharges, and paroxysmal activity in the right temporal lobe. Most affected individuals have reported feeding issues before age 12 months, with some having concerns immediately after birth. About 34% of affected individuals have dysphagia accompanied by aspiration. Many affected individuals have persistent feeding issues, along with poor growth, throughout life. Several have required placement of feeding tubes. Poor appetite Gastroesophageal reflux disease Swallowing difficulty (dysphagia) Pica Diarrhea Overeating, which can lead to weight gain in rare affected individuals Abdominal pain Bloating Pes planus Arachnodactyly Scoliosis, including kyphosis and lordosis, which is most frequently neuromuscular in origin Hip dysplasia Rarer findings include: Navicular bone drop with calcaneal adduction Bone, muscle, and joint pain Arthritis and stiffness of joints Almond-shaped eyes Short palpebral fissures Short philtrum Long columella Hypoplastic alae nasi Full lower lip Micrognathia • Speech and language is severely affected, with the majority of affected individuals being nonverbal or minimally verbal and others with speech apraxia or difficulties with articulation. In those who acquired speech, most did so between ages one and five years. • Most affected individuals have delays in the acquisition of both gross and fine motor skills in infancy. Many affected individuals are nonambulatory. All affected individuals significantly benefit from intensive therapy services, and many also use orthoses in addition to other devices. Referral to a rehabilitation specialist / physiatrist and orthopedist is recommended for appropriate supports. Most individuals require significant support in daily activities. • Many affected individuals have low cognitive skills and low adaptive skill sets using the Vineland Adaptive Behavior Scales. Most cognitive scales show floor effects below the first centile for many testing domains of standardized cognitive assessment. Most individuals require special education and support in daily activities into adulthood. • The most common diagnoses include anxiety (68%), self-injurious behaviors (38%), and autism spectrum disorder (34%). • Attention-deficit/hyperactivity disorder was diagnosed in about 15% of affected individuals, but a higher number of caregivers reported concerns regarding attention, hyperactivity, and distractibility. • Some affected individuals demonstrated stereotypies and intermittent developmental regression that can be suggestive of Rett syndrome (see • Electromyography done on one affected individual showed selective lower extremity denervation. • Of three affected individuals who underwent muscle biopsy, two were found to have abnormalities and the third was normal. One affected individual was found to have mild type II fiber atrophy; the other affected individual had reduced activity in the respiratory chain enzymes in complexes II and III. • Electromyography done on one affected individual showed selective lower extremity denervation. • Of three affected individuals who underwent muscle biopsy, two were found to have abnormalities and the third was normal. One affected individual was found to have mild type II fiber atrophy; the other affected individual had reduced activity in the respiratory chain enzymes in complexes II and III. • Motor planning problems • Ataxia • Stereotypies • Clumsiness • Abnormal gait • Motor planning problems • Ataxia • Stereotypies • Clumsiness • Abnormal gait • Electromyography done on one affected individual showed selective lower extremity denervation. • Of three affected individuals who underwent muscle biopsy, two were found to have abnormalities and the third was normal. One affected individual was found to have mild type II fiber atrophy; the other affected individual had reduced activity in the respiratory chain enzymes in complexes II and III. • Motor planning problems • Ataxia • Stereotypies • Clumsiness • Abnormal gait • The average age of presentation of first seizure is 8.7 years (range: age 3-34 years). • The semiology of clinical seizures is variable. • Staring episodes (69%) are the most common seizure type. • Febrile seizures are present in 23% of affected individuals. • Other seizure semiologies include tonic-clonic (43%), tonic (38%), spasms (23%), clonic (15%), and myoclonic (15%). • Staring episodes (69%) are the most common seizure type. • Febrile seizures are present in 23% of affected individuals. • Other seizure semiologies include tonic-clonic (43%), tonic (38%), spasms (23%), clonic (15%), and myoclonic (15%). • Abnormal EEG findings include diffuse slowing of the background, left-sided posterior and midline epileptic discharges, and paroxysmal activity in the right temporal lobe. • Staring episodes (69%) are the most common seizure type. • Febrile seizures are present in 23% of affected individuals. • Other seizure semiologies include tonic-clonic (43%), tonic (38%), spasms (23%), clonic (15%), and myoclonic (15%). • Most affected individuals have reported feeding issues before age 12 months, with some having concerns immediately after birth. • About 34% of affected individuals have dysphagia accompanied by aspiration. • Many affected individuals have persistent feeding issues, along with poor growth, throughout life. Several have required placement of feeding tubes. • Most affected individuals have reported feeding issues before age 12 months, with some having concerns immediately after birth. • About 34% of affected individuals have dysphagia accompanied by aspiration. • Many affected individuals have persistent feeding issues, along with poor growth, throughout life. Several have required placement of feeding tubes. • • Poor appetite • Gastroesophageal reflux disease • Swallowing difficulty (dysphagia) • Pica • Diarrhea • Overeating, which can lead to weight gain in rare affected individuals • Abdominal pain • Bloating • Poor appetite • Gastroesophageal reflux disease • Swallowing difficulty (dysphagia) • Pica • Diarrhea • Overeating, which can lead to weight gain in rare affected individuals • Abdominal pain • Bloating • Most affected individuals have reported feeding issues before age 12 months, with some having concerns immediately after birth. • About 34% of affected individuals have dysphagia accompanied by aspiration. • Many affected individuals have persistent feeding issues, along with poor growth, throughout life. Several have required placement of feeding tubes. • Poor appetite • Gastroesophageal reflux disease • Swallowing difficulty (dysphagia) • Pica • Diarrhea • Overeating, which can lead to weight gain in rare affected individuals • Abdominal pain • Bloating • Pes planus • Arachnodactyly • Scoliosis, including kyphosis and lordosis, which is most frequently neuromuscular in origin • Hip dysplasia • Rarer findings include: • Navicular bone drop with calcaneal adduction • Bone, muscle, and joint pain • Arthritis and stiffness of joints • Pes planus • Arachnodactyly • Scoliosis, including kyphosis and lordosis, which is most frequently neuromuscular in origin • Hip dysplasia • Navicular bone drop with calcaneal adduction • Bone, muscle, and joint pain • Arthritis and stiffness of joints • Almond-shaped eyes • Short palpebral fissures • Short philtrum • Long columella • Hypoplastic alae nasi • Full lower lip • Micrognathia • Almond-shaped eyes • Short palpebral fissures • Short philtrum • Long columella • Hypoplastic alae nasi • Full lower lip • Micrognathia • Pes planus • Arachnodactyly • Scoliosis, including kyphosis and lordosis, which is most frequently neuromuscular in origin • Hip dysplasia • Navicular bone drop with calcaneal adduction • Bone, muscle, and joint pain • Arthritis and stiffness of joints • Almond-shaped eyes • Short palpebral fissures • Short philtrum • Long columella • Hypoplastic alae nasi • Full lower lip • Micrognathia ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been identified. ## Prevalence The overall prevalence remains unknown; to date, 49 individuals from 45 families have been reported with this disorder. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Selected Disorders of Interest in the Differential Diagnosis of AD = autosomal dominant; ASD = autism spectrum disorder; DD = developmental delay; Individuals with Angelman syndrome (AS) typically represent simplex cases and have the disorder as the result of a See also ## 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 Brain MRI EEG 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 evaluate for aspiration risk & dysphagia Consider eval for gastric tube placement in patients w/dysphagia &/or aspiration risk. Gross motor & fine motor skills Scoliosis Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) To evaluate for precocious or delayed puberty Consider referral to endocrinologist if such findings 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; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; VFSS = videofluoroscopic swallowing study Medical geneticist, certified genetic counselor, certified advanced genetic nurse Treatment of Manifestations in Individuals with Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Affected persons have responded well to levetiracetam & valproic acid. Education of parents/caregivers Positioning & mobility devices may be considered. Consider medications such as baclofen, Botox Surgical intervention to correct severe scoliosis, hip dysplasia, & extremity abnormalities Supportive braces 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; CVI = cortical visual impairment; DD/ID = developmental delay / intellectual disability; OT = occupational therapy; PT = physical therapy; SSRIs = selective serotonin reuptake inhibitors 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 types of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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 the use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. Recommended Surveillance for Individuals with Eval of nutritional status & safety of oral intake Monitor for feeding issues, abnormal bowel movements, GERD, pica, abdominal pain, & aspiration risk. Monitor those w/seizures as clinically indicated. Low threshold for overnight EEG monitoring Assess for new manifestations such as seizures, changes in tone, mvmt disorders, & developmental regression. GERD = gastrointestinal reflux disease; OT = occupational therapy; PT = physical therapy To assess for precocious or delayed puberty See No targeted therapies are approved or under investigation for use in Search • To incl motor, adaptive, cognitive, & speech/language eval • Eval for early intervention / special education • Brain MRI • EEG • 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 evaluate for aspiration risk & dysphagia • Consider eval for gastric tube placement in patients w/dysphagia &/or aspiration risk. • Gross motor & fine motor skills • Scoliosis • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • To evaluate for precocious or delayed puberty • Consider referral to endocrinologist if such findings 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. • Affected persons have responded well to levetiracetam & valproic acid. • Education of parents/caregivers • Positioning & mobility devices may be considered. • Consider medications such as baclofen, Botox • Surgical intervention to correct severe scoliosis, hip dysplasia, & extremity abnormalities • Supportive braces • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or Special Olympics. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding types of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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 types of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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 types of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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 the use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • Eval of nutritional status & safety of oral intake • Monitor for feeding issues, abnormal bowel movements, GERD, pica, abdominal pain, & aspiration risk. • Monitor those w/seizures as clinically indicated. • Low threshold for overnight EEG monitoring • Assess for new manifestations such as seizures, changes in tone, mvmt disorders, & developmental regression. ## 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 Brain MRI EEG 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 evaluate for aspiration risk & dysphagia Consider eval for gastric tube placement in patients w/dysphagia &/or aspiration risk. Gross motor & fine motor skills Scoliosis Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) To evaluate for precocious or delayed puberty Consider referral to endocrinologist if such findings 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; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; VFSS = videofluoroscopic swallowing study Medical geneticist, certified genetic counselor, certified advanced genetic nurse • To incl motor, adaptive, cognitive, & speech/language eval • Eval for early intervention / special education • Brain MRI • EEG • 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 evaluate for aspiration risk & dysphagia • Consider eval for gastric tube placement in patients w/dysphagia &/or aspiration risk. • Gross motor & fine motor skills • Scoliosis • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • To evaluate for precocious or delayed puberty • Consider referral to endocrinologist if such findings are present. • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Treatment of Manifestations in Individuals with Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Affected persons have responded well to levetiracetam & valproic acid. Education of parents/caregivers Positioning & mobility devices may be considered. Consider medications such as baclofen, Botox Surgical intervention to correct severe scoliosis, hip dysplasia, & extremity abnormalities Supportive braces 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; CVI = cortical visual impairment; DD/ID = developmental delay / intellectual disability; OT = occupational therapy; PT = physical therapy; SSRIs = selective serotonin reuptake inhibitors 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 types of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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 the use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Affected persons have responded well to levetiracetam & valproic acid. • Education of parents/caregivers • Positioning & mobility devices may be considered. • Consider medications such as baclofen, Botox • Surgical intervention to correct severe scoliosis, hip dysplasia, & extremity abnormalities • Supportive braces • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or Special Olympics. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding types of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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 types of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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 types of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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 the 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 types of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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 types of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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 types of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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 types of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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 the 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 the use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## Social/Behavioral Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ## Surveillance Recommended Surveillance for Individuals with Eval of nutritional status & safety of oral intake Monitor for feeding issues, abnormal bowel movements, GERD, pica, abdominal pain, & aspiration risk. Monitor those w/seizures as clinically indicated. Low threshold for overnight EEG monitoring Assess for new manifestations such as seizures, changes in tone, mvmt disorders, & developmental regression. GERD = gastrointestinal reflux disease; OT = occupational therapy; PT = physical therapy To assess for precocious or delayed puberty • Eval of nutritional status & safety of oral intake • Monitor for feeding issues, abnormal bowel movements, GERD, pica, abdominal pain, & aspiration risk. • Monitor those w/seizures as clinically indicated. • Low threshold for overnight EEG monitoring • Assess for new manifestations such as seizures, changes in tone, mvmt disorders, & developmental regression. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation No targeted therapies are approved or under investigation for use in Search ## Genetic Counseling Almost all females reported to date with Rarely, a female diagnosed with Vertical transmission of an Affected male and female sibs born to consanguineous parents are presumed to have Molecular genetic testing of the parents is recommended to confirm parental genetic status and to allow reliable recurrence risk assessment. The mother of a proband who is found to be heterozygous for an If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only [ If the mother of the proband has an Females who inherit the pathogenic variant are at high risk of being affected; however, a female with favorably skewed X-chromosome inactivation may be unaffected or have a mild phenotype [ Males who inherit the pathogenic variant will be affected. Hemizygous males have variable phenotypes ranging from severe manifestations (described in 11 of the 16 affected males reported to date) to only mild developmental delay with autism spectrum disorder and psychiatric diagnoses (described in five males) [ If the father of the proband has a mosaic If a female 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, the mother may be a heterozygote, the affected male may have a * Including monozygotic twin males [ Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. If the proband represents a simplex case and the If the mother of the proband has an Females who inherit the pathogenic variant are at high risk of being affected; however, a female with favorably skewed X-chromosome inactivation may be unaffected or have a mild phenotype [ Males who inherit the pathogenic variant will be affected. Hemizygous males have variable phenotypes ranging from severe manifestations (described in 11 of the 16 males reported to date) to only mild developmental delay with autism spectrum disorder and psychiatric diagnoses (described in 5 males) [ Females with an Affected males are not known to reproduce. 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 heterozygotes or who are at increased risk of being heterozygotes. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • Almost all females reported to date with • Rarely, a female diagnosed with • Vertical transmission of an • Affected male and female sibs born to consanguineous parents are presumed to have • Vertical transmission of an • Affected male and female sibs born to consanguineous parents are presumed to have • Molecular genetic testing of the parents is recommended to confirm parental genetic status and to allow reliable recurrence risk assessment. • The mother of a proband who is found to be heterozygous for an • 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 [ • Vertical transmission of an • Affected male and female sibs born to consanguineous parents are presumed to have • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only [ • If the mother of the proband has an • Females who inherit the pathogenic variant are at high risk of being affected; however, a female with favorably skewed X-chromosome inactivation may be unaffected or have a mild phenotype [ • Males who inherit the pathogenic variant will be affected. Hemizygous males have variable phenotypes ranging from severe manifestations (described in 11 of the 16 affected males reported to date) to only mild developmental delay with autism spectrum disorder and psychiatric diagnoses (described in five males) [ • Females who inherit the pathogenic variant are at high risk of being affected; however, a female with favorably skewed X-chromosome inactivation may be unaffected or have a mild phenotype [ • Males who inherit the pathogenic variant will be affected. Hemizygous males have variable phenotypes ranging from severe manifestations (described in 11 of the 16 affected males reported to date) to only mild developmental delay with autism spectrum disorder and psychiatric diagnoses (described in five males) [ • If the father of the proband has a mosaic • If a female proband represents a simplex case and if the • Females who inherit the pathogenic variant are at high risk of being affected; however, a female with favorably skewed X-chromosome inactivation may be unaffected or have a mild phenotype [ • Males who inherit the pathogenic variant will be affected. Hemizygous males have variable phenotypes ranging from severe manifestations (described in 11 of the 16 affected males reported to date) to only mild developmental delay with autism spectrum disorder and psychiatric diagnoses (described in five males) [ • 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, the mother may be a heterozygote, the affected male may have a • * Including monozygotic twin males [ • Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. • If the proband represents a simplex case and the • If the mother of the proband has an • Females who inherit the pathogenic variant are at high risk of being affected; however, a female with favorably skewed X-chromosome inactivation may be unaffected or have a mild phenotype [ • Males who inherit the pathogenic variant will be affected. Hemizygous males have variable phenotypes ranging from severe manifestations (described in 11 of the 16 males reported to date) to only mild developmental delay with autism spectrum disorder and psychiatric diagnoses (described in 5 males) [ • Females who inherit the pathogenic variant are at high risk of being affected; however, a female with favorably skewed X-chromosome inactivation may be unaffected or have a mild phenotype [ • Males who inherit the pathogenic variant will be affected. Hemizygous males have variable phenotypes ranging from severe manifestations (described in 11 of the 16 males reported to date) to only mild developmental delay with autism spectrum disorder and psychiatric diagnoses (described in 5 males) [ • Females who inherit the pathogenic variant are at high risk of being affected; however, a female with favorably skewed X-chromosome inactivation may be unaffected or have a mild phenotype [ • Males who inherit the pathogenic variant will be affected. Hemizygous males have variable phenotypes ranging from severe manifestations (described in 11 of the 16 males reported to date) to only mild developmental delay with autism spectrum disorder and psychiatric diagnoses (described in 5 males) [ • Females with an • Affected males are not known to reproduce. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are heterozygotes or who are at increased risk of being heterozygotes. ## Mode of Inheritance ## Risk to Family Members Almost all females reported to date with Rarely, a female diagnosed with Vertical transmission of an Affected male and female sibs born to consanguineous parents are presumed to have Molecular genetic testing of the parents is recommended to confirm parental genetic status and to allow reliable recurrence risk assessment. The mother of a proband who is found to be heterozygous for an If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only [ If the mother of the proband has an Females who inherit the pathogenic variant are at high risk of being affected; however, a female with favorably skewed X-chromosome inactivation may be unaffected or have a mild phenotype [ Males who inherit the pathogenic variant will be affected. Hemizygous males have variable phenotypes ranging from severe manifestations (described in 11 of the 16 affected males reported to date) to only mild developmental delay with autism spectrum disorder and psychiatric diagnoses (described in five males) [ If the father of the proband has a mosaic If a female 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, the mother may be a heterozygote, the affected male may have a * Including monozygotic twin males [ Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. If the proband represents a simplex case and the If the mother of the proband has an Females who inherit the pathogenic variant are at high risk of being affected; however, a female with favorably skewed X-chromosome inactivation may be unaffected or have a mild phenotype [ Males who inherit the pathogenic variant will be affected. Hemizygous males have variable phenotypes ranging from severe manifestations (described in 11 of the 16 males reported to date) to only mild developmental delay with autism spectrum disorder and psychiatric diagnoses (described in 5 males) [ Females with an Affected males are not known to reproduce. Note: Molecular genetic testing may be able to identify the family member in whom a • Almost all females reported to date with • Rarely, a female diagnosed with • Vertical transmission of an • Affected male and female sibs born to consanguineous parents are presumed to have • Vertical transmission of an • Affected male and female sibs born to consanguineous parents are presumed to have • Molecular genetic testing of the parents is recommended to confirm parental genetic status and to allow reliable recurrence risk assessment. • The mother of a proband who is found to be heterozygous for an • 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 [ • Vertical transmission of an • Affected male and female sibs born to consanguineous parents are presumed to have • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only [ • If the mother of the proband has an • Females who inherit the pathogenic variant are at high risk of being affected; however, a female with favorably skewed X-chromosome inactivation may be unaffected or have a mild phenotype [ • Males who inherit the pathogenic variant will be affected. Hemizygous males have variable phenotypes ranging from severe manifestations (described in 11 of the 16 affected males reported to date) to only mild developmental delay with autism spectrum disorder and psychiatric diagnoses (described in five males) [ • Females who inherit the pathogenic variant are at high risk of being affected; however, a female with favorably skewed X-chromosome inactivation may be unaffected or have a mild phenotype [ • Males who inherit the pathogenic variant will be affected. Hemizygous males have variable phenotypes ranging from severe manifestations (described in 11 of the 16 affected males reported to date) to only mild developmental delay with autism spectrum disorder and psychiatric diagnoses (described in five males) [ • If the father of the proband has a mosaic • If a female proband represents a simplex case and if the • Females who inherit the pathogenic variant are at high risk of being affected; however, a female with favorably skewed X-chromosome inactivation may be unaffected or have a mild phenotype [ • Males who inherit the pathogenic variant will be affected. Hemizygous males have variable phenotypes ranging from severe manifestations (described in 11 of the 16 affected males reported to date) to only mild developmental delay with autism spectrum disorder and psychiatric diagnoses (described in five males) [ • 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, the mother may be a heterozygote, the affected male may have a • * Including monozygotic twin males [ • Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. • If the proband represents a simplex case and the • If the mother of the proband has an • Females who inherit the pathogenic variant are at high risk of being affected; however, a female with favorably skewed X-chromosome inactivation may be unaffected or have a mild phenotype [ • Males who inherit the pathogenic variant will be affected. Hemizygous males have variable phenotypes ranging from severe manifestations (described in 11 of the 16 males reported to date) to only mild developmental delay with autism spectrum disorder and psychiatric diagnoses (described in 5 males) [ • Females who inherit the pathogenic variant are at high risk of being affected; however, a female with favorably skewed X-chromosome inactivation may be unaffected or have a mild phenotype [ • Males who inherit the pathogenic variant will be affected. Hemizygous males have variable phenotypes ranging from severe manifestations (described in 11 of the 16 males reported to date) to only mild developmental delay with autism spectrum disorder and psychiatric diagnoses (described in 5 males) [ • Females who inherit the pathogenic variant are at high risk of being affected; however, a female with favorably skewed X-chromosome inactivation may be unaffected or have a mild phenotype [ • Males who inherit the pathogenic variant will be affected. Hemizygous males have variable phenotypes ranging from severe manifestations (described in 11 of the 16 males reported to date) to only mild developmental delay with autism spectrum disorder and psychiatric diagnoses (described in 5 males) [ • Females with an • Affected males are not known to reproduce. ## 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 heterozygotes or who are at increased risk of being heterozygotes. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are heterozygotes or who are at increased risk of being heterozygotes. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • • • • • • • • • • • • • • • ## Molecular Genetics HNRNPH2-Related Neurodevelopmental Disorder: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for HNRNPH2-Related Neurodevelopmental Disorder ( Heterogeneous nuclear ribonucleoproteins (HNRNPs) are a group of proteins that bind to RNA and have multiple roles in RNA metabolism, including transcription, splicing, translation, transfer to the cytoplasm, and mRNA stability and decay. There are more than 20 HNRNPs, designated HNRNP A-U. Pathogenic variants affecting the genes that encode the HNRNPs result in various neurodevelopmental and neurodegenerative disorders [ Consistent with this, more than 90% of individuals with ## Molecular Pathogenesis Heterogeneous nuclear ribonucleoproteins (HNRNPs) are a group of proteins that bind to RNA and have multiple roles in RNA metabolism, including transcription, splicing, translation, transfer to the cytoplasm, and mRNA stability and decay. There are more than 20 HNRNPs, designated HNRNP A-U. Pathogenic variants affecting the genes that encode the HNRNPs result in various neurodevelopmental and neurodegenerative disorders [ Consistent with this, more than 90% of individuals with ## Chapter Notes See We would like to thank the families who are affected by Dr Bain would like to personally thank the first research assistant to work on this project, Ms Olivia Thornburg. The natural history study would not be as successful without her dedication and hard work. 15 September 2022 (ma) Review posted live 1 June 2022 (sm) Original submission • 15 September 2022 (ma) Review posted live • 1 June 2022 (sm) Original submission ## Author Notes See ## Acknowledgments We would like to thank the families who are affected by Dr Bain would like to personally thank the first research assistant to work on this project, Ms Olivia Thornburg. The natural history study would not be as successful without her dedication and hard work. ## Revision History 15 September 2022 (ma) Review posted live 1 June 2022 (sm) Original submission • 15 September 2022 (ma) Review posted live • 1 June 2022 (sm) Original submission ## References ## Literature Cited	[ "JM Bain, MT Cho, A Telegrafi, A Wilson, S Brooks, C Botti, G Gowans, LA Autullo, V Krishnamurthy, MC Willing, TL Toler, B Ben-Zev, O Elpeleg, Y Shen, K Retterer, KG Monaghan, WK Chung. Variants in HNRNPH2 on the X chromosome are associated with a neurodevelopmental disorder in females.. Am J Hum Genet. 2016;99:728-34", "JM Bain, O Thornburg, C Pan, D Rome-Martin, L Boyle, X Fan, O Devinsky, R Frye, S Hamp, CG Keator, NM LaMarca, ABR Maddocks, M Madruga-Garrido, KY Niederhoffer, F Novara, A Peron, E Poole-Di Salvo, R Salazar, SA Skinner, G Soares, S Goldman, WK Chung. Detailed clinical and psychological phenotype of the X-linked HNRNPH2-related neurodevelopmental disorder.. Neurol Genet. 2021;7", "AB Caughey, AH Krist, TA Wolff, MJ Barry, JT Henderson, DK Owens, KW Davidson, MA Simon, CM Mangione. USPSTF approach to addressing sex and gender when making recommendations for clinical preventive services.. JAMA 2021;326:1953-61", "T Geuens, D Bouhy, V. Timmerman. The hnRNP family: insights into their role in health and disease.. Hum Genet. 2016;135:851-67", "MA Gillentine, T Wang, K Hoekzema, J Rosenfeld, P Liu, H Guo, CN Kim, BBA De Vries, L Vissers, M Nordenskjold, M Kvarnung, A Lindstrand, A Nordgren, J Gecz, M Iascone, A Cereda, A Scatigno, S Maitz, G Zanni, E Bertini, C Zweier, S Schuhmann, A Wiesener, M Pepper, H Panjwani, E Torti, F Abid, I Anselm, S Srivastava, P Atwal, CA Bacino, G Bhat, K Cobian, LM Bird, J Friedman, MS Wright, B Callewaert, F Petit, S Mathieu, A Afenjar, CK Christensen, KM White, O Elpeleg, I Berger, EJ Espineli, C Fagerberg, C Brasch-Andersen, LK Hansen, T Feyma, S Hughes, I Thiffault, B Sullivan, S Yan, K Keller, B Keren, C Mignot, F Kooy, M Meuwissen, A Basinger, M Kukolich, M Philips, L Ortega, M Drummond-Borg, M Lauridsen, K Sorensen, A Lehman. CAUSES Study, Lopez-Rangel E, Levy P, Lessel D, Lotze T, Madan-Khetarpal S, Sebastian J, Vento J, Vats D, Benman LM, Mckee S, Mirzaa GM, Muss C, Pappas J, Peeters H, Romano C, Elia M, Galesi O, Simon MEH, van Gassen KLI, Simpson K, Stratton R, Syed S, Thevenon J, Palafoll IV, Vitobello A, Bournez M, Faivre L, Xia K; SPARK Consortium, Earl RK, Nowakowski T, Bernier RA, Eichler EE. Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders.. Genome Med. 2021;13:63", "S Harmsen, R Buchert, E Mayatepek, TB Haack, F Distelmaier. Bain type of X-linked syndromic mental retardation in boys.. Clin Genet. 2019;95:734-5", "WM Jepsen, K Ramsey, S Szelinger, L Llaci, C Balak, N Belnap, C Bilagody, M De Both, R Gupta, M Naymik, R Pandey, IS Piras, M Sanchez-Castillo, S Rangasamy, V Narayanan, M Huentelman. Two additional males with X-linked, syndromic mental retardation carry de novo mutations in HNRNPH2.. Clin Genet. 2019;96:183-5", "HJ Kreienkamp, M Wagner, H Weigand, A McConkie-Rossell, M McDonald, B Keren, C Mignot, J Gauthier, JF Soucy, JL Michaud, M Dumas, R Smith, U Löbel, M Hempel, C Kubisch, J Denecke, PM Campeau, JM Bain, D Lessel. Variant-specific effects define the phenotypic spectrum of HNRNPH2-associated neurodevelopmental disorders in males.. Hum Genet. 2022;141:257-72", "SC Reichert, R Li, SA Turner, RH van Jaarsveld, MPG Massink, MH van den Boogaard, M Del Toro, A Rodríguez-Palmero, S Fourcade, A Schlüter, L Planas-Serra, A Pujol, M Iascone, S Maitz, L Loong, H Stewart, E De Franco, S Ellard, J Frank, R Lewandowski. HNRNPH1-related syndromic intellectual disability: seven additional cases suggestive of a distinct syndromic neurodevelopmental syndrome.. Clin Genet. 2020;98:91-8", "S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24", "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", "PH Somashekar, DL Narayanan, S Jagadeesh, B Suresh, RD Vaishnavi, S Bielas, KM Girisha, A Shukla. Bain type of X-linked syndromic mental retardation in a male with a pathogenic variant in HNRNPH2.. Am J Med Genet Part A. 2020;182:183-8", "AM White-Brown, G Lemire, YA Ito, O Thornburg, JM Bain, DA Dyment. A disease-causing variant in HNRNPH2 inherited from an unaffected mother with skewed X-inactivation.. Am J Med Genet A. 2022;188:668-71" ]	15/9/2022			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
hnrnpu-ndd	hnrnpu-ndd	[ "Developmental and Epileptic Encephalopathy 54", "Early Infantile Epileptic Encephalopathy Type 54", "Early Infantile Epileptic Encephalopathy Type 54", "Developmental and Epileptic Encephalopathy 54", "Heterogeneous nuclear ribonucleoprotein U", "HNRNPU", "HNRNPU-Related Neurodevelopmental Disorder" ]		Meena Balasubramanian	Summary The diagnosis of	## Diagnosis No consensus clinical diagnostic criteria for Generalized hypotonia of infancy Infant feeding difficulties Speech and language delay and/ or absent speech Autism spectrum disorder or autistic traits Nonspecific dysmorphic facial features (See Epilepsy, including generalized tonic-clonic seizures and absence seizures Short stature Strabismus Ventriculomegaly Thinning of the corpus callosum 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 Three additional individuals with contiguous gene deletions or duplications (not included in these calculations) have been reported (see Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and 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 One affected individual had deletion of the last three exons of • Generalized hypotonia of infancy • Infant feeding difficulties • Speech and language delay and/ or absent speech • Autism spectrum disorder or autistic traits • Nonspecific dysmorphic facial features (See • Epilepsy, including generalized tonic-clonic seizures and absence seizures • Short stature • Strabismus • Ventriculomegaly • Thinning of the corpus callosum • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings Generalized hypotonia of infancy Infant feeding difficulties Speech and language delay and/ or absent speech Autism spectrum disorder or autistic traits Nonspecific dysmorphic facial features (See Epilepsy, including generalized tonic-clonic seizures and absence seizures Short stature Strabismus Ventriculomegaly Thinning of the corpus callosum • Generalized hypotonia of infancy • Infant feeding difficulties • Speech and language delay and/ or absent speech • Autism spectrum disorder or autistic traits • Nonspecific dysmorphic facial features (See • Epilepsy, including generalized tonic-clonic seizures and absence seizures • Short stature • Strabismus • Ventriculomegaly • Thinning of the corpus callosum ## 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 Three additional individuals with contiguous gene deletions or duplications (not included in these calculations) have been reported (see Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and 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 One affected individual had deletion of the last three exons of • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics To date, 83 individuals have been identified with a pathogenic variant in Select Features of Of note, some persons have both types of seizures, such that the combined percentages are more than 100%. Speech delay is common and most reported individuals are nonverbal, although ascertainment bias against more mildly affected individuals may have skewed this finding to the more severe end of the Limited speech and ability to speak in short sentences has been described in some individuals. To date, most individuals have required special educational provisions, although children with The vast majority of reported adults have required assisted living, which has allowed them some degree of independence. About 60% of individuals have generalized tonic-clonic seizures; 44% have absence seizures. Rarer types of seizures have included the following: two individuals with West syndrome [ Most affected individuals have seizures as a presenting feature along with developmental delay. Seizures often respond to standard anti-seizure medication, although some may require more than one anti-seizure medication or a trial of such medications to attain reasonable seizure control. Ketogenic diet and newer medications to control seizures have been trialed (see About one third meet the formal clinical diagnostic criteria of an autism spectrum disorder, whereas others have autistic-like features. In contrast, some are described as having a very friendly, placid personality. Less common behavioral phenotypes included obsessive-compulsive disorder and self-stimulatory behaviors. Other associated behaviors (more rarely seen): Aggressive or destructive behavior Hand flapping Agitation Hyperventilation episodes (See also Attention-deficit disorder Abnormal head shape (frontal bossing, microcephaly, dolichocephaly) Prominent forehead Highly arched, thin eyebrows Palpebral fissure abnormalities (both upslanted and downslanted) Epicanthus Thin vermilion of the upper lip Low-hanging columella Widely spaced teeth Atrial septal defect Ventricular septal defect Patent ductus arteriosus Tricuspid atresia, tetralogy of Fallot, aortic dilatation, and transposition of the great arteries together in one affected individual Of 62 individuals reported in the literature who had a brain MRI imaging, 38 (61%) had abnormalities noted. The most common abnormality was ventriculomegaly, followed by thinning of the corpus callosum. Joint hyperlaxity (in 8 individuals) Butterfly vertebrae (1 individual) and scoliosis (3 individuals) Polydactyly, including bilateral postaxial polydactyly of the hand (1 individual) and preaxial polydactyly of the right foot (3 individuals) Cutaneous syndactyly of fingers 2 and 3 Fifth digit clinodactyly Hallux valgus No genotype-phenotype correlations have been identified. The prevalence of this condition is unknown. To date, approximately 83 individuals with • Speech delay is common and most reported individuals are nonverbal, although ascertainment bias against more mildly affected individuals may have skewed this finding to the more severe end of the • Limited speech and ability to speak in short sentences has been described in some individuals. • To date, most individuals have required special educational provisions, although children with • The vast majority of reported adults have required assisted living, which has allowed them some degree of independence. • About 60% of individuals have generalized tonic-clonic seizures; 44% have absence seizures. • Rarer types of seizures have included the following: two individuals with West syndrome [ • Most affected individuals have seizures as a presenting feature along with developmental delay. • Seizures often respond to standard anti-seizure medication, although some may require more than one anti-seizure medication or a trial of such medications to attain reasonable seizure control. • Ketogenic diet and newer medications to control seizures have been trialed (see • About 60% of individuals have generalized tonic-clonic seizures; 44% have absence seizures. • Rarer types of seizures have included the following: two individuals with West syndrome [ • Most affected individuals have seizures as a presenting feature along with developmental delay. • Seizures often respond to standard anti-seizure medication, although some may require more than one anti-seizure medication or a trial of such medications to attain reasonable seizure control. • Ketogenic diet and newer medications to control seizures have been trialed (see • About 60% of individuals have generalized tonic-clonic seizures; 44% have absence seizures. • Rarer types of seizures have included the following: two individuals with West syndrome [ • Most affected individuals have seizures as a presenting feature along with developmental delay. • Seizures often respond to standard anti-seizure medication, although some may require more than one anti-seizure medication or a trial of such medications to attain reasonable seizure control. • Ketogenic diet and newer medications to control seizures have been trialed (see • About one third meet the formal clinical diagnostic criteria of an autism spectrum disorder, whereas others have autistic-like features. • In contrast, some are described as having a very friendly, placid personality. • Less common behavioral phenotypes included obsessive-compulsive disorder and self-stimulatory behaviors. • Other associated behaviors (more rarely seen): • Aggressive or destructive behavior • Hand flapping • Agitation • Hyperventilation episodes (See also • Attention-deficit disorder • Aggressive or destructive behavior • Hand flapping • Agitation • Hyperventilation episodes (See also • Attention-deficit disorder • Aggressive or destructive behavior • Hand flapping • Agitation • Hyperventilation episodes (See also • Attention-deficit disorder • Abnormal head shape (frontal bossing, microcephaly, dolichocephaly) • Prominent forehead • Highly arched, thin eyebrows • Palpebral fissure abnormalities (both upslanted and downslanted) • Epicanthus • Thin vermilion of the upper lip • Low-hanging columella • Widely spaced teeth • Atrial septal defect • Ventricular septal defect • Patent ductus arteriosus • Tricuspid atresia, tetralogy of Fallot, aortic dilatation, and transposition of the great arteries together in one affected individual • Of 62 individuals reported in the literature who had a brain MRI imaging, 38 (61%) had abnormalities noted. • The most common abnormality was ventriculomegaly, followed by thinning of the corpus callosum. • Joint hyperlaxity (in 8 individuals) • Butterfly vertebrae (1 individual) and scoliosis (3 individuals) • Polydactyly, including bilateral postaxial polydactyly of the hand (1 individual) and preaxial polydactyly of the right foot (3 individuals) • Cutaneous syndactyly of fingers 2 and 3 • Fifth digit clinodactyly • Hallux valgus • Joint hyperlaxity (in 8 individuals) • Butterfly vertebrae (1 individual) and scoliosis (3 individuals) • Polydactyly, including bilateral postaxial polydactyly of the hand (1 individual) and preaxial polydactyly of the right foot (3 individuals) • Cutaneous syndactyly of fingers 2 and 3 • Fifth digit clinodactyly • Hallux valgus • Joint hyperlaxity (in 8 individuals) • Butterfly vertebrae (1 individual) and scoliosis (3 individuals) • Polydactyly, including bilateral postaxial polydactyly of the hand (1 individual) and preaxial polydactyly of the right foot (3 individuals) • Cutaneous syndactyly of fingers 2 and 3 • Fifth digit clinodactyly • Hallux valgus ## Clinical Description To date, 83 individuals have been identified with a pathogenic variant in Select Features of Of note, some persons have both types of seizures, such that the combined percentages are more than 100%. Speech delay is common and most reported individuals are nonverbal, although ascertainment bias against more mildly affected individuals may have skewed this finding to the more severe end of the Limited speech and ability to speak in short sentences has been described in some individuals. To date, most individuals have required special educational provisions, although children with The vast majority of reported adults have required assisted living, which has allowed them some degree of independence. About 60% of individuals have generalized tonic-clonic seizures; 44% have absence seizures. Rarer types of seizures have included the following: two individuals with West syndrome [ Most affected individuals have seizures as a presenting feature along with developmental delay. Seizures often respond to standard anti-seizure medication, although some may require more than one anti-seizure medication or a trial of such medications to attain reasonable seizure control. Ketogenic diet and newer medications to control seizures have been trialed (see About one third meet the formal clinical diagnostic criteria of an autism spectrum disorder, whereas others have autistic-like features. In contrast, some are described as having a very friendly, placid personality. Less common behavioral phenotypes included obsessive-compulsive disorder and self-stimulatory behaviors. Other associated behaviors (more rarely seen): Aggressive or destructive behavior Hand flapping Agitation Hyperventilation episodes (See also Attention-deficit disorder Abnormal head shape (frontal bossing, microcephaly, dolichocephaly) Prominent forehead Highly arched, thin eyebrows Palpebral fissure abnormalities (both upslanted and downslanted) Epicanthus Thin vermilion of the upper lip Low-hanging columella Widely spaced teeth Atrial septal defect Ventricular septal defect Patent ductus arteriosus Tricuspid atresia, tetralogy of Fallot, aortic dilatation, and transposition of the great arteries together in one affected individual Of 62 individuals reported in the literature who had a brain MRI imaging, 38 (61%) had abnormalities noted. The most common abnormality was ventriculomegaly, followed by thinning of the corpus callosum. Joint hyperlaxity (in 8 individuals) Butterfly vertebrae (1 individual) and scoliosis (3 individuals) Polydactyly, including bilateral postaxial polydactyly of the hand (1 individual) and preaxial polydactyly of the right foot (3 individuals) Cutaneous syndactyly of fingers 2 and 3 Fifth digit clinodactyly Hallux valgus • Speech delay is common and most reported individuals are nonverbal, although ascertainment bias against more mildly affected individuals may have skewed this finding to the more severe end of the • Limited speech and ability to speak in short sentences has been described in some individuals. • To date, most individuals have required special educational provisions, although children with • The vast majority of reported adults have required assisted living, which has allowed them some degree of independence. • About 60% of individuals have generalized tonic-clonic seizures; 44% have absence seizures. • Rarer types of seizures have included the following: two individuals with West syndrome [ • Most affected individuals have seizures as a presenting feature along with developmental delay. • Seizures often respond to standard anti-seizure medication, although some may require more than one anti-seizure medication or a trial of such medications to attain reasonable seizure control. • Ketogenic diet and newer medications to control seizures have been trialed (see • About 60% of individuals have generalized tonic-clonic seizures; 44% have absence seizures. • Rarer types of seizures have included the following: two individuals with West syndrome [ • Most affected individuals have seizures as a presenting feature along with developmental delay. • Seizures often respond to standard anti-seizure medication, although some may require more than one anti-seizure medication or a trial of such medications to attain reasonable seizure control. • Ketogenic diet and newer medications to control seizures have been trialed (see • About 60% of individuals have generalized tonic-clonic seizures; 44% have absence seizures. • Rarer types of seizures have included the following: two individuals with West syndrome [ • Most affected individuals have seizures as a presenting feature along with developmental delay. • Seizures often respond to standard anti-seizure medication, although some may require more than one anti-seizure medication or a trial of such medications to attain reasonable seizure control. • Ketogenic diet and newer medications to control seizures have been trialed (see • About one third meet the formal clinical diagnostic criteria of an autism spectrum disorder, whereas others have autistic-like features. • In contrast, some are described as having a very friendly, placid personality. • Less common behavioral phenotypes included obsessive-compulsive disorder and self-stimulatory behaviors. • Other associated behaviors (more rarely seen): • Aggressive or destructive behavior • Hand flapping • Agitation • Hyperventilation episodes (See also • Attention-deficit disorder • Aggressive or destructive behavior • Hand flapping • Agitation • Hyperventilation episodes (See also • Attention-deficit disorder • Aggressive or destructive behavior • Hand flapping • Agitation • Hyperventilation episodes (See also • Attention-deficit disorder • Abnormal head shape (frontal bossing, microcephaly, dolichocephaly) • Prominent forehead • Highly arched, thin eyebrows • Palpebral fissure abnormalities (both upslanted and downslanted) • Epicanthus • Thin vermilion of the upper lip • Low-hanging columella • Widely spaced teeth • Atrial septal defect • Ventricular septal defect • Patent ductus arteriosus • Tricuspid atresia, tetralogy of Fallot, aortic dilatation, and transposition of the great arteries together in one affected individual • Of 62 individuals reported in the literature who had a brain MRI imaging, 38 (61%) had abnormalities noted. • The most common abnormality was ventriculomegaly, followed by thinning of the corpus callosum. • Joint hyperlaxity (in 8 individuals) • Butterfly vertebrae (1 individual) and scoliosis (3 individuals) • Polydactyly, including bilateral postaxial polydactyly of the hand (1 individual) and preaxial polydactyly of the right foot (3 individuals) • Cutaneous syndactyly of fingers 2 and 3 • Fifth digit clinodactyly • Hallux valgus • Joint hyperlaxity (in 8 individuals) • Butterfly vertebrae (1 individual) and scoliosis (3 individuals) • Polydactyly, including bilateral postaxial polydactyly of the hand (1 individual) and preaxial polydactyly of the right foot (3 individuals) • Cutaneous syndactyly of fingers 2 and 3 • Fifth digit clinodactyly • Hallux valgus • Joint hyperlaxity (in 8 individuals) • Butterfly vertebrae (1 individual) and scoliosis (3 individuals) • Polydactyly, including bilateral postaxial polydactyly of the hand (1 individual) and preaxial polydactyly of the right foot (3 individuals) • Cutaneous syndactyly of fingers 2 and 3 • Fifth digit clinodactyly • Hallux valgus ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been identified. ## Prevalence The prevalence of this condition is unknown. To date, approximately 83 individuals with ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Because the phenotypic features associated with ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with To incl brain MRI if unresolved/refractory seizures are present Consider EEG if seizures are a concern. To incl motor, adaptive, cognitive, & speech/language eval Eval for early intervention / special education To incl eval of feeding ability & nutritional status Consider eval for swallowing dysfunction & gastric tube placement in those w/dysphagia or continued poor growth on oral feedings alone. Gross motor & fine motor skills Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Community or Social work involvement for parental support; Home nursing referral. ADD = attention-deficit disorder; ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; UTI = urinary tract infection See also Medical geneticist, certified genetic counselor, certified advanced genetic nurse Treatment of Manifestations in Individuals with Many ASMs may be effective; sodium valproate is the most commonly used & effective medication. Ketogenic diet & newer ASMs may be required for refractory seizures. 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; BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; DD = developmental delay; ID = intellectual disability; OT = occupational therapy; PT = physical therapy For individuals on valproate and other ASMs, routine monitoring of liver function tests and observation for behavioral dysregulation should be considered. 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, 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. Very occasionally, individuals with a Recommended Surveillance for Individuals with Measurement of growth parameters Eval of nutritional status & safety of oral intake Monitor those w/seizures as clinically indicated. Assess for new manifestations such as seizures & changes in tone. OT = occupational therapy; PT = physical therapy Avoid activities and agents that may induce seizures, as the majority of affected individuals have a seizure disorder. See Sustained single-dose gene therapy treatments for genetic forms of epilepsy, including Search • To incl brain MRI if unresolved/refractory seizures are present • Consider EEG if seizures are a concern. • To incl motor, adaptive, cognitive, & speech/language eval • Eval for early intervention / special education • To incl eval of feeding ability & nutritional status • Consider eval for swallowing dysfunction & gastric tube placement in those w/dysphagia or continued poor growth on oral feedings alone. • Gross motor & fine motor skills • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Community or • Social work involvement for parental support; • Home nursing referral. • Many ASMs may be effective; sodium valproate is the most commonly used & effective medication. • Ketogenic diet & newer ASMs may be required for refractory seizures. • 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 and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as seizures & changes in tone. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with To incl brain MRI if unresolved/refractory seizures are present Consider EEG if seizures are a concern. To incl motor, adaptive, cognitive, & speech/language eval Eval for early intervention / special education To incl eval of feeding ability & nutritional status Consider eval for swallowing dysfunction & gastric tube placement in those w/dysphagia or continued poor growth on oral feedings alone. Gross motor & fine motor skills Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Community or Social work involvement for parental support; Home nursing referral. ADD = attention-deficit disorder; ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; UTI = urinary tract infection See also Medical geneticist, certified genetic counselor, certified advanced genetic nurse • To incl brain MRI if unresolved/refractory seizures are present • Consider EEG if seizures are a concern. • To incl motor, adaptive, cognitive, & speech/language eval • Eval for early intervention / special education • To incl eval of feeding ability & nutritional status • Consider eval for swallowing dysfunction & gastric tube placement in those w/dysphagia or continued poor growth on oral feedings alone. • Gross motor & fine motor skills • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Treatment of Manifestations in Individuals with Many ASMs may be effective; sodium valproate is the most commonly used & effective medication. Ketogenic diet & newer ASMs may be required for refractory seizures. 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; BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; DD = developmental delay; ID = intellectual disability; OT = occupational therapy; PT = physical therapy For individuals on valproate and other ASMs, routine monitoring of liver function tests and observation for behavioral dysregulation should be considered. 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, 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. Very occasionally, individuals with a • Many ASMs may be effective; sodium valproate is the most commonly used & effective medication. • Ketogenic diet & newer ASMs may be required for refractory seizures. • 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 and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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, 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, 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, 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. Very occasionally, individuals with a ## Surveillance Recommended Surveillance for Individuals with Measurement of growth parameters Eval of nutritional status & safety of oral intake Monitor those w/seizures as clinically indicated. Assess for new manifestations such as seizures & changes in tone. 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. ## Agents/Circumstances to Avoid Avoid activities and agents that may induce seizures, as the majority of affected individuals have a seizure disorder. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Sustained single-dose gene therapy treatments for genetic forms of epilepsy, including Search ## Genetic Counseling Most probands reported to date with Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Presumed parental mosaicism has been reported in one family with two affected sibs [ Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. Each child of an individual with Individuals with The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. Risk to future pregnancies is presumed to be low as the proband most likely has a Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • Most probands reported to date with • Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Presumed parental mosaicism has been reported in one family with two affected sibs [ • Note: Testing of parental leukocyte 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. Presumed parental mosaicism has been reported in one family with two affected sibs [ • Note: Testing of parental leukocyte 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. Presumed parental mosaicism has been reported in one family with two affected sibs [ • Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • Each child of an individual with • Individuals with • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. ## Mode of Inheritance ## Risk to Family Members Most probands reported to date with Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Presumed parental mosaicism has been reported in one family with two affected sibs [ Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. Each child of an individual with Individuals with • Most probands reported to date with • Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Presumed parental mosaicism has been reported in one family with two affected sibs [ • Note: Testing of parental leukocyte 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. Presumed parental mosaicism has been reported in one family with two affected sibs [ • Note: Testing of parental leukocyte 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. Presumed parental mosaicism has been reported in one family with two affected sibs [ • Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • Each child of an individual with • Individuals with ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. ## Prenatal Testing and Preimplantation Genetic Testing Risk to future pregnancies is presumed to be low as the proband most likely has a Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources Canada United Kingdom • • • • Canada • • • • • • • United Kingdom • • • • ## Molecular Genetics HNRNPU-Related Neurodevelopmental Disorder: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for HNRNPU-Related Neurodevelopmental Disorder ( ## Molecular Pathogenesis ## Chapter Notes In the area of pediatric dysmorphology / genomic medicine, Dr Balasubramanian has led several studies focused on genotype-phenotype correlation in newly identified genes from next-generation sequencing studies such as the Deciphering Developmental Disorders (DDD) study, and has several first/senior author articles published in this area on large cohorts of individuals with new syndromal diagnoses. Her research is now focused on exploring disease mechanisms and establishing international registries for these disorders to better understand the natural history of these conditions. Dr Balasubramanian has published the largest cohort of people so far with Dr Balasubramanian's web pages: Dr Balasubramanian would like to thank all the families and their clinicians who have so far contributed to ongoing 10 March 2022 (ma) Review posted live 22 September 2021 (mb) Original submission • 10 March 2022 (ma) Review posted live • 22 September 2021 (mb) Original submission ## Author Notes In the area of pediatric dysmorphology / genomic medicine, Dr Balasubramanian has led several studies focused on genotype-phenotype correlation in newly identified genes from next-generation sequencing studies such as the Deciphering Developmental Disorders (DDD) study, and has several first/senior author articles published in this area on large cohorts of individuals with new syndromal diagnoses. Her research is now focused on exploring disease mechanisms and establishing international registries for these disorders to better understand the natural history of these conditions. Dr Balasubramanian has published the largest cohort of people so far with Dr Balasubramanian's web pages: ## Acknowledgments Dr Balasubramanian would like to thank all the families and their clinicians who have so far contributed to ongoing ## Revision History 10 March 2022 (ma) Review posted live 22 September 2021 (mb) Original submission • 10 March 2022 (ma) Review posted live • 22 September 2021 (mb) Original submission ## References ## Literature Cited	[ "AS Allen, SF Berkovic, P Cossette, N Delanty, D Dlugos, EE Eichler, MP Epstein, T Glauser, DB Goldstein, Y Han, EL Heinzen, Y Hitomi, KB Howell, MR Johnson, R Kuzniecky, DH Lowenstein, YF Lu, MR Madou, AG Marson, HC Mefford, S Esmaeeli Nieh, TJ O'Brien, R Ottman, S Petrovski, A Poduri, EK Ruzzo, IE Scheffer, EH Sherr, CJ Yuskaitis, B Abou-Khalil, BK Alldredge, JF Bautista, SF Berkovic, A Boro, GD Cascino, D Consalvo, P Crumrine, O Devinsky, D Dlugos, MP Epstein, M Fiol, NB Fountain, J French, D Friedman, EB Geller, T Glauser, S Glynn, SR Haut, J Hayward, SL Helmers, S Joshi, A Kanner, HE Kirsch, RC Knowlton, EH Kossoff, R Kuperman, R Kuzniecky, DH Lowenstein, SM McGuire, PV Motika, EJ Novotny, R Ottman, JM Paolicchi, JM Parent, K Park, A Poduri, IE Scheffer, RA Shellhaas, EH Sherr, JJ Shih, R Singh, J Sirven, MC Smith, J Sullivan, L Lin Thio, A Venkat, EP Vining, GK Von Allmen, JL Weisenberg, P Widdess-Walsh, MR Winawer. De novo mutations in epileptic encephalopathies.. Nature. 2013;501:217-21", "HS Bi, XY Yang, JH Yuan, F Yang, D Xu, YJ Guo, L Zhang, CC Zhou, F Wang, SH Sun. H19 inhibits RNA polymerase II-mediated transcription by disrupting the hnRNP U-actin complex.. Biochim Biophys Acta. 2013;1830:4899-906", "NC Bramswig, HJ Lüdecke, FF Hamdan, J Altmüller, F Beleggia, NH Elcioglu, C Freyer, EH Gerkes, YK Demirkol, KG Knupp, A Kuechler. Heterozygous HNRNPU variants cause early onset epilepsy and severe intellectual disability.. Hum Genet. 2017;136:821-34", "A Caliebe, HY Kroes, JJ van der Smagt, JI Martin-Subero, H Tonnies, R van’t Slot, AJ Nievelstein, H Muhle, U Stephani, K Alfke, I Stefanova, Y Hellenbroich, G Gillessen-Kaesbach, R Hochstenbach, R Siebert, M Poot. Four patients with speech delay, seizures, and variable corpus callosum thickness sharing a 0.440 Mb deletion in region 1q44 containing the HNRPU gene.. Eur J Med Genet. 2010;53:179-85", "CG de Kovel, EH Brilstra, MJ van Kempen, R Van't Slot, IJ Nijman, Z Afawi, P De Jonghe, T Djémié, R Guerrini, K Hardies, I Helbig, R Hendrickx, M Kanaan, U Kramer, AE Lehesjoki, JR Lemke, C Marini, D Mei, RS Møller, M Pendziwiat, H Stamberger, A Suls, S Weckhuysen, BP Koeleman. Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients.. Mol Genet Genomic Med. 2016;4:568-80", "C Depienne, C Nava, B Keren, S Heide, A Rastetter, S Passemard, S Chantot-Bastaraud, ML Moutard, PB Agrawal, G VanNoy, JM Stoler. Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU.. Hum Genet. 2017;136:463-79", "A Durkin, S Albaba, AE Fry, JE Morton, A Douglas, A Beleza, D Williams, CML Volker-Touw, SA Lynch, N Canham, V Clowes, V Straub, K Lachlan, F Gibbon, ME Gamal, V Varghese, MJ Parker, R Newbury-Ecob, PE Turnpenny, A Gardham, N Ghali, M Balasubramanian. Clinical findings of 21 previously unreported probands with HNRNPU-related syndrome and comprehensive literature.. Am J Med Genet A. 2020;182:1637-54", "Y Hasegawa, N Brockdorff, S Kawano, K Tsutui, K Tsutui, S. Nakagawa. The matrix protein hnRNP U is required for chromosomal localization of Xist RNA.. Dev Cell. 2010;19:469-76", "JM Havrilla, BS Pedersen, RM Layer, AR Quinlan. A map of constrained coding regions in the human genome.. Nat Genet. 2019;51:88-95", "N Hinokuma, M Nakashima, H Asai, K Nakamura, S Akaboshi, M Fukuoka, M Togawa, S Oana, K Ohno, M Kasai, C Ogawa, K Yamamoto, K Okumiya, PF Chong, R Kira, S Uchino, T Fukuyama, T Shinagawa, Y Miyata, Y Abe, A Hojo, K Kobayashi, Y Maegaki, N Ishikawa, H Ikeda, M Amamoto, T Mizuguchi, K Iwama, T Itai, S Miyatake, H Saitsu, N Matsumoto, M Kato. Clinical and genetic characteristics of patients with Doose syndrome.. Epilepsia Open. 2020;5:442-50", "MS Leduc, HT Chao, C Qu, M Walkiewicz, R Xiao, P Magoulas, S Pan, J Beuten, W He, JA Bernstein, CP Schaaf. Clinical and molecular characterization of de novo loss of function variants in HNRNPU.. Am J Med Genet A. 2017;173:2680-9", "AC Need, V Shashi, Y Hitomi, K Schoch, KV Shianna, MT McDonald, MH Meisler, DB Goldstein. Clinical application of exome sequencing in undiagnosed genetic conditions.. J Med Genet. 2012;49:353-61", "RS Nozawa, L Boteva, DC Soares, C Naughton, AR Dun, A Buckle, B Ramsahoye, PC Bruton, RS Saleeb, M Arnedo, B Hill. SAF-A regulates interphase chromosome structure through oligomerization with chromatin-associated RNAs.. Cell. 2017;169:1214-27.e18", "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, H Oguni, Y Otani, A Nishikawa, S Ito, K Eto, T Nakazawa, K Yamamoto-Shimojima, JI Takanashi, S Nagata, T Yamamoto. An episode of acute encephalopathy with biphasic seizures and late reduced diffusion followed by hemiplegia and intractable epilepsy observed in a patient with a novel frameshift mutation in HNRNPU.. Brain Dev. 2018;40:813-8", "Z Song, Y Zhang, C Yang, Z Yi, F Li, J Xue, X Yang, B Li. De novo frameshift variants of HNRNPU in patients with early infantile epileptic encephalopathy: two case reports and literature review.. Int J Dev Neurosci. 2021;81:663-8", "C Spagnoli, S Rizzi, GG Salerno, D Frattini, J Koskenvuo, C Fusco. Pharmacologic treatment of severe breathing abnormalities in a case of HNRNPU epileptic encephalopathy.. Mol Syndromol. 2021;12:101-5", "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 Taylor, M Spiller, K Ranguin, A Vitobello, C Philippe, AL Bruel, G Cappuccio, N Brunetti-Pierri, M Willems, B Isidor, K Park, M Balasubramanian. Expanding the phenotype of HNRNPU-related neurodevelopmental disorder with emphasis on seizure phenotype and review of literature.. Am J Med Genet A. 2022;188:1497-514", "G Thierry, C Bénéteau, O Pichon, E Flori, B Isidor, F Popelard, MA Delrue, L Duboscq-Bidot, AC Thuresson, BW van Bon, D Cailley, C Rooryck, A Paubel, C Metay, A Dusser, L Pasquier, M Béri, C Bonnet, S Jaillard, C Dubourg, B Tou, MP Quéré, C Soussi-Zander, A Toutain, D Lacombe, B Arveiler, BB de Vries, P Jonveaux, A David, C Le Caignec. Molecular characterization of 1q44 microdeletion in 11 patients reveals three candidate genes for intellectual disability and seizures.. Am J Med Genet A. 2012;158A:1633-40", "TM Yates, PC Vasudevan, KE Chandler, DE Donnelly, Z Stark, S Sadedin, J Willoughby, M Balasubramanian. De novo mutations in HNRNPU result in a neurodevelopmental syndrome.. Am J Med Genet A. 2017;173:3003-12" ]	10/3/2022			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
homocystinuria	homocystinuria	[ "Classic Homocystinuria", "Classic Homocystinuria", "Cystathionine beta-synthase", "CBS", "Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency" ]	Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency	Stephanie J Sacharow, Jonathan D Picker, Harvey L Levy	Summary Homocystinuria caused by cystathionine β-synthase (CBS) deficiency is characterized by involvement of the eye (ectopia lentis and/or severe myopia), skeletal system (excessive height, long limbs, scolioisis, and pectus excavatum), vascular system (thromboembolism), and CNS (developmental delay/intellectual disability). All four ‒ or only one ‒ of the systems can be involved; expressivity is variable for all of the clinical signs. It is not unusual for a previously asymptomatic individual to present in adult years with only a thromboembolic event that is often cerebrovascular. Two phenotypic variants are recognized, B Thromboembolism is the major cause of early death and morbidity. IQ in individuals with untreated homocystinuria ranges widely, from 10 to 138. In B The cardinal biochemical features of homocystinuria include markedly increased concentrations of plasma total homocysteine and methionine. The diagnosis can be substantiated by detection of biallelic pathogenic variants in Homocystinuria 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 family members and prenatal testing for a pregnancy at increased risk are possible if the	## Diagnosis Guidelines for the diagnosis and management of classic homocystinuria have been developed in Europe [ Classic homocystinuria is caused by deficiency of cystathionine β-synthase (CBS), a pyridoxine (vitamin B Homocystinuria caused by CBS deficiency (classic homocystinuria) Classic homocystinuria can be detected in some (not all) affected individuals by screening the newborn blood spot specimen for hypermethioninemia. The method used to measure methionine on newborn screening is tandem mass spectrometry (MS/MS). If the initial screening test result exceeds the cut-off level of methionine, follow-up testing is required. This may be: A repeat dried blood specimen submitted to the newborn screening program; or Quantitative plasma amino acid analysis and analysis of plasma total homocysteine as recommended in Newborn Screening ACT Sheets and Confirmatory Algorithms for Methionine by the American College of Medical Genetics (see The choice between the dried blood specimen and the plasma analyses is based on the recommendation of the screening program, which usually depends on the degree of the methionine increase in the initial screen. If (1) above is selected, and if the result confirms hypermethioninemia, plasma total homocysteine analysis and plasma amino acid analysis for methionine concentration should be performed to confirm or exclude the diagnosis of classic homocystinuria ( Of note: At least one newborn screening program performs second-tier testing for homocysteine on all newborn specimens with elevated methionine in order to reduce the frequency of false positive results [ Newborn screening is for methionine and not for homocysteine. Thus, other causes of elevated total homocysteine, such as disorders of remethylation (e.g., methylenetetrahydrofolate reductase deficiency and the cobalamin defects; see Virtually all infants with classic homocystinuria detected by newborn screening programs have had pyridoxine (vitamin B Measurement of total homocysteine as a primary newborn screening marker is used in Qatar, which has the highest reported incidence of homocystinuria [ The major clinical findings in classic homocystinuria: Ectopia lentis (dislocation of the ocular lens) and/or severe myopia Skeletal abnormalities (e.g., excessive height, long narrow limbs [dolichostenomelia], scoliosis, pectus excavatum) that may give the clinical impression of Marfan syndrome, but without joint hypermobility Vascular abnormalities characterized by thromboembolism Developmental delay/intellectual disability The diagnosis of classic homocystinuria Plasma homocysteine concentration must be determined in the absence of pyridoxine supplementation (including a multivitamin) for two weeks. The cardinal biochemical features, including markedly increased concentrations of plasma total homocysteine (tHcy) and methionine, are summarized in Cardinal Biochemical Findings that Establish the Diagnosis of Homocystinuria Click Plasma tHcy measurement is an effective method for assuring accurate diagnosis of homocystinuria. Even after a week of storage without deproteinization, virtually all tHcy can still be recovered by a method of preparation that includes a reducing agent such as dithiothreitol [ Molecular genetic testing approaches can include Sequence analysis of Targeted analysis is performed only in the Qatari population, in which a single pathogenic variant ( For an introduction to multigene panels click Molecular Genetic Testing Used in Homocystinuria Caused by Cystathionine β-Synthase 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. Nine individuals with deletions or duplications involving 25 or more nucleotides have been reported to date [ Analysis of CBS enzyme activity may be performed when molecular analysis fails to identify two pathogenic variants in Note: Enzyme activity testing, which has been used in the past to confirm the diagnosis of homocystinuria when molecular testing genetic testing results are not diagnostic, is no longer available in the US. The affected individual is given 100 mg pyridoxine daily for two consecutive days; concentrations of plasma total homocysteine and amino acids are measured 48 hours after the first dose. A reduction of 30% or more in plasma total homocysteine and/or plasma methionine concentration suggests B If no significant change occurs, 200 mg pyridoxine is given orally for two consecutive days and the plasma total homocysteine and amino acid analysis are repeated after 48 hours on this dose. If still no change has occurred, 300 mg of pyridoxine is given to the neonate. If plasma homocysteine and methionine concentrations are not significantly decreased after the last dose of pyridoxine, it is concluded that the individual is B The affected individual is given 100 mg pyridoxine daily for two consecutive days, and the concentrations of plasma total homocysteine and amino acids are again measured 48 hours after the first dose. A reduction of 30% or more in plasma total homocysteine and/or plasma methionine concentration suggests B If no significant change occurs, 200 mg pyridoxine is given orally for two consecutive days and the plasma total homocysteine and amino acid analysis are repeated after 48 hours on this dose. If still no change has occurred, 500 mg of pyridoxine is given orally to a child or adult. If plasma homocysteine and methionine concentrations are not significantly decreased after the last dose of pyridoxine, it is concluded that the individual is B Note: (1) Infants should not receive more than 300 mg of pyridoxine. Several infants given daily doses of 500 mg pyridoxine developed respiratory failure and required ventilatory support. The respiratory symptoms resolved on withdrawal of pyridoxine [ • A repeat dried blood specimen submitted to the newborn screening program; or • Quantitative plasma amino acid analysis and analysis of plasma total homocysteine as recommended in Newborn Screening ACT Sheets and Confirmatory Algorithms for Methionine by the American College of Medical Genetics (see • At least one newborn screening program performs second-tier testing for homocysteine on all newborn specimens with elevated methionine in order to reduce the frequency of false positive results [ • Newborn screening is for methionine and not for homocysteine. Thus, other causes of elevated total homocysteine, such as disorders of remethylation (e.g., methylenetetrahydrofolate reductase deficiency and the cobalamin defects; see • Virtually all infants with classic homocystinuria detected by newborn screening programs have had pyridoxine (vitamin B • Measurement of total homocysteine as a primary newborn screening marker is used in Qatar, which has the highest reported incidence of homocystinuria [ • Ectopia lentis (dislocation of the ocular lens) and/or severe myopia • Skeletal abnormalities (e.g., excessive height, long narrow limbs [dolichostenomelia], scoliosis, pectus excavatum) that may give the clinical impression of Marfan syndrome, but without joint hypermobility • Vascular abnormalities characterized by thromboembolism • Developmental delay/intellectual disability • Sequence analysis of • Targeted analysis is performed only in the Qatari population, in which a single pathogenic variant ( • The affected individual is given 100 mg pyridoxine daily for two consecutive days; concentrations of plasma total homocysteine and amino acids are measured 48 hours after the first dose. • A reduction of 30% or more in plasma total homocysteine and/or plasma methionine concentration suggests B • If no significant change occurs, 200 mg pyridoxine is given orally for two consecutive days and the plasma total homocysteine and amino acid analysis are repeated after 48 hours on this dose. • If still no change has occurred, 300 mg of pyridoxine is given to the neonate. If plasma homocysteine and methionine concentrations are not significantly decreased after the last dose of pyridoxine, it is concluded that the individual is B • A reduction of 30% or more in plasma total homocysteine and/or plasma methionine concentration suggests B • If no significant change occurs, 200 mg pyridoxine is given orally for two consecutive days and the plasma total homocysteine and amino acid analysis are repeated after 48 hours on this dose. • If still no change has occurred, 300 mg of pyridoxine is given to the neonate. If plasma homocysteine and methionine concentrations are not significantly decreased after the last dose of pyridoxine, it is concluded that the individual is B • The affected individual is given 100 mg pyridoxine daily for two consecutive days, and the concentrations of plasma total homocysteine and amino acids are again measured 48 hours after the first dose. • A reduction of 30% or more in plasma total homocysteine and/or plasma methionine concentration suggests B • If no significant change occurs, 200 mg pyridoxine is given orally for two consecutive days and the plasma total homocysteine and amino acid analysis are repeated after 48 hours on this dose. • If still no change has occurred, 500 mg of pyridoxine is given orally to a child or adult. If plasma homocysteine and methionine concentrations are not significantly decreased after the last dose of pyridoxine, it is concluded that the individual is B • A reduction of 30% or more in plasma total homocysteine and/or plasma methionine concentration suggests B • If no significant change occurs, 200 mg pyridoxine is given orally for two consecutive days and the plasma total homocysteine and amino acid analysis are repeated after 48 hours on this dose. • If still no change has occurred, 500 mg of pyridoxine is given orally to a child or adult. If plasma homocysteine and methionine concentrations are not significantly decreased after the last dose of pyridoxine, it is concluded that the individual is B • A reduction of 30% or more in plasma total homocysteine and/or plasma methionine concentration suggests B • If no significant change occurs, 200 mg pyridoxine is given orally for two consecutive days and the plasma total homocysteine and amino acid analysis are repeated after 48 hours on this dose. • If still no change has occurred, 300 mg of pyridoxine is given to the neonate. If plasma homocysteine and methionine concentrations are not significantly decreased after the last dose of pyridoxine, it is concluded that the individual is B • A reduction of 30% or more in plasma total homocysteine and/or plasma methionine concentration suggests B • If no significant change occurs, 200 mg pyridoxine is given orally for two consecutive days and the plasma total homocysteine and amino acid analysis are repeated after 48 hours on this dose. • If still no change has occurred, 500 mg of pyridoxine is given orally to a child or adult. If plasma homocysteine and methionine concentrations are not significantly decreased after the last dose of pyridoxine, it is concluded that the individual is B ## Suggestive Findings Homocystinuria caused by CBS deficiency (classic homocystinuria) Classic homocystinuria can be detected in some (not all) affected individuals by screening the newborn blood spot specimen for hypermethioninemia. The method used to measure methionine on newborn screening is tandem mass spectrometry (MS/MS). If the initial screening test result exceeds the cut-off level of methionine, follow-up testing is required. This may be: A repeat dried blood specimen submitted to the newborn screening program; or Quantitative plasma amino acid analysis and analysis of plasma total homocysteine as recommended in Newborn Screening ACT Sheets and Confirmatory Algorithms for Methionine by the American College of Medical Genetics (see The choice between the dried blood specimen and the plasma analyses is based on the recommendation of the screening program, which usually depends on the degree of the methionine increase in the initial screen. If (1) above is selected, and if the result confirms hypermethioninemia, plasma total homocysteine analysis and plasma amino acid analysis for methionine concentration should be performed to confirm or exclude the diagnosis of classic homocystinuria ( Of note: At least one newborn screening program performs second-tier testing for homocysteine on all newborn specimens with elevated methionine in order to reduce the frequency of false positive results [ Newborn screening is for methionine and not for homocysteine. Thus, other causes of elevated total homocysteine, such as disorders of remethylation (e.g., methylenetetrahydrofolate reductase deficiency and the cobalamin defects; see Virtually all infants with classic homocystinuria detected by newborn screening programs have had pyridoxine (vitamin B Measurement of total homocysteine as a primary newborn screening marker is used in Qatar, which has the highest reported incidence of homocystinuria [ The major clinical findings in classic homocystinuria: Ectopia lentis (dislocation of the ocular lens) and/or severe myopia Skeletal abnormalities (e.g., excessive height, long narrow limbs [dolichostenomelia], scoliosis, pectus excavatum) that may give the clinical impression of Marfan syndrome, but without joint hypermobility Vascular abnormalities characterized by thromboembolism Developmental delay/intellectual disability • A repeat dried blood specimen submitted to the newborn screening program; or • Quantitative plasma amino acid analysis and analysis of plasma total homocysteine as recommended in Newborn Screening ACT Sheets and Confirmatory Algorithms for Methionine by the American College of Medical Genetics (see • At least one newborn screening program performs second-tier testing for homocysteine on all newborn specimens with elevated methionine in order to reduce the frequency of false positive results [ • Newborn screening is for methionine and not for homocysteine. Thus, other causes of elevated total homocysteine, such as disorders of remethylation (e.g., methylenetetrahydrofolate reductase deficiency and the cobalamin defects; see • Virtually all infants with classic homocystinuria detected by newborn screening programs have had pyridoxine (vitamin B • Measurement of total homocysteine as a primary newborn screening marker is used in Qatar, which has the highest reported incidence of homocystinuria [ • Ectopia lentis (dislocation of the ocular lens) and/or severe myopia • Skeletal abnormalities (e.g., excessive height, long narrow limbs [dolichostenomelia], scoliosis, pectus excavatum) that may give the clinical impression of Marfan syndrome, but without joint hypermobility • Vascular abnormalities characterized by thromboembolism • Developmental delay/intellectual disability ## Newborn Screening Classic homocystinuria can be detected in some (not all) affected individuals by screening the newborn blood spot specimen for hypermethioninemia. The method used to measure methionine on newborn screening is tandem mass spectrometry (MS/MS). If the initial screening test result exceeds the cut-off level of methionine, follow-up testing is required. This may be: A repeat dried blood specimen submitted to the newborn screening program; or Quantitative plasma amino acid analysis and analysis of plasma total homocysteine as recommended in Newborn Screening ACT Sheets and Confirmatory Algorithms for Methionine by the American College of Medical Genetics (see The choice between the dried blood specimen and the plasma analyses is based on the recommendation of the screening program, which usually depends on the degree of the methionine increase in the initial screen. If (1) above is selected, and if the result confirms hypermethioninemia, plasma total homocysteine analysis and plasma amino acid analysis for methionine concentration should be performed to confirm or exclude the diagnosis of classic homocystinuria ( Of note: At least one newborn screening program performs second-tier testing for homocysteine on all newborn specimens with elevated methionine in order to reduce the frequency of false positive results [ Newborn screening is for methionine and not for homocysteine. Thus, other causes of elevated total homocysteine, such as disorders of remethylation (e.g., methylenetetrahydrofolate reductase deficiency and the cobalamin defects; see Virtually all infants with classic homocystinuria detected by newborn screening programs have had pyridoxine (vitamin B Measurement of total homocysteine as a primary newborn screening marker is used in Qatar, which has the highest reported incidence of homocystinuria [ • A repeat dried blood specimen submitted to the newborn screening program; or • Quantitative plasma amino acid analysis and analysis of plasma total homocysteine as recommended in Newborn Screening ACT Sheets and Confirmatory Algorithms for Methionine by the American College of Medical Genetics (see • At least one newborn screening program performs second-tier testing for homocysteine on all newborn specimens with elevated methionine in order to reduce the frequency of false positive results [ • Newborn screening is for methionine and not for homocysteine. Thus, other causes of elevated total homocysteine, such as disorders of remethylation (e.g., methylenetetrahydrofolate reductase deficiency and the cobalamin defects; see • Virtually all infants with classic homocystinuria detected by newborn screening programs have had pyridoxine (vitamin B • Measurement of total homocysteine as a primary newborn screening marker is used in Qatar, which has the highest reported incidence of homocystinuria [ ## Clinical Findings The major clinical findings in classic homocystinuria: Ectopia lentis (dislocation of the ocular lens) and/or severe myopia Skeletal abnormalities (e.g., excessive height, long narrow limbs [dolichostenomelia], scoliosis, pectus excavatum) that may give the clinical impression of Marfan syndrome, but without joint hypermobility Vascular abnormalities characterized by thromboembolism Developmental delay/intellectual disability • Ectopia lentis (dislocation of the ocular lens) and/or severe myopia • Skeletal abnormalities (e.g., excessive height, long narrow limbs [dolichostenomelia], scoliosis, pectus excavatum) that may give the clinical impression of Marfan syndrome, but without joint hypermobility • Vascular abnormalities characterized by thromboembolism • Developmental delay/intellectual disability ## Establishing the Diagnosis The diagnosis of classic homocystinuria Plasma homocysteine concentration must be determined in the absence of pyridoxine supplementation (including a multivitamin) for two weeks. The cardinal biochemical features, including markedly increased concentrations of plasma total homocysteine (tHcy) and methionine, are summarized in Cardinal Biochemical Findings that Establish the Diagnosis of Homocystinuria Click Plasma tHcy measurement is an effective method for assuring accurate diagnosis of homocystinuria. Even after a week of storage without deproteinization, virtually all tHcy can still be recovered by a method of preparation that includes a reducing agent such as dithiothreitol [ Molecular genetic testing approaches can include Sequence analysis of Targeted analysis is performed only in the Qatari population, in which a single pathogenic variant ( For an introduction to multigene panels click Molecular Genetic Testing Used in Homocystinuria Caused by Cystathionine β-Synthase 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. Nine individuals with deletions or duplications involving 25 or more nucleotides have been reported to date [ Analysis of CBS enzyme activity may be performed when molecular analysis fails to identify two pathogenic variants in Note: Enzyme activity testing, which has been used in the past to confirm the diagnosis of homocystinuria when molecular testing genetic testing results are not diagnostic, is no longer available in the US. • Sequence analysis of • Targeted analysis is performed only in the Qatari population, in which a single pathogenic variant ( ## Plasma Homocysteine and Amino Acids Plasma homocysteine concentration must be determined in the absence of pyridoxine supplementation (including a multivitamin) for two weeks. The cardinal biochemical features, including markedly increased concentrations of plasma total homocysteine (tHcy) and methionine, are summarized in Cardinal Biochemical Findings that Establish the Diagnosis of Homocystinuria Click Plasma tHcy measurement is an effective method for assuring accurate diagnosis of homocystinuria. Even after a week of storage without deproteinization, virtually all tHcy can still be recovered by a method of preparation that includes a reducing agent such as dithiothreitol [ ## Molecular Genetic Testing Molecular genetic testing approaches can include Sequence analysis of Targeted analysis is performed only in the Qatari population, in which a single pathogenic variant ( For an introduction to multigene panels click Molecular Genetic Testing Used in Homocystinuria Caused by Cystathionine β-Synthase 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. Nine individuals with deletions or duplications involving 25 or more nucleotides have been reported to date [ • Sequence analysis of • Targeted analysis is performed only in the Qatari population, in which a single pathogenic variant ( ## CBS Enzyme Activity in Cultured Fibroblasts Analysis of CBS enzyme activity may be performed when molecular analysis fails to identify two pathogenic variants in Note: Enzyme activity testing, which has been used in the past to confirm the diagnosis of homocystinuria when molecular testing genetic testing results are not diagnostic, is no longer available in the US. ## Testing Following Establishment of the Diagnosis The affected individual is given 100 mg pyridoxine daily for two consecutive days; concentrations of plasma total homocysteine and amino acids are measured 48 hours after the first dose. A reduction of 30% or more in plasma total homocysteine and/or plasma methionine concentration suggests B If no significant change occurs, 200 mg pyridoxine is given orally for two consecutive days and the plasma total homocysteine and amino acid analysis are repeated after 48 hours on this dose. If still no change has occurred, 300 mg of pyridoxine is given to the neonate. If plasma homocysteine and methionine concentrations are not significantly decreased after the last dose of pyridoxine, it is concluded that the individual is B The affected individual is given 100 mg pyridoxine daily for two consecutive days, and the concentrations of plasma total homocysteine and amino acids are again measured 48 hours after the first dose. A reduction of 30% or more in plasma total homocysteine and/or plasma methionine concentration suggests B If no significant change occurs, 200 mg pyridoxine is given orally for two consecutive days and the plasma total homocysteine and amino acid analysis are repeated after 48 hours on this dose. If still no change has occurred, 500 mg of pyridoxine is given orally to a child or adult. If plasma homocysteine and methionine concentrations are not significantly decreased after the last dose of pyridoxine, it is concluded that the individual is B Note: (1) Infants should not receive more than 300 mg of pyridoxine. Several infants given daily doses of 500 mg pyridoxine developed respiratory failure and required ventilatory support. The respiratory symptoms resolved on withdrawal of pyridoxine [ • The affected individual is given 100 mg pyridoxine daily for two consecutive days; concentrations of plasma total homocysteine and amino acids are measured 48 hours after the first dose. • A reduction of 30% or more in plasma total homocysteine and/or plasma methionine concentration suggests B • If no significant change occurs, 200 mg pyridoxine is given orally for two consecutive days and the plasma total homocysteine and amino acid analysis are repeated after 48 hours on this dose. • If still no change has occurred, 300 mg of pyridoxine is given to the neonate. If plasma homocysteine and methionine concentrations are not significantly decreased after the last dose of pyridoxine, it is concluded that the individual is B • A reduction of 30% or more in plasma total homocysteine and/or plasma methionine concentration suggests B • If no significant change occurs, 200 mg pyridoxine is given orally for two consecutive days and the plasma total homocysteine and amino acid analysis are repeated after 48 hours on this dose. • If still no change has occurred, 300 mg of pyridoxine is given to the neonate. If plasma homocysteine and methionine concentrations are not significantly decreased after the last dose of pyridoxine, it is concluded that the individual is B • The affected individual is given 100 mg pyridoxine daily for two consecutive days, and the concentrations of plasma total homocysteine and amino acids are again measured 48 hours after the first dose. • A reduction of 30% or more in plasma total homocysteine and/or plasma methionine concentration suggests B • If no significant change occurs, 200 mg pyridoxine is given orally for two consecutive days and the plasma total homocysteine and amino acid analysis are repeated after 48 hours on this dose. • If still no change has occurred, 500 mg of pyridoxine is given orally to a child or adult. If plasma homocysteine and methionine concentrations are not significantly decreased after the last dose of pyridoxine, it is concluded that the individual is B • A reduction of 30% or more in plasma total homocysteine and/or plasma methionine concentration suggests B • If no significant change occurs, 200 mg pyridoxine is given orally for two consecutive days and the plasma total homocysteine and amino acid analysis are repeated after 48 hours on this dose. • If still no change has occurred, 500 mg of pyridoxine is given orally to a child or adult. If plasma homocysteine and methionine concentrations are not significantly decreased after the last dose of pyridoxine, it is concluded that the individual is B • A reduction of 30% or more in plasma total homocysteine and/or plasma methionine concentration suggests B • If no significant change occurs, 200 mg pyridoxine is given orally for two consecutive days and the plasma total homocysteine and amino acid analysis are repeated after 48 hours on this dose. • If still no change has occurred, 300 mg of pyridoxine is given to the neonate. If plasma homocysteine and methionine concentrations are not significantly decreased after the last dose of pyridoxine, it is concluded that the individual is B • A reduction of 30% or more in plasma total homocysteine and/or plasma methionine concentration suggests B • If no significant change occurs, 200 mg pyridoxine is given orally for two consecutive days and the plasma total homocysteine and amino acid analysis are repeated after 48 hours on this dose. • If still no change has occurred, 500 mg of pyridoxine is given orally to a child or adult. If plasma homocysteine and methionine concentrations are not significantly decreased after the last dose of pyridoxine, it is concluded that the individual is B ## Clinical Characteristics Homocystinuria is characterized by involvement of the eye, skeletal system, vascular system, and CNS. All four or only one of the systems can be involved. Expressivity is variable for all of the clinical signs. It is not unusual for a previously asymptomatic individual to present in adult years with only a thromboembolic event that is often cerebrovascular [ The two phenotypic variants of classic homocystinuria are B High myopia may be present in the absence of ectopia lentis. Individuals with homocystinuria are prone to osteoporosis, especially of the vertebrae and long bones; 50% of individuals show signs of osteoporosis by their teens. Osteoporosis may be detected radiographically by lateral view of the lumbar spine or bone density studies. DXA bone density analysis usually shows reduced density in the lumbar spine and hip [ Scoliosis, high-arched palate, arachnodactyly, pes cavus, pectus excavatum or pectus carinatum, and genu valgum are also frequently seen. Among B Pregnancy increases the risk for thromboembolism, especially in the postpartum period [ Seizures occur in 21% of untreated individuals. Many individuals have psychiatric problems including personality disorder, anxiety, depression, obsessive-compulsive behavior, and psychotic episodes. Psychosis may be a presenting sign in adolescence [ Extrapyramidal signs such as dystonia may occur. The presence of a single "Homocystinuria" was named for excess homocystine in the urine, though now it is primarily detected by increased total homocysteine in plasma. Homocystinuria may be caused by genetically determined deficient activity of cystathionine β-synthase (CBS), or a variety of genetic problems that ultimately interfere with conversion of homocysteine to methionine (e.g., methylenetetrahydrofolate reductase deficiency and abnormalities of cobalamin transport or metabolism). For details on the latter conditions, see Non-genetically determined severe dietary lack of cobalamin (vitamin B To attain maximum specificity when using the term "homocystinuria," the particular defect in question may be added; e.g., "homocystinuria caused by CBS deficiency" [ Classic homocystinuria as defined in this Prevalence is at present undetermined; both newborn screening and clinical ascertainment underestimate prevalence because of undetected cases [ ## Clinical Description Homocystinuria is characterized by involvement of the eye, skeletal system, vascular system, and CNS. All four or only one of the systems can be involved. Expressivity is variable for all of the clinical signs. It is not unusual for a previously asymptomatic individual to present in adult years with only a thromboembolic event that is often cerebrovascular [ The two phenotypic variants of classic homocystinuria are B High myopia may be present in the absence of ectopia lentis. Individuals with homocystinuria are prone to osteoporosis, especially of the vertebrae and long bones; 50% of individuals show signs of osteoporosis by their teens. Osteoporosis may be detected radiographically by lateral view of the lumbar spine or bone density studies. DXA bone density analysis usually shows reduced density in the lumbar spine and hip [ Scoliosis, high-arched palate, arachnodactyly, pes cavus, pectus excavatum or pectus carinatum, and genu valgum are also frequently seen. Among B Pregnancy increases the risk for thromboembolism, especially in the postpartum period [ Seizures occur in 21% of untreated individuals. Many individuals have psychiatric problems including personality disorder, anxiety, depression, obsessive-compulsive behavior, and psychotic episodes. Psychosis may be a presenting sign in adolescence [ Extrapyramidal signs such as dystonia may occur. ## Genotype-Phenotype Correlations The presence of a single ## Nomenclature "Homocystinuria" was named for excess homocystine in the urine, though now it is primarily detected by increased total homocysteine in plasma. Homocystinuria may be caused by genetically determined deficient activity of cystathionine β-synthase (CBS), or a variety of genetic problems that ultimately interfere with conversion of homocysteine to methionine (e.g., methylenetetrahydrofolate reductase deficiency and abnormalities of cobalamin transport or metabolism). For details on the latter conditions, see Non-genetically determined severe dietary lack of cobalamin (vitamin B To attain maximum specificity when using the term "homocystinuria," the particular defect in question may be added; e.g., "homocystinuria caused by CBS deficiency" [ Classic homocystinuria as defined in this ## Prevalence Prevalence is at present undetermined; both newborn screening and clinical ascertainment underestimate prevalence because of undetected cases [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The clinical condition that most closely mimics classic homocystinuria is Increased concentrations of homocysteine or methionine also occur in biochemical genetic disorders that generally fall into two groups (see Biochemical Aspects of Disorders Affecting Methionine Metabolism GNMT = glycine N-methyltransferase; MAT = methionine adenosyltransferase; MTHFR = methylenetetrahydrofolate reductase ## Management To establish the extent of disease and needs in all individuals diagnosed with homocystinuria caused by cystathionine β-synthase deficiency, the following are recommended: Consultation with a clinical geneticist/medical biochemical geneticist for additional testing and treatment plan Pyridoxine (vitamin B Consultation with a genetic counselor for genetic counseling and recurrence risk counseling Treatment should be managed by a biochemical geneticist and metabolic dietician and aimed at prevention of primary manifestations of homocystinuria. For published management guidelines, see Complications should be managed appropriately (e.g., surgery for ectopia lentis) [ The principles of treatment are to correct the biochemical abnormalities – especially to control the elevated plasma homocysteine concentrations as much as possible, to prevent or at least reduce the complications of homocystinuria [ The best results have been reported in those individuals identified by newborn screening and treated shortly after birth in whom the plasma free homocystine concentration is maintained below 11 µmol/L (preferably, ≤5 µmol/L) [ These goals may need revision when very long-term data becomes available. Measures used to control total plasma homocysteine concentration include vitamin B Details about each aspect of treatment follow. Pyridoxine may also be included in treatment despite evidence of B The majority of B The diet for homocystinuria is very complex and the skills of an experienced metabolic dietician must be utilized. Dietary treatment reduces methionine intake by restricting natural protein intake. However, to prevent protein malnutrition, a methionine-free amino acid formula supplying the other amino acids (as well as cysteine, which may be an essential amino acid in CBS deficiency) is provided. Breast feeding may be continued in combination with the methionine-free amino acid infant formula [ For children the initial betaine dose is 50 mg/kg twice daily, adjusted according to response (increased weekly by 50 mg/kg increments). For adults the initial dose is 3 g twice daily. The dose and frequency are adjusted according to biochemical response. There is unlikely to be any benefit in exceeding a dose of 150-200 mg/kg/day [ Betaine may be added to the treatment regimen in individuals poorly compliant with dietary treatment or may become the major treatment modality in those intolerant of the diet. Individuals who are pyridoxine non-responsive who were unable to attain metabolic control with diet substantially reduced their plasma homocysteine concentrations when betaine was supplemented [ Side effects of betaine are few. (1) Some affected individuals develop a detectable body odor, resulting in reduced compliance. (2) The increase in methionine produced by betaine is usually harmless; however, cerebral edema has occurred when hypermethioninemia is extreme (>1000 µmol/L) [ Note: In a murine model for homocystinuria the effect of betaine treatment diminished significantly over time [ Affected individuals should be monitored at regular intervals to detect any clinical complications that may develop, to assess dietary compliance, and to measure plasma total homocysteine and methionine concentrations. Infants should be monitored monthly for the first six months of life and bimonthly until age one year, then every three months until age three years. Semiannual monitoring through the remainder of childhood and annual monitoring in adolescence and adulthood are indicated. Complications should be promptly addressed with appropriate therapy. Plasma total homocysteine and methionine concentrations should be monitored in all persons receiving betaine (see Vitamin B Regular ophthalmology assessments can identify eye complications such as progressive myopia and ectopia lentis and allow for early treatment and prevention of further complications such as retinal detachment. DXA scans should be performed every three to five years following adolescence to monitor for osteoporosis [ Oral contraceptives, which may tend to increase coagulability and represent risk for thromboembolism, should be avoided in females with homocystinuria. Surgery should also be avoided if possible because the increase in plasma homocysteine concentrations during surgery and especially post-surgery elevates the risk for a thromboembolic event. If surgery is required, intravenous fluids containing 5% dextrose in 0.5 N saline at 1.5 times maintenance should be administered before, during, and after surgery until fluids can be taken orally. If fluids at 1.5 times maintenance represent a cardiovascular risk as a result of fluid overload, basic fluid maintenance may be administered with careful clinical observation. Plasma concentrations of total homocysteine and amino acids should be measured in at-risk sibs as soon as possible after birth so that morbidity and mortality can be reduced by early diagnosis and treatment. If the See Because women with homocystinuria may be at greater than average risk for thromboembolism, especially post partum, prophylactic anticoagulation during the third trimester of pregnancy and post partum is recommended. The usual regimen is injection of low molecular-weight heparin during the last two weeks of pregnancy and the first six weeks post partum [ Maternal homocystinuria, unlike maternal phenylketonuria (see CBS enzyme replacement therapy is currently in development in the preclinical phase [ Search • Consultation with a clinical geneticist/medical biochemical geneticist for additional testing and treatment plan • Pyridoxine (vitamin B • Consultation with a genetic counselor for genetic counseling and recurrence risk counseling ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in all individuals diagnosed with homocystinuria caused by cystathionine β-synthase deficiency, the following are recommended: Consultation with a clinical geneticist/medical biochemical geneticist for additional testing and treatment plan Pyridoxine (vitamin B Consultation with a genetic counselor for genetic counseling and recurrence risk counseling • Consultation with a clinical geneticist/medical biochemical geneticist for additional testing and treatment plan • Pyridoxine (vitamin B • Consultation with a genetic counselor for genetic counseling and recurrence risk counseling ## Treatment of Manifestations Treatment should be managed by a biochemical geneticist and metabolic dietician and aimed at prevention of primary manifestations of homocystinuria. For published management guidelines, see Complications should be managed appropriately (e.g., surgery for ectopia lentis) [ ## Prevention of Primary Manifestations The principles of treatment are to correct the biochemical abnormalities – especially to control the elevated plasma homocysteine concentrations as much as possible, to prevent or at least reduce the complications of homocystinuria [ The best results have been reported in those individuals identified by newborn screening and treated shortly after birth in whom the plasma free homocystine concentration is maintained below 11 µmol/L (preferably, ≤5 µmol/L) [ These goals may need revision when very long-term data becomes available. Measures used to control total plasma homocysteine concentration include vitamin B Details about each aspect of treatment follow. Pyridoxine may also be included in treatment despite evidence of B The majority of B The diet for homocystinuria is very complex and the skills of an experienced metabolic dietician must be utilized. Dietary treatment reduces methionine intake by restricting natural protein intake. However, to prevent protein malnutrition, a methionine-free amino acid formula supplying the other amino acids (as well as cysteine, which may be an essential amino acid in CBS deficiency) is provided. Breast feeding may be continued in combination with the methionine-free amino acid infant formula [ For children the initial betaine dose is 50 mg/kg twice daily, adjusted according to response (increased weekly by 50 mg/kg increments). For adults the initial dose is 3 g twice daily. The dose and frequency are adjusted according to biochemical response. There is unlikely to be any benefit in exceeding a dose of 150-200 mg/kg/day [ Betaine may be added to the treatment regimen in individuals poorly compliant with dietary treatment or may become the major treatment modality in those intolerant of the diet. Individuals who are pyridoxine non-responsive who were unable to attain metabolic control with diet substantially reduced their plasma homocysteine concentrations when betaine was supplemented [ Side effects of betaine are few. (1) Some affected individuals develop a detectable body odor, resulting in reduced compliance. (2) The increase in methionine produced by betaine is usually harmless; however, cerebral edema has occurred when hypermethioninemia is extreme (>1000 µmol/L) [ Note: In a murine model for homocystinuria the effect of betaine treatment diminished significantly over time [ ## Surveillance Affected individuals should be monitored at regular intervals to detect any clinical complications that may develop, to assess dietary compliance, and to measure plasma total homocysteine and methionine concentrations. Infants should be monitored monthly for the first six months of life and bimonthly until age one year, then every three months until age three years. Semiannual monitoring through the remainder of childhood and annual monitoring in adolescence and adulthood are indicated. Complications should be promptly addressed with appropriate therapy. Plasma total homocysteine and methionine concentrations should be monitored in all persons receiving betaine (see Vitamin B Regular ophthalmology assessments can identify eye complications such as progressive myopia and ectopia lentis and allow for early treatment and prevention of further complications such as retinal detachment. DXA scans should be performed every three to five years following adolescence to monitor for osteoporosis [ ## Agents/Circumstances to Avoid Oral contraceptives, which may tend to increase coagulability and represent risk for thromboembolism, should be avoided in females with homocystinuria. Surgery should also be avoided if possible because the increase in plasma homocysteine concentrations during surgery and especially post-surgery elevates the risk for a thromboembolic event. If surgery is required, intravenous fluids containing 5% dextrose in 0.5 N saline at 1.5 times maintenance should be administered before, during, and after surgery until fluids can be taken orally. If fluids at 1.5 times maintenance represent a cardiovascular risk as a result of fluid overload, basic fluid maintenance may be administered with careful clinical observation. ## Evaluation of Relatives at Risk Plasma concentrations of total homocysteine and amino acids should be measured in at-risk sibs as soon as possible after birth so that morbidity and mortality can be reduced by early diagnosis and treatment. If the See ## Pregnancy Management Because women with homocystinuria may be at greater than average risk for thromboembolism, especially post partum, prophylactic anticoagulation during the third trimester of pregnancy and post partum is recommended. The usual regimen is injection of low molecular-weight heparin during the last two weeks of pregnancy and the first six weeks post partum [ Maternal homocystinuria, unlike maternal phenylketonuria (see ## Therapies Under Investigation CBS enzyme replacement therapy is currently in development in the preclinical phase [ Search ## Genetic Counseling Homocystinuria caused by cystathionine β-synthase deficiency (classic homocystinuria) is inherited in an autosomal recessive manner. The unaffected parents of an affected individual are obligate heterozygotes (i.e., carriers of at least one Heterozygotes (carriers) are asymptomatic and are not at risk of developing homocystinuria. Because it is possible (though unlikely) that a parent has classic homocystinuria but has remained asymptomatic, it is appropriate to obtain a detailed medical history and perform an examination as well as plasma homocysteine and amino acid analysis in both parents. This becomes even more imperative if the mother is considering future pregnancies, as affected women are at increased risk for thromboembolic events during pregnancy. 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 homocystinuria. The offspring of an individual with classic homocystinuria have at least one The offspring of a proband whose partner is a carrier have a 50% chance of being affected and a 50% chance of being carriers. All offspring of a proband whose partner also has classic homocystinuria will have classic homocystinuria. Heterozygotes for CBS deficiency have normal fasting plasma total homocysteine concentration. Plasma total homocysteine concentration response after methionine loading (100 mg methionine/kg [671 µmol/kg]) is abnormal in 73% of heterozygotes with pyridoxine non-responsive homocystinuria and 33% of heterozygotes with pyridoxine-responsive homocystinuria [ Note: Caution should be exercised in performing a methionine loading test because adverse reactions have been reported [ 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 If 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 unaffected parents of an affected individual are obligate heterozygotes (i.e., carriers of at least one • Heterozygotes (carriers) are asymptomatic and are not at risk of developing homocystinuria. • Because it is possible (though unlikely) that a parent has classic homocystinuria but has remained asymptomatic, it is appropriate to obtain a detailed medical history and perform an examination as well as plasma homocysteine and amino acid analysis in both parents. This becomes even more imperative if the mother is considering future pregnancies, as affected women are at increased risk for thromboembolic events during pregnancy. • 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 homocystinuria. • The offspring of an individual with classic homocystinuria have at least one • The offspring of a proband whose partner is a carrier have a 50% chance of being affected and a 50% chance of being carriers. • All offspring of a proband whose partner also has classic homocystinuria will have classic homocystinuria. • Heterozygotes for CBS deficiency have normal fasting plasma total homocysteine concentration. • Plasma total homocysteine concentration response after methionine loading (100 mg methionine/kg [671 µmol/kg]) is abnormal in 73% of heterozygotes with pyridoxine non-responsive homocystinuria and 33% of heterozygotes with pyridoxine-responsive homocystinuria [ • Note: Caution should be exercised in performing a methionine loading test because adverse reactions have been reported [ • 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 Homocystinuria caused by cystathionine β-synthase deficiency (classic homocystinuria) is inherited in an autosomal recessive manner. ## Risk to Family Members The unaffected parents of an affected individual are obligate heterozygotes (i.e., carriers of at least one Heterozygotes (carriers) are asymptomatic and are not at risk of developing homocystinuria. Because it is possible (though unlikely) that a parent has classic homocystinuria but has remained asymptomatic, it is appropriate to obtain a detailed medical history and perform an examination as well as plasma homocysteine and amino acid analysis in both parents. This becomes even more imperative if the mother is considering future pregnancies, as affected women are at increased risk for thromboembolic events during pregnancy. 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 homocystinuria. The offspring of an individual with classic homocystinuria have at least one The offspring of a proband whose partner is a carrier have a 50% chance of being affected and a 50% chance of being carriers. All offspring of a proband whose partner also has classic homocystinuria will have classic homocystinuria. • The unaffected parents of an affected individual are obligate heterozygotes (i.e., carriers of at least one • Heterozygotes (carriers) are asymptomatic and are not at risk of developing homocystinuria. • Because it is possible (though unlikely) that a parent has classic homocystinuria but has remained asymptomatic, it is appropriate to obtain a detailed medical history and perform an examination as well as plasma homocysteine and amino acid analysis in both parents. This becomes even more imperative if the mother is considering future pregnancies, as affected women are at increased risk for thromboembolic events during pregnancy. • 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 homocystinuria. • The offspring of an individual with classic homocystinuria have at least one • The offspring of a proband whose partner is a carrier have a 50% chance of being affected and a 50% chance of being carriers. • All offspring of a proband whose partner also has classic homocystinuria will have classic homocystinuria. ## Carrier Detection Heterozygotes for CBS deficiency have normal fasting plasma total homocysteine concentration. Plasma total homocysteine concentration response after methionine loading (100 mg methionine/kg [671 µmol/kg]) is abnormal in 73% of heterozygotes with pyridoxine non-responsive homocystinuria and 33% of heterozygotes with pyridoxine-responsive homocystinuria [ Note: Caution should be exercised in performing a methionine loading test because adverse reactions have been reported [ • Heterozygotes for CBS deficiency have normal fasting plasma total homocysteine concentration. • Plasma total homocysteine concentration response after methionine loading (100 mg methionine/kg [671 µmol/kg]) is abnormal in 73% of heterozygotes with pyridoxine non-responsive homocystinuria and 33% of heterozygotes with pyridoxine-responsive homocystinuria [ • Note: Caution should be exercised in performing a methionine loading test because adverse reactions have been reported [ ## 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 If 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 TEMPLE (Tools Enabling Metabolic Parents LEarning) United Kingdom Screening, Technology and Research in Genetics (STAR-G) United Kingdom Health Resources & Services Administration • • TEMPLE (Tools Enabling Metabolic Parents LEarning) • United Kingdom • • • • • Screening, Technology and Research in Genetics (STAR-G) • • • • • • • United Kingdom • • • Health Resources & Services Administration • ## Molecular Genetics Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency ( The two most common p.Ile278Thr is pan ethnic; overall, it accounts for nearly 25% of all pathogenic variants, including 29% of the variant alleles in the UK and 18% in the US [ p.Gly307Ser is the leading cause of homocystinuria in Ireland (71% of pathogenic variants). It has also been detected frequently in US and Australian affected individuals of "Celtic" origin, including families of Irish, Scottish, English, French, and Portuguese ancestry. It accounts for 21% of pathogenic variants in the UK and 8% in the US [ Variants listed in the table have been provided by the authors. • p.Ile278Thr is pan ethnic; overall, it accounts for nearly 25% of all pathogenic variants, including 29% of the variant alleles in the UK and 18% in the US [ • p.Gly307Ser is the leading cause of homocystinuria in Ireland (71% of pathogenic variants). It has also been detected frequently in US and Australian affected individuals of "Celtic" origin, including families of Irish, Scottish, English, French, and Portuguese ancestry. It accounts for 21% of pathogenic variants in the UK and 8% in the US [ ## References ## Published Guidelines / Consensus Statements ## Literature Cited ## Chapter Notes Authors' website: 18 May 2017 (ha) Comprehensive update posted live 13 November 2014 (me) Comprehensive update posted live 26 April 2011 (me) Comprehensive update posted live 29 March 2006 (me) Comprehensive update posted live 15 August 2005 (cd) Revision: sequence analysis of entire coding region no longer clinically available 15 January 2004 (ca) Review posted live 2 September 2003 (hl) Original submission • 18 May 2017 (ha) Comprehensive update posted live • 13 November 2014 (me) Comprehensive update posted live • 26 April 2011 (me) Comprehensive update posted live • 29 March 2006 (me) Comprehensive update posted live • 15 August 2005 (cd) Revision: sequence analysis of entire coding region no longer clinically available • 15 January 2004 (ca) Review posted live • 2 September 2003 (hl) Original submission ## Author Notes Authors' website: ## Revision History 18 May 2017 (ha) Comprehensive update posted live 13 November 2014 (me) Comprehensive update posted live 26 April 2011 (me) Comprehensive update posted live 29 March 2006 (me) Comprehensive update posted live 15 August 2005 (cd) Revision: sequence analysis of entire coding region no longer clinically available 15 January 2004 (ca) Review posted live 2 September 2003 (hl) Original submission • 18 May 2017 (ha) Comprehensive update posted live • 13 November 2014 (me) Comprehensive update posted live • 26 April 2011 (me) Comprehensive update posted live • 29 March 2006 (me) Comprehensive update posted live • 15 August 2005 (cd) Revision: sequence analysis of entire coding region no longer clinically available • 15 January 2004 (ca) Review posted live • 2 September 2003 (hl) Original submission Methionine metabolic pathway Pathway demonstrating disorders in the biochemical differential diagnosis for homocystinuria	[ "AAM Morris, V Kožich, S Santra, G Andria, TIM Ben-Omran, AB Chakrapani, E Crushell, MJ Henderson, M Hochuli, M Huemer, MCH Janssen, F Maillot, PD Mayne, J McNulty, TM Morrison, H Ogier, S O’Sullivan, M Pavlíková, I Talvares de Almeida, A Terry, S Yap, HJ Blom, KA Chapman. Guidelines for the diagnosis and management of cystathionine β-synthase deficiency.. J Inherit Metab Dis 2017;40:49-74" ]	15/1/2004	18/5/2017	15/8/2005	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
hops	hops	[ "Alkaline phosphatase, tissue-nonspecific isozyme", "ALPL", "Hypophosphatasia" ]	Hypophosphatasia	Kathryn M Dahir, Mark E Nunes	Summary Hypophosphatasia is characterized by defective mineralization of growing or remodeling bone, with or without root-intact tooth loss, in the presence of low activity of serum and bone alkaline phosphatase (ALP). Biallelic The clinical diagnosis of hypophosphatasia can be established in a proband based on clinical diagnostic criteria. The molecular diagnosis of hypophosphatasia can be established in a proband with one major or two minor criteria and biallelic loss-of-function Perinatal and infantile hypophosphatasia are typically inherited in an autosomal recessive manner. Milder forms of hypophosphatasia, especially adult and odontohypophosphatasia, may be inherited in an autosomal recessive or autosomal dominant manner depending on the effect that the Once the	## Diagnosis Clinical diagnostic criteria for hypophosphatasia have been published [ Hypophosphatasia Clinical features of infantile rickets: growth failure, craniotabes, craniosynostosis, blue sclerae, flail chest, costochondral enlargement ("rachitic rosary"), scoliosis, thickening of wrists, knees, and ankles, bowing of the legs, lax ligaments, and hypotonia Premature loss of deciduous teeth beginning with the incisors (unusually and characteristically, the dental root remains attached to the lost tooth); dental caries and early loss or extraction of adult teeth (See Vitamin B Bone pain Typically normal serum calcium and ionized calcium. Note: May be elevated, particularly in the first year of life. Typically normal serum and urine inorganic phosphate. Note: May be elevated. Normal serum vitamin D (25-hydroxy and 1,25-dihydroxy) and parathyroid hormone Prenatal long bone bowing with osteochondral spurs Infantile rickets: undermineralized bones, widened-appearing sutures, brachycephaly, rachitic costochondral rib changes (see Focal bony defects of the metaphyses resembling radiolucent "tongues" (see Defective mineralization of growing/remodeling bone and/or teeth. Bone mineral content increases with age; there may be improved mineralization during adolescence with decreased mineralization in middle age. Alveolar bone loss resulting in premature loss of deciduous teeth typically involving the anterior mandible, with the central incisors lost first. However, any tooth may be affected (see Pathologic fractures. Growing children may have a predilection to metaphyseal fractures; however, epiphyseal and diaphyseal fractures are also seen. In adults, metatarsal stress fractures and femoral pseudofractures prevail. Osteomalacia with lateral pseudofractures ("Looser zones") in adult hypophosphatasia (See Elevation of natural substrates: plasma vitamin B Atypical femoral fractures (pseudofractures) Recurrent metatarsal fractures Poorly healing fractures Chronic musculoskeletal pain Early atraumatic loss of teeth Chondrocalcinosis Nephrocalcinosis Elevation of natural substrates: plasma vitamin B Early nontraumatic loss of primary teeth Presence of rickets on radiographs Short stature or linear growth failure over time Gross motor delay Craniosynostosis Nephrocalcinosis Vitamin B The molecular diagnosis of hypophosphatasia Biallelic loss-of-function A heterozygous Note: (1) Individuals with a heterozygous loss-of-function Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click When the phenotype is indistinguishable from many other skeletal dysplasias, c For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Hypophosphatasia NA = not applicable See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click In individuals with severe (perinatal and infantile) hypophosphatasia, biallelic Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. A few larger Anecdotal reports of individuals with clinical and biochemical features of adult hypophosphatasia with no detected • Clinical features of infantile rickets: growth failure, craniotabes, craniosynostosis, blue sclerae, flail chest, costochondral enlargement ("rachitic rosary"), scoliosis, thickening of wrists, knees, and ankles, bowing of the legs, lax ligaments, and hypotonia • Premature loss of deciduous teeth beginning with the incisors (unusually and characteristically, the dental root remains attached to the lost tooth); dental caries and early loss or extraction of adult teeth (See • Vitamin B • Bone pain • Typically normal serum calcium and ionized calcium. Note: May be elevated, particularly in the first year of life. • Typically normal serum and urine inorganic phosphate. Note: May be elevated. • Normal serum vitamin D (25-hydroxy and 1,25-dihydroxy) and parathyroid hormone • Prenatal long bone bowing with osteochondral spurs • Infantile rickets: undermineralized bones, widened-appearing sutures, brachycephaly, rachitic costochondral rib changes (see • Focal bony defects of the metaphyses resembling radiolucent "tongues" (see • Defective mineralization of growing/remodeling bone and/or teeth. Bone mineral content increases with age; there may be improved mineralization during adolescence with decreased mineralization in middle age. • Alveolar bone loss resulting in premature loss of deciduous teeth typically involving the anterior mandible, with the central incisors lost first. However, any tooth may be affected (see • Pathologic fractures. Growing children may have a predilection to metaphyseal fractures; however, epiphyseal and diaphyseal fractures are also seen. In adults, metatarsal stress fractures and femoral pseudofractures prevail. • Osteomalacia with lateral pseudofractures ("Looser zones") in adult hypophosphatasia (See • Elevation of natural substrates: plasma vitamin B • Atypical femoral fractures (pseudofractures) • Recurrent metatarsal fractures • Poorly healing fractures • Chronic musculoskeletal pain • Early atraumatic loss of teeth • Chondrocalcinosis • Nephrocalcinosis • Elevation of natural substrates: plasma vitamin B • Early nontraumatic loss of primary teeth • Presence of rickets on radiographs • Short stature or linear growth failure over time • Gross motor delay • Craniosynostosis • Nephrocalcinosis • Vitamin B • Biallelic loss-of-function • A heterozygous ## Suggestive Findings Hypophosphatasia Clinical features of infantile rickets: growth failure, craniotabes, craniosynostosis, blue sclerae, flail chest, costochondral enlargement ("rachitic rosary"), scoliosis, thickening of wrists, knees, and ankles, bowing of the legs, lax ligaments, and hypotonia Premature loss of deciduous teeth beginning with the incisors (unusually and characteristically, the dental root remains attached to the lost tooth); dental caries and early loss or extraction of adult teeth (See Vitamin B Bone pain Typically normal serum calcium and ionized calcium. Note: May be elevated, particularly in the first year of life. Typically normal serum and urine inorganic phosphate. Note: May be elevated. Normal serum vitamin D (25-hydroxy and 1,25-dihydroxy) and parathyroid hormone Prenatal long bone bowing with osteochondral spurs Infantile rickets: undermineralized bones, widened-appearing sutures, brachycephaly, rachitic costochondral rib changes (see Focal bony defects of the metaphyses resembling radiolucent "tongues" (see Defective mineralization of growing/remodeling bone and/or teeth. Bone mineral content increases with age; there may be improved mineralization during adolescence with decreased mineralization in middle age. Alveolar bone loss resulting in premature loss of deciduous teeth typically involving the anterior mandible, with the central incisors lost first. However, any tooth may be affected (see Pathologic fractures. Growing children may have a predilection to metaphyseal fractures; however, epiphyseal and diaphyseal fractures are also seen. In adults, metatarsal stress fractures and femoral pseudofractures prevail. Osteomalacia with lateral pseudofractures ("Looser zones") in adult hypophosphatasia (See • Clinical features of infantile rickets: growth failure, craniotabes, craniosynostosis, blue sclerae, flail chest, costochondral enlargement ("rachitic rosary"), scoliosis, thickening of wrists, knees, and ankles, bowing of the legs, lax ligaments, and hypotonia • Premature loss of deciduous teeth beginning with the incisors (unusually and characteristically, the dental root remains attached to the lost tooth); dental caries and early loss or extraction of adult teeth (See • Vitamin B • Bone pain • Typically normal serum calcium and ionized calcium. Note: May be elevated, particularly in the first year of life. • Typically normal serum and urine inorganic phosphate. Note: May be elevated. • Normal serum vitamin D (25-hydroxy and 1,25-dihydroxy) and parathyroid hormone • Prenatal long bone bowing with osteochondral spurs • Infantile rickets: undermineralized bones, widened-appearing sutures, brachycephaly, rachitic costochondral rib changes (see • Focal bony defects of the metaphyses resembling radiolucent "tongues" (see • Defective mineralization of growing/remodeling bone and/or teeth. Bone mineral content increases with age; there may be improved mineralization during adolescence with decreased mineralization in middle age. • Alveolar bone loss resulting in premature loss of deciduous teeth typically involving the anterior mandible, with the central incisors lost first. However, any tooth may be affected (see • Pathologic fractures. Growing children may have a predilection to metaphyseal fractures; however, epiphyseal and diaphyseal fractures are also seen. In adults, metatarsal stress fractures and femoral pseudofractures prevail. • Osteomalacia with lateral pseudofractures ("Looser zones") in adult hypophosphatasia (See ## Establishing the Diagnosis Elevation of natural substrates: plasma vitamin B Atypical femoral fractures (pseudofractures) Recurrent metatarsal fractures Poorly healing fractures Chronic musculoskeletal pain Early atraumatic loss of teeth Chondrocalcinosis Nephrocalcinosis Elevation of natural substrates: plasma vitamin B Early nontraumatic loss of primary teeth Presence of rickets on radiographs Short stature or linear growth failure over time Gross motor delay Craniosynostosis Nephrocalcinosis Vitamin B The molecular diagnosis of hypophosphatasia Biallelic loss-of-function A heterozygous Note: (1) Individuals with a heterozygous loss-of-function Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click When the phenotype is indistinguishable from many other skeletal dysplasias, c For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Hypophosphatasia NA = not applicable See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click In individuals with severe (perinatal and infantile) hypophosphatasia, biallelic Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. A few larger Anecdotal reports of individuals with clinical and biochemical features of adult hypophosphatasia with no detected • Elevation of natural substrates: plasma vitamin B • Atypical femoral fractures (pseudofractures) • Recurrent metatarsal fractures • Poorly healing fractures • Chronic musculoskeletal pain • Early atraumatic loss of teeth • Chondrocalcinosis • Nephrocalcinosis • Elevation of natural substrates: plasma vitamin B • Early nontraumatic loss of primary teeth • Presence of rickets on radiographs • Short stature or linear growth failure over time • Gross motor delay • Craniosynostosis • Nephrocalcinosis • Vitamin B • Biallelic loss-of-function • A heterozygous ## Clinical Diagnosis Elevation of natural substrates: plasma vitamin B Atypical femoral fractures (pseudofractures) Recurrent metatarsal fractures Poorly healing fractures Chronic musculoskeletal pain Early atraumatic loss of teeth Chondrocalcinosis Nephrocalcinosis Elevation of natural substrates: plasma vitamin B Early nontraumatic loss of primary teeth Presence of rickets on radiographs Short stature or linear growth failure over time Gross motor delay Craniosynostosis Nephrocalcinosis Vitamin B • Elevation of natural substrates: plasma vitamin B • Atypical femoral fractures (pseudofractures) • Recurrent metatarsal fractures • Poorly healing fractures • Chronic musculoskeletal pain • Early atraumatic loss of teeth • Chondrocalcinosis • Nephrocalcinosis • Elevation of natural substrates: plasma vitamin B • Early nontraumatic loss of primary teeth • Presence of rickets on radiographs • Short stature or linear growth failure over time • Gross motor delay • Craniosynostosis • Nephrocalcinosis • Vitamin B ## Molecular Diagnosis The molecular diagnosis of hypophosphatasia Biallelic loss-of-function A heterozygous Note: (1) Individuals with a heterozygous loss-of-function Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click When the phenotype is indistinguishable from many other skeletal dysplasias, c For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Hypophosphatasia NA = not applicable See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click In individuals with severe (perinatal and infantile) hypophosphatasia, biallelic Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. A few larger Anecdotal reports of individuals with clinical and biochemical features of adult hypophosphatasia with no detected • Biallelic loss-of-function • A heterozygous ## For an introduction to multigene panels click ## When the phenotype is indistinguishable from many other skeletal dysplasias, c For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Hypophosphatasia NA = not applicable See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click In individuals with severe (perinatal and infantile) hypophosphatasia, biallelic Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. A few larger Anecdotal reports of individuals with clinical and biochemical features of adult hypophosphatasia with no detected ## Clinical Characteristics Hypophosphatasia is characterized by defective mineralization of bone and/or teeth and reduced serum alkaline phosphatase (ALP). Biallelic Select Clinical, Radiographic, and Laboratory Features of Hypophosphatasia by Type Hypomineralization Osteochondral spurs Long bone bowing Pretibial dimpling Growth deficiency (incl weight, length, & head circumference) Long bone bowing Benign postnatal course Craniosynostosis Hypomineralization Rachitic ribs ↑ serum calcium & phosphorus Hypercalciuria Additional clinical & radiographic features of infantile rickets Alveolar bone loss (anterior mandible) Premature loss of deciduous teeth Impaired motor skills Short stature Skeletal deformity Bone pain/fractures Focal metaphyseal defects resembling radiolucent "tongues" Premature loss of deciduous teeth (incisors) Impaired motor skills Stress fractures: metatarsal, tibia Chondrocalcinosis Impaired mobility Dental caries & early loss or extraction of adult teeth Osteopenia/osteoporosis Poor fracture healing Fatigue Pain Decreased quality of life Exfoliation (incisors) Dental caries Based on the Hypophophatasia (HPP) Registry (see AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance Clinical features of infantile rickets: growth failure, craniotabes, blue sclerae, scoliosis, thickening of wrists and ankles, bowing of lower extremities, lax ligaments, and hypotonia Radiographic features of infantile rickets: widened-appearing sutures, brachycephaly, flail chest, flared metaphyses, poorly ossified epiphyses, and bowed long bones in the lower extremities Bone histology reveals rachitic abnormalities of the growth plate. Histochemical testing of osteoclasts reveals lack of membrane-associated ALP activity. Osteoclasts and osteoblasts otherwise appear normal. Tooth histology reveals a decrease in cementum, which varies with the severity of the disease. "The dentoalveolar complex, i.e., the tooth and supporting connective tissues of the surrounding periodontia, include four unique hard tissues: enamel, dentin, cementum, and alveolar bone, and all can be affected by hypophosphatasia" [ Most individuals with hypophosphatasia have unique Less severe phenotypes have been observed in individuals with biallelic loss-of-function variants that allow residual enzymatic activity or heterozygous variants exhibiting a dominant-negative effect [ While some argue that penetrance is complete, reduced penetrance is possible in autosomal dominant hypophosphatasia due to Hypophosphatasia takes its name from low activity of the enzyme ALP, rather than reflecting serum concentration of phosphorus. In classifications of genetic conditions, hypophosphatasia may be considered a metabolic bone disease, a skeletal dysplasia, a metaphyseal dysplasia, a dental disorder, or a disorder of membrane-bound ectoenzyme activity in the extracellular matrix. Based on pediatric hospital records in Ontario, Canada, the birth prevalence of (autosomal recessive) perinatal and infantile hypophosphatasia was estimated at 1:100,000 [ In the Canadian Mennonite population, the prevalence of the perinatal (severe) form is 1:2,500 (carrier frequency of 1/25) due to the founder variant On the basis of molecular diagnosis in France and elsewhere in Europe, the prevalence of severe forms of hypophosphastia has been estimated at 1:300,000. For mild forms (perinatal benign, mild childhood, adult, and odontohypophosphatasia), the prevalence is expected to be as high as 1:6,300 [ In Japan, the birth prevalence of severe hypophosphatasia may be estimated at 1:150,000 on the basis of the frequency of individuals homozygous for the pathogenic variant In China, some pathogenic variants have been reported [ In Africa, no individuals with hypophosphatasia have been reported in the medical literature outside of North Africa and South Africa; however, clinical ascertainment bias is significant. African American individuals with hypophosphatasia are rare; it is assumed that pathogenic variants in this population represent European admixture. • Hypomineralization • Osteochondral spurs • Long bone bowing • Pretibial dimpling • Growth deficiency (incl weight, length, & head circumference) • Long bone bowing • Benign postnatal course • Craniosynostosis • Hypomineralization • Rachitic ribs • ↑ serum calcium & phosphorus • Hypercalciuria • Additional clinical & radiographic features of infantile rickets • Alveolar bone loss (anterior mandible) • Premature loss of deciduous teeth • Impaired motor skills • Short stature • Skeletal deformity • Bone pain/fractures • Focal metaphyseal defects resembling radiolucent "tongues" • Premature loss of deciduous teeth (incisors) • Impaired motor skills • Stress fractures: metatarsal, tibia • Chondrocalcinosis • Impaired mobility • Dental caries & early loss or extraction of adult teeth • Osteopenia/osteoporosis • Poor fracture healing • Fatigue • Pain • Decreased quality of life • Exfoliation (incisors) • Dental caries • Bone histology reveals rachitic abnormalities of the growth plate. Histochemical testing of osteoclasts reveals lack of membrane-associated ALP activity. Osteoclasts and osteoblasts otherwise appear normal. • Tooth histology reveals a decrease in cementum, which varies with the severity of the disease. "The dentoalveolar complex, i.e., the tooth and supporting connective tissues of the surrounding periodontia, include four unique hard tissues: enamel, dentin, cementum, and alveolar bone, and all can be affected by hypophosphatasia" [ ## Clinical Description Hypophosphatasia is characterized by defective mineralization of bone and/or teeth and reduced serum alkaline phosphatase (ALP). Biallelic Select Clinical, Radiographic, and Laboratory Features of Hypophosphatasia by Type Hypomineralization Osteochondral spurs Long bone bowing Pretibial dimpling Growth deficiency (incl weight, length, & head circumference) Long bone bowing Benign postnatal course Craniosynostosis Hypomineralization Rachitic ribs ↑ serum calcium & phosphorus Hypercalciuria Additional clinical & radiographic features of infantile rickets Alveolar bone loss (anterior mandible) Premature loss of deciduous teeth Impaired motor skills Short stature Skeletal deformity Bone pain/fractures Focal metaphyseal defects resembling radiolucent "tongues" Premature loss of deciduous teeth (incisors) Impaired motor skills Stress fractures: metatarsal, tibia Chondrocalcinosis Impaired mobility Dental caries & early loss or extraction of adult teeth Osteopenia/osteoporosis Poor fracture healing Fatigue Pain Decreased quality of life Exfoliation (incisors) Dental caries Based on the Hypophophatasia (HPP) Registry (see AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance Clinical features of infantile rickets: growth failure, craniotabes, blue sclerae, scoliosis, thickening of wrists and ankles, bowing of lower extremities, lax ligaments, and hypotonia Radiographic features of infantile rickets: widened-appearing sutures, brachycephaly, flail chest, flared metaphyses, poorly ossified epiphyses, and bowed long bones in the lower extremities Bone histology reveals rachitic abnormalities of the growth plate. Histochemical testing of osteoclasts reveals lack of membrane-associated ALP activity. Osteoclasts and osteoblasts otherwise appear normal. Tooth histology reveals a decrease in cementum, which varies with the severity of the disease. "The dentoalveolar complex, i.e., the tooth and supporting connective tissues of the surrounding periodontia, include four unique hard tissues: enamel, dentin, cementum, and alveolar bone, and all can be affected by hypophosphatasia" [ • Hypomineralization • Osteochondral spurs • Long bone bowing • Pretibial dimpling • Growth deficiency (incl weight, length, & head circumference) • Long bone bowing • Benign postnatal course • Craniosynostosis • Hypomineralization • Rachitic ribs • ↑ serum calcium & phosphorus • Hypercalciuria • Additional clinical & radiographic features of infantile rickets • Alveolar bone loss (anterior mandible) • Premature loss of deciduous teeth • Impaired motor skills • Short stature • Skeletal deformity • Bone pain/fractures • Focal metaphyseal defects resembling radiolucent "tongues" • Premature loss of deciduous teeth (incisors) • Impaired motor skills • Stress fractures: metatarsal, tibia • Chondrocalcinosis • Impaired mobility • Dental caries & early loss or extraction of adult teeth • Osteopenia/osteoporosis • Poor fracture healing • Fatigue • Pain • Decreased quality of life • Exfoliation (incisors) • Dental caries • Bone histology reveals rachitic abnormalities of the growth plate. Histochemical testing of osteoclasts reveals lack of membrane-associated ALP activity. Osteoclasts and osteoblasts otherwise appear normal. • Tooth histology reveals a decrease in cementum, which varies with the severity of the disease. "The dentoalveolar complex, i.e., the tooth and supporting connective tissues of the surrounding periodontia, include four unique hard tissues: enamel, dentin, cementum, and alveolar bone, and all can be affected by hypophosphatasia" [ ## Genotype-Phenotype Correlations Most individuals with hypophosphatasia have unique Less severe phenotypes have been observed in individuals with biallelic loss-of-function variants that allow residual enzymatic activity or heterozygous variants exhibiting a dominant-negative effect [ ## Penetrance While some argue that penetrance is complete, reduced penetrance is possible in autosomal dominant hypophosphatasia due to ## Nomenclature Hypophosphatasia takes its name from low activity of the enzyme ALP, rather than reflecting serum concentration of phosphorus. In classifications of genetic conditions, hypophosphatasia may be considered a metabolic bone disease, a skeletal dysplasia, a metaphyseal dysplasia, a dental disorder, or a disorder of membrane-bound ectoenzyme activity in the extracellular matrix. ## Prevalence Based on pediatric hospital records in Ontario, Canada, the birth prevalence of (autosomal recessive) perinatal and infantile hypophosphatasia was estimated at 1:100,000 [ In the Canadian Mennonite population, the prevalence of the perinatal (severe) form is 1:2,500 (carrier frequency of 1/25) due to the founder variant On the basis of molecular diagnosis in France and elsewhere in Europe, the prevalence of severe forms of hypophosphastia has been estimated at 1:300,000. For mild forms (perinatal benign, mild childhood, adult, and odontohypophosphatasia), the prevalence is expected to be as high as 1:6,300 [ In Japan, the birth prevalence of severe hypophosphatasia may be estimated at 1:150,000 on the basis of the frequency of individuals homozygous for the pathogenic variant In China, some pathogenic variants have been reported [ In Africa, no individuals with hypophosphatasia have been reported in the medical literature outside of North Africa and South Africa; however, clinical ascertainment bias is significant. African American individuals with hypophosphatasia are rare; it is assumed that pathogenic variants in this population represent European admixture. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The differential diagnosis of hypophosphatasia depends on the age at which the diagnosis is considered. Clinical features that help differentiate hypophosphatasia from other conditions include bone hypomineralization prenatally and immediately postnatally; elevated serum concentrations of calcium and phosphorus postnatally; and persistently low serum alkaline phosphatase (ALP) enzyme activity. Early prenatal ultrasound examination may lead to a consideration of Achondrogenesis and hypochondrogenesis are characterized by early hydrops, short trunk, barrel-shaped thorax, and a prominent abdomen. Achondrogenesis types IA/B present with extreme micromelia, short hands and feet, poor mineralization, a large head, a flat face, and a short neck. Achondrogenesis type II is less severe, appears later in gestation, and is often associated with polyhydramnios. Hypochondrogenesis shares features with hypophosphatasia such as a small thorax, short limbs, a flat face with micrognathia, a short trunk, macrocephaly, a flat nose, and a depressed nasal bridge. (See Outwardly difficult to distinguish, OI type II, thanatophoric dysplasia, campomelic dysplasia, and chondrodysplasias with bone mineralization defects are readily distinguished from hypophosphatasia by radiographs. In individuals in which the diagnosis is in doubt, analysis of serum ALP activity, pyridoxal 5'-phosphate (PLP) or vitamin B Irritability, poor feeding, growth deficiency (affecting weight, length, and head circumference), hypotonia, and seizures place infantile hypophosphatasia in a broad differential diagnosis that includes inborn errors of energy metabolism, organic acidemia, primary and secondary rickets, neglect, and non-accidental trauma. Infantile hypophosphatasia is suspected with low serum ALP enzyme activity, making the argument for routine screening of serum ALP enzyme activity in infants and children with poor weight gain, growth deficiency, unexplained seizures, and suspected non-accidental skeletal injury. Acquired Disorders and Disorders of Unknown Cause in the Differential Diagnosis of Infantile and Childhood Hypophosphatasia High serum ALP activity Low serum calcium & phosphorus Low serum vitamin D High serum parathyroid hormone Like OI, medical history, family history, physical exam, routine lab tests, radiographic imaging, & clinical course all contribute to distinguishing hypophosphatasia from child abuse. Multiple fractures are less typical of hypophosphatasia. Family history may be particularly instructive: the perinatal (severe) type is AR, & childhood (juvenile), adult, & odontohypophosphatasia types are AD; all have been reported in a single family ascertained by unexplained fracture in a child. Serial measurement of serum ALP activity is usually sufficient to identify hypophosphatasia in this circumstance. AD = autosomal dominant; ALP = alkaline phosphatase; AR = autosomal recessive; OI = osteogenesis imperfecta Hereditary Disorders in the Differential Diagnosis of Infantile and Childhood-Onset Hypophosphatasia Several aspects of CF contribute to vitamin D insufficiency leading to ↓ bone density & fracture propensity. CF & hypophosphatasia both cause symmetric growth deficiency. Restrictive lung disease can be present w/both diagnoses, but chronic respiratory infections in CF are readily distinguishable from the rachitic chest deformity in infantile hypophosphatasia. Characterized by late closure of fontanels & cranial sutures, aplastic clavicles, delayed mineralization of pubic rami, & delayed eruption of deciduous & permanent teeth Skeletal dysplasia is distinguishable from hypophosphatasia on clinical exam & skeletal survey. Dental dysplasia does not result in early tooth loss, & enamel hypoplasia is readily distinguishable from odontohypophosphatasia. Restrictive lung disease (due to diaphragmatic weakness & scoliosis), proximal myopathy, & disuse osteopenia may resemble infantile & childhood hypophosphatasia. Spasticity & myopathic features become progressively more dominant, readily distinguishing CMYO3 from hypophosphatasia. Characterized by small thorax, limb shortening, bowing of the long bones, & a variety of other skeletal & extraskeletal defects CD may be identified on prenatal ultrasound exam. Many newborns w/CD die shortly after birth secondary to respiratory insufficiency. AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance For additional genes associated with OI, see Acquired Disorders and Disorders of Unknown Cause in the Differential Diagnosis of Adult Hypophosphatasia and Odontohypophosphatasia ALP = alkaline phosphatase See Hereditary Disorders in the Differential Diagnosis of Adult Hypophosphatasia and Odontohypophosphatasia Rarer disorders assoc w/premature tooth loss & periodontal disease Periodontal disease is usually earlier in onset & more severe than that seen w/odontohypophosphatasia. Both Papillon-Lefevre syndrome & HMS are usually assoc w/palmar keratosis, further distinguishing them from odontohypophosphatasia. Measurement of serum ALP enzyme activity is reasonable when either disorder is considered. AD = autosomal dominant; ALP = alkaline phosphatase; AR = autosomal recessive; MOI = mode of inheritance Vascular EDS is almost always inherited in an autosomal dominant manner, but rare examples of biallelic inheritance have been reported. • Achondrogenesis and hypochondrogenesis are characterized by early hydrops, short trunk, barrel-shaped thorax, and a prominent abdomen. Achondrogenesis types IA/B present with extreme micromelia, short hands and feet, poor mineralization, a large head, a flat face, and a short neck. Achondrogenesis type II is less severe, appears later in gestation, and is often associated with polyhydramnios. Hypochondrogenesis shares features with hypophosphatasia such as a small thorax, short limbs, a flat face with micrognathia, a short trunk, macrocephaly, a flat nose, and a depressed nasal bridge. (See • High serum ALP activity • Low serum calcium & phosphorus • Low serum vitamin D • High serum parathyroid hormone • Like OI, medical history, family history, physical exam, routine lab tests, radiographic imaging, & clinical course all contribute to distinguishing hypophosphatasia from child abuse. • Multiple fractures are less typical of hypophosphatasia. • Family history may be particularly instructive: the perinatal (severe) type is AR, & childhood (juvenile), adult, & odontohypophosphatasia types are AD; all have been reported in a single family ascertained by unexplained fracture in a child. • Serial measurement of serum ALP activity is usually sufficient to identify hypophosphatasia in this circumstance. • Several aspects of CF contribute to vitamin D insufficiency leading to ↓ bone density & fracture propensity. • CF & hypophosphatasia both cause symmetric growth deficiency. • Restrictive lung disease can be present w/both diagnoses, but chronic respiratory infections in CF are readily distinguishable from the rachitic chest deformity in infantile hypophosphatasia. • Characterized by late closure of fontanels & cranial sutures, aplastic clavicles, delayed mineralization of pubic rami, & delayed eruption of deciduous & permanent teeth • Skeletal dysplasia is distinguishable from hypophosphatasia on clinical exam & skeletal survey. • Dental dysplasia does not result in early tooth loss, & enamel hypoplasia is readily distinguishable from odontohypophosphatasia. • Restrictive lung disease (due to diaphragmatic weakness & scoliosis), proximal myopathy, & disuse osteopenia may resemble infantile & childhood hypophosphatasia. • Spasticity & myopathic features become progressively more dominant, readily distinguishing CMYO3 from hypophosphatasia. • Characterized by small thorax, limb shortening, bowing of the long bones, & a variety of other skeletal & extraskeletal defects • CD may be identified on prenatal ultrasound exam. • Many newborns w/CD die shortly after birth secondary to respiratory insufficiency. • Rarer disorders assoc w/premature tooth loss & periodontal disease • Periodontal disease is usually earlier in onset & more severe than that seen w/odontohypophosphatasia. • Both Papillon-Lefevre syndrome & HMS are usually assoc w/palmar keratosis, further distinguishing them from odontohypophosphatasia. • Measurement of serum ALP enzyme activity is reasonable when either disorder is considered. ## In Utero Early prenatal ultrasound examination may lead to a consideration of Achondrogenesis and hypochondrogenesis are characterized by early hydrops, short trunk, barrel-shaped thorax, and a prominent abdomen. Achondrogenesis types IA/B present with extreme micromelia, short hands and feet, poor mineralization, a large head, a flat face, and a short neck. Achondrogenesis type II is less severe, appears later in gestation, and is often associated with polyhydramnios. Hypochondrogenesis shares features with hypophosphatasia such as a small thorax, short limbs, a flat face with micrognathia, a short trunk, macrocephaly, a flat nose, and a depressed nasal bridge. (See • Achondrogenesis and hypochondrogenesis are characterized by early hydrops, short trunk, barrel-shaped thorax, and a prominent abdomen. Achondrogenesis types IA/B present with extreme micromelia, short hands and feet, poor mineralization, a large head, a flat face, and a short neck. Achondrogenesis type II is less severe, appears later in gestation, and is often associated with polyhydramnios. Hypochondrogenesis shares features with hypophosphatasia such as a small thorax, short limbs, a flat face with micrognathia, a short trunk, macrocephaly, a flat nose, and a depressed nasal bridge. (See ## At Birth Outwardly difficult to distinguish, OI type II, thanatophoric dysplasia, campomelic dysplasia, and chondrodysplasias with bone mineralization defects are readily distinguished from hypophosphatasia by radiographs. In individuals in which the diagnosis is in doubt, analysis of serum ALP activity, pyridoxal 5'-phosphate (PLP) or vitamin B ## Infancy and Childhood Irritability, poor feeding, growth deficiency (affecting weight, length, and head circumference), hypotonia, and seizures place infantile hypophosphatasia in a broad differential diagnosis that includes inborn errors of energy metabolism, organic acidemia, primary and secondary rickets, neglect, and non-accidental trauma. Infantile hypophosphatasia is suspected with low serum ALP enzyme activity, making the argument for routine screening of serum ALP enzyme activity in infants and children with poor weight gain, growth deficiency, unexplained seizures, and suspected non-accidental skeletal injury. Acquired Disorders and Disorders of Unknown Cause in the Differential Diagnosis of Infantile and Childhood Hypophosphatasia High serum ALP activity Low serum calcium & phosphorus Low serum vitamin D High serum parathyroid hormone Like OI, medical history, family history, physical exam, routine lab tests, radiographic imaging, & clinical course all contribute to distinguishing hypophosphatasia from child abuse. Multiple fractures are less typical of hypophosphatasia. Family history may be particularly instructive: the perinatal (severe) type is AR, & childhood (juvenile), adult, & odontohypophosphatasia types are AD; all have been reported in a single family ascertained by unexplained fracture in a child. Serial measurement of serum ALP activity is usually sufficient to identify hypophosphatasia in this circumstance. AD = autosomal dominant; ALP = alkaline phosphatase; AR = autosomal recessive; OI = osteogenesis imperfecta Hereditary Disorders in the Differential Diagnosis of Infantile and Childhood-Onset Hypophosphatasia Several aspects of CF contribute to vitamin D insufficiency leading to ↓ bone density & fracture propensity. CF & hypophosphatasia both cause symmetric growth deficiency. Restrictive lung disease can be present w/both diagnoses, but chronic respiratory infections in CF are readily distinguishable from the rachitic chest deformity in infantile hypophosphatasia. Characterized by late closure of fontanels & cranial sutures, aplastic clavicles, delayed mineralization of pubic rami, & delayed eruption of deciduous & permanent teeth Skeletal dysplasia is distinguishable from hypophosphatasia on clinical exam & skeletal survey. Dental dysplasia does not result in early tooth loss, & enamel hypoplasia is readily distinguishable from odontohypophosphatasia. Restrictive lung disease (due to diaphragmatic weakness & scoliosis), proximal myopathy, & disuse osteopenia may resemble infantile & childhood hypophosphatasia. Spasticity & myopathic features become progressively more dominant, readily distinguishing CMYO3 from hypophosphatasia. Characterized by small thorax, limb shortening, bowing of the long bones, & a variety of other skeletal & extraskeletal defects CD may be identified on prenatal ultrasound exam. Many newborns w/CD die shortly after birth secondary to respiratory insufficiency. AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance For additional genes associated with OI, see • High serum ALP activity • Low serum calcium & phosphorus • Low serum vitamin D • High serum parathyroid hormone • Like OI, medical history, family history, physical exam, routine lab tests, radiographic imaging, & clinical course all contribute to distinguishing hypophosphatasia from child abuse. • Multiple fractures are less typical of hypophosphatasia. • Family history may be particularly instructive: the perinatal (severe) type is AR, & childhood (juvenile), adult, & odontohypophosphatasia types are AD; all have been reported in a single family ascertained by unexplained fracture in a child. • Serial measurement of serum ALP activity is usually sufficient to identify hypophosphatasia in this circumstance. • Several aspects of CF contribute to vitamin D insufficiency leading to ↓ bone density & fracture propensity. • CF & hypophosphatasia both cause symmetric growth deficiency. • Restrictive lung disease can be present w/both diagnoses, but chronic respiratory infections in CF are readily distinguishable from the rachitic chest deformity in infantile hypophosphatasia. • Characterized by late closure of fontanels & cranial sutures, aplastic clavicles, delayed mineralization of pubic rami, & delayed eruption of deciduous & permanent teeth • Skeletal dysplasia is distinguishable from hypophosphatasia on clinical exam & skeletal survey. • Dental dysplasia does not result in early tooth loss, & enamel hypoplasia is readily distinguishable from odontohypophosphatasia. • Restrictive lung disease (due to diaphragmatic weakness & scoliosis), proximal myopathy, & disuse osteopenia may resemble infantile & childhood hypophosphatasia. • Spasticity & myopathic features become progressively more dominant, readily distinguishing CMYO3 from hypophosphatasia. • Characterized by small thorax, limb shortening, bowing of the long bones, & a variety of other skeletal & extraskeletal defects • CD may be identified on prenatal ultrasound exam. • Many newborns w/CD die shortly after birth secondary to respiratory insufficiency. ## Adulthood and Odontohypophosphatasia Acquired Disorders and Disorders of Unknown Cause in the Differential Diagnosis of Adult Hypophosphatasia and Odontohypophosphatasia ALP = alkaline phosphatase See Hereditary Disorders in the Differential Diagnosis of Adult Hypophosphatasia and Odontohypophosphatasia Rarer disorders assoc w/premature tooth loss & periodontal disease Periodontal disease is usually earlier in onset & more severe than that seen w/odontohypophosphatasia. Both Papillon-Lefevre syndrome & HMS are usually assoc w/palmar keratosis, further distinguishing them from odontohypophosphatasia. Measurement of serum ALP enzyme activity is reasonable when either disorder is considered. AD = autosomal dominant; ALP = alkaline phosphatase; AR = autosomal recessive; MOI = mode of inheritance Vascular EDS is almost always inherited in an autosomal dominant manner, but rare examples of biallelic inheritance have been reported. • Rarer disorders assoc w/premature tooth loss & periodontal disease • Periodontal disease is usually earlier in onset & more severe than that seen w/odontohypophosphatasia. • Both Papillon-Lefevre syndrome & HMS are usually assoc w/palmar keratosis, further distinguishing them from odontohypophosphatasia. • Measurement of serum ALP enzyme activity is reasonable when either disorder is considered. ## Management Medical management guidelines for the treatment of hypophosphatasia with asfotase alfa have been published [ To establish the extent of disease and needs in an individual diagnosed with hypophosphatasia, the evaluations summarized in Perinatal Hypophosphatasia: Recommended Evaluations Following Initial Diagnosis Serum calcium, phosphorus, magnesium Referral to endocrinologist for mgmt of bone health Orthopedic eval Skeletal survey incl radiographs of skull to assess for craniosynostosis Blood urea nitrogen & serum creatinine concentration Referral to nephrologist Community or Social work involvement for parental support Home nursing referral MOI = mode of inheritance Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Hypophosphatasia: Recommended Evaluations Following Initial Diagnosis in Older Individuals Orthopedic eval Skeletal survey incl radiographs of skull to assess for craniosynostosis Serum 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, & nPTH to assess for confounding comorbidity (e.g., vitamin D deficiency) Referral to endocrinologist for mgmt of bone health Eye exam to assess for ectopic calcifications Blood urea nitrogen & serum creatinine concentration Renal ultrasound to assess for hypercalciuria & nephrocalcinosis Referral to nephrologist MOI = mode of inheritance; nPTH = parathyroid hormone, N-terminal part Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) There is no cure for hypophosphatasia. Asfotase alfa ERT has been shown to improve pulmonary function, calcium homeostasis / bone health, and survival in individuals with the infantile and early childhood (juvenile) hypophosphatasia. There is growing experience with ERT in individuals with perinatal (severe) hypophosphatasia and emerging experience with ERT in treating osteomalacia in adults. Hypophosphatasia: Targeted Therapy Infants: total dose ≤9 mg/kg per week Adolescents & adults: total dose 6 mg/kg per week The treatment duration and long-term effects of enzyme replacement therapy (ERT) with asfotase alfa remain unknown for perinatal and infantile hypophosphatasia. In theory, ERT would be less effective once endochondral bone formation is complete after the epiphyses fuse. Clinical trials in adults are limited to those with documented childhood disease, and in theory the treatment has occurred after endochondral bone formation is complete (remodeling phase). Biochemical and limited functional improvement can be documented, but treatment end points, duration, and long-term effects are unknown for adult hypophosphatasia [ Monitoring those on asfotase alfa therapy remains challenging due to limitations in and clinical availability of biochemical markers such as PPi and PLP, requiring careful clinical assessment rather than dose adjustments based on lab values. Despite these challenges, the therapy remains a cornerstone for managing pediatric-onset hypophosphatasia in adults, with evidence supporting its ability to mitigate long-term disease complications and enhance well-being of individuals with hypophosphatasia [ At all ages, 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 Hypophosphatasia: Treatment of Manifestations Respiratory support per pulmonologist Asfotase alfa (see Physical medicine & rehab, PT, & OT to optimize mobility & autonomy Low-impact physical activity & exercise Mgmt of primary & secondary skeletal manifestations per orthopedist Internal fixation has been suggested as optimal mgmt. Consider foot orthotics for tarsal fractures & pseudofractures in adults. Teriparatide, a recombinant protein containing the 34 N-terminal residues of human parathyroid hormone, is a potent stimulator of TNSALP in osteoblasts & has been used for osteoporosis. Case reports describe significant improvement in fracture healing & bone pain (suggesting beneficial effect on bone remodeling), improved mineralization, long-term fracture reduction, & improvement in QOL. Use of teriparatide in hypophosphatasia is off-label; to date, there are no prospective studies or clinical trials. Teriparatide is contraindicated in children (see Referral to skilled pain mgmt professionals NSAIDs Mgmt per neurologist to prophylactically or prospectively treat seizures & manage myopathy Seizures may respond to treatment w/vitamin B Psychological support & social work support Referral to mental health professionals ALP = alkaline phosphatase; CNS = central nervous system; ERT = enzyme replacement therapy; NSAIDs = nonsteroidal anti-inflammatory drugs; OT = occupational therapy; PLP = pyridoxal phosphate; PT = physical therapy; QOL = quality of life; TNSALP = alkaline phosphatase, tissue-nonspecific isozyme To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in Hypophosphatasia: Recommended Surveillance In infants: at onset of treatment, ages 3, 6, & 12 mos, then every 6 mos In children/adults: at onset of treatment, 2 weeks, 3, 6, & 12 mos after initiating treatment, then annually Plasma PLP Urine PEA Serum ionized calcium (or serum calcium adjusted for albumin concentration) Serum phosphorus In infants: at onset of treatment, ages 1, 3, 6, & 12 mos, then annually In children/adults: at onset of treatment, 3 mos after initiating treatment, then annually In infants: at onset of treatment, ages 1, 3, 6, & 12 mos, then annually once normal levels reached In children/adults: at onset of treatment, 3, 6, & 12 mos after initiating treatment, then annually once normal levels reached Complete blood count Liver function (bilirubin, ALT, AST) In infants: at onset of treatment, ages 3, 6, 9, & 12 mos, then annually In children/adults: at onset of treatment, 6 mos after initiating treatment, then annually Creatinine, BUN Urine calcium-to-creatinine ratio to assess for nephrocalcinosis In infants: at onset of treatment, then every 3 mos; monitor closely during acute phase until stable In children/adults: at onset of treatment, 6 mos after initiating treatment, then annually ALT = alanine transaminase; AST = aspartate transaminase; BUN = blood urea nitrogen; eGFR = estimated glomerular filtration rate; OT = occupational therapy; PEA = phosphoethanolamine; PLP = pyridoxal 5′-phosphate; PT = physical therapy; PTH = parathyroid hormone 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. Regardless of age, clinically asymptomatic individuals found to have a familial See The use of asfotase alfa ERT during human pregnancy has not been extensively studied; therefore, any potential risk to the fetus of a pregnant woman is unknown. See Search • Serum calcium, phosphorus, magnesium • Referral to endocrinologist for mgmt of bone health • Orthopedic eval • Skeletal survey incl radiographs of skull to assess for craniosynostosis • Blood urea nitrogen & serum creatinine concentration • Referral to nephrologist • Community or • Social work involvement for parental support • Home nursing referral • Orthopedic eval • Skeletal survey incl radiographs of skull to assess for craniosynostosis • Serum 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, & nPTH to assess for confounding comorbidity (e.g., vitamin D deficiency) • Referral to endocrinologist for mgmt of bone health • Eye exam to assess for ectopic calcifications • Blood urea nitrogen & serum creatinine concentration • Renal ultrasound to assess for hypercalciuria & nephrocalcinosis • Referral to nephrologist • Infants: total dose ≤9 mg/kg per week • Adolescents & adults: total dose 6 mg/kg per week • Respiratory support per pulmonologist • Asfotase alfa (see • Physical medicine & rehab, PT, & OT to optimize mobility & autonomy • Low-impact physical activity & exercise • Mgmt of primary & secondary skeletal manifestations per orthopedist • Internal fixation has been suggested as optimal mgmt. • Consider foot orthotics for tarsal fractures & pseudofractures in adults. • Teriparatide, a recombinant protein containing the 34 N-terminal residues of human parathyroid hormone, is a potent stimulator of TNSALP in osteoblasts & has been used for osteoporosis. • Case reports describe significant improvement in fracture healing & bone pain (suggesting beneficial effect on bone remodeling), improved mineralization, long-term fracture reduction, & improvement in QOL. • Use of teriparatide in hypophosphatasia is off-label; to date, there are no prospective studies or clinical trials. • Teriparatide is contraindicated in children (see • Referral to skilled pain mgmt professionals • NSAIDs • Mgmt per neurologist to prophylactically or prospectively treat seizures & manage myopathy • Seizures may respond to treatment w/vitamin B • Psychological support & social work support • Referral to mental health professionals • In infants: at onset of treatment, ages 3, 6, & 12 mos, then every 6 mos • In children/adults: at onset of treatment, 2 weeks, 3, 6, & 12 mos after initiating treatment, then annually • Plasma PLP • Urine PEA • Serum ionized calcium (or serum calcium adjusted for albumin concentration) • Serum phosphorus • In infants: at onset of treatment, ages 1, 3, 6, & 12 mos, then annually • In children/adults: at onset of treatment, 3 mos after initiating treatment, then annually • In infants: at onset of treatment, ages 1, 3, 6, & 12 mos, then annually once normal levels reached • In children/adults: at onset of treatment, 3, 6, & 12 mos after initiating treatment, then annually once normal levels reached • Complete blood count • Liver function (bilirubin, ALT, AST) • In infants: at onset of treatment, ages 3, 6, 9, & 12 mos, then annually • In children/adults: at onset of treatment, 6 mos after initiating treatment, then annually • Creatinine, BUN • Urine calcium-to-creatinine ratio to assess for nephrocalcinosis • In infants: at onset of treatment, then every 3 mos; monitor closely during acute phase until stable • In children/adults: at onset of treatment, 6 mos after initiating treatment, then annually ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with hypophosphatasia, the evaluations summarized in Perinatal Hypophosphatasia: Recommended Evaluations Following Initial Diagnosis Serum calcium, phosphorus, magnesium Referral to endocrinologist for mgmt of bone health Orthopedic eval Skeletal survey incl radiographs of skull to assess for craniosynostosis Blood urea nitrogen & serum creatinine concentration Referral to nephrologist Community or Social work involvement for parental support Home nursing referral MOI = mode of inheritance Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Hypophosphatasia: Recommended Evaluations Following Initial Diagnosis in Older Individuals Orthopedic eval Skeletal survey incl radiographs of skull to assess for craniosynostosis Serum 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, & nPTH to assess for confounding comorbidity (e.g., vitamin D deficiency) Referral to endocrinologist for mgmt of bone health Eye exam to assess for ectopic calcifications Blood urea nitrogen & serum creatinine concentration Renal ultrasound to assess for hypercalciuria & nephrocalcinosis Referral to nephrologist MOI = mode of inheritance; nPTH = parathyroid hormone, N-terminal part Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Serum calcium, phosphorus, magnesium • Referral to endocrinologist for mgmt of bone health • Orthopedic eval • Skeletal survey incl radiographs of skull to assess for craniosynostosis • Blood urea nitrogen & serum creatinine concentration • Referral to nephrologist • Community or • Social work involvement for parental support • Home nursing referral • Orthopedic eval • Skeletal survey incl radiographs of skull to assess for craniosynostosis • Serum 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, & nPTH to assess for confounding comorbidity (e.g., vitamin D deficiency) • Referral to endocrinologist for mgmt of bone health • Eye exam to assess for ectopic calcifications • Blood urea nitrogen & serum creatinine concentration • Renal ultrasound to assess for hypercalciuria & nephrocalcinosis • Referral to nephrologist ## Treatment of Manifestations There is no cure for hypophosphatasia. Asfotase alfa ERT has been shown to improve pulmonary function, calcium homeostasis / bone health, and survival in individuals with the infantile and early childhood (juvenile) hypophosphatasia. There is growing experience with ERT in individuals with perinatal (severe) hypophosphatasia and emerging experience with ERT in treating osteomalacia in adults. Hypophosphatasia: Targeted Therapy Infants: total dose ≤9 mg/kg per week Adolescents & adults: total dose 6 mg/kg per week The treatment duration and long-term effects of enzyme replacement therapy (ERT) with asfotase alfa remain unknown for perinatal and infantile hypophosphatasia. In theory, ERT would be less effective once endochondral bone formation is complete after the epiphyses fuse. Clinical trials in adults are limited to those with documented childhood disease, and in theory the treatment has occurred after endochondral bone formation is complete (remodeling phase). Biochemical and limited functional improvement can be documented, but treatment end points, duration, and long-term effects are unknown for adult hypophosphatasia [ Monitoring those on asfotase alfa therapy remains challenging due to limitations in and clinical availability of biochemical markers such as PPi and PLP, requiring careful clinical assessment rather than dose adjustments based on lab values. Despite these challenges, the therapy remains a cornerstone for managing pediatric-onset hypophosphatasia in adults, with evidence supporting its ability to mitigate long-term disease complications and enhance well-being of individuals with hypophosphatasia [ At all ages, 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 Hypophosphatasia: Treatment of Manifestations Respiratory support per pulmonologist Asfotase alfa (see Physical medicine & rehab, PT, & OT to optimize mobility & autonomy Low-impact physical activity & exercise Mgmt of primary & secondary skeletal manifestations per orthopedist Internal fixation has been suggested as optimal mgmt. Consider foot orthotics for tarsal fractures & pseudofractures in adults. Teriparatide, a recombinant protein containing the 34 N-terminal residues of human parathyroid hormone, is a potent stimulator of TNSALP in osteoblasts & has been used for osteoporosis. Case reports describe significant improvement in fracture healing & bone pain (suggesting beneficial effect on bone remodeling), improved mineralization, long-term fracture reduction, & improvement in QOL. Use of teriparatide in hypophosphatasia is off-label; to date, there are no prospective studies or clinical trials. Teriparatide is contraindicated in children (see Referral to skilled pain mgmt professionals NSAIDs Mgmt per neurologist to prophylactically or prospectively treat seizures & manage myopathy Seizures may respond to treatment w/vitamin B Psychological support & social work support Referral to mental health professionals ALP = alkaline phosphatase; CNS = central nervous system; ERT = enzyme replacement therapy; NSAIDs = nonsteroidal anti-inflammatory drugs; OT = occupational therapy; PLP = pyridoxal phosphate; PT = physical therapy; QOL = quality of life; TNSALP = alkaline phosphatase, tissue-nonspecific isozyme • Infants: total dose ≤9 mg/kg per week • Adolescents & adults: total dose 6 mg/kg per week • Respiratory support per pulmonologist • Asfotase alfa (see • Physical medicine & rehab, PT, & OT to optimize mobility & autonomy • Low-impact physical activity & exercise • Mgmt of primary & secondary skeletal manifestations per orthopedist • Internal fixation has been suggested as optimal mgmt. • Consider foot orthotics for tarsal fractures & pseudofractures in adults. • Teriparatide, a recombinant protein containing the 34 N-terminal residues of human parathyroid hormone, is a potent stimulator of TNSALP in osteoblasts & has been used for osteoporosis. • Case reports describe significant improvement in fracture healing & bone pain (suggesting beneficial effect on bone remodeling), improved mineralization, long-term fracture reduction, & improvement in QOL. • Use of teriparatide in hypophosphatasia is off-label; to date, there are no prospective studies or clinical trials. • Teriparatide is contraindicated in children (see • Referral to skilled pain mgmt professionals • NSAIDs • Mgmt per neurologist to prophylactically or prospectively treat seizures & manage myopathy • Seizures may respond to treatment w/vitamin B • Psychological support & social work support • Referral to mental health professionals ## Targeted Therapy Asfotase alfa ERT has been shown to improve pulmonary function, calcium homeostasis / bone health, and survival in individuals with the infantile and early childhood (juvenile) hypophosphatasia. There is growing experience with ERT in individuals with perinatal (severe) hypophosphatasia and emerging experience with ERT in treating osteomalacia in adults. Hypophosphatasia: Targeted Therapy Infants: total dose ≤9 mg/kg per week Adolescents & adults: total dose 6 mg/kg per week The treatment duration and long-term effects of enzyme replacement therapy (ERT) with asfotase alfa remain unknown for perinatal and infantile hypophosphatasia. In theory, ERT would be less effective once endochondral bone formation is complete after the epiphyses fuse. Clinical trials in adults are limited to those with documented childhood disease, and in theory the treatment has occurred after endochondral bone formation is complete (remodeling phase). Biochemical and limited functional improvement can be documented, but treatment end points, duration, and long-term effects are unknown for adult hypophosphatasia [ Monitoring those on asfotase alfa therapy remains challenging due to limitations in and clinical availability of biochemical markers such as PPi and PLP, requiring careful clinical assessment rather than dose adjustments based on lab values. Despite these challenges, the therapy remains a cornerstone for managing pediatric-onset hypophosphatasia in adults, with evidence supporting its ability to mitigate long-term disease complications and enhance well-being of individuals with hypophosphatasia [ • Infants: total dose ≤9 mg/kg per week • Adolescents & adults: total dose 6 mg/kg per week ## Supportive Care At all ages, 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 Hypophosphatasia: Treatment of Manifestations Respiratory support per pulmonologist Asfotase alfa (see Physical medicine & rehab, PT, & OT to optimize mobility & autonomy Low-impact physical activity & exercise Mgmt of primary & secondary skeletal manifestations per orthopedist Internal fixation has been suggested as optimal mgmt. Consider foot orthotics for tarsal fractures & pseudofractures in adults. Teriparatide, a recombinant protein containing the 34 N-terminal residues of human parathyroid hormone, is a potent stimulator of TNSALP in osteoblasts & has been used for osteoporosis. Case reports describe significant improvement in fracture healing & bone pain (suggesting beneficial effect on bone remodeling), improved mineralization, long-term fracture reduction, & improvement in QOL. Use of teriparatide in hypophosphatasia is off-label; to date, there are no prospective studies or clinical trials. Teriparatide is contraindicated in children (see Referral to skilled pain mgmt professionals NSAIDs Mgmt per neurologist to prophylactically or prospectively treat seizures & manage myopathy Seizures may respond to treatment w/vitamin B Psychological support & social work support Referral to mental health professionals ALP = alkaline phosphatase; CNS = central nervous system; ERT = enzyme replacement therapy; NSAIDs = nonsteroidal anti-inflammatory drugs; OT = occupational therapy; PLP = pyridoxal phosphate; PT = physical therapy; QOL = quality of life; TNSALP = alkaline phosphatase, tissue-nonspecific isozyme • Respiratory support per pulmonologist • Asfotase alfa (see • Physical medicine & rehab, PT, & OT to optimize mobility & autonomy • Low-impact physical activity & exercise • Mgmt of primary & secondary skeletal manifestations per orthopedist • Internal fixation has been suggested as optimal mgmt. • Consider foot orthotics for tarsal fractures & pseudofractures in adults. • Teriparatide, a recombinant protein containing the 34 N-terminal residues of human parathyroid hormone, is a potent stimulator of TNSALP in osteoblasts & has been used for osteoporosis. • Case reports describe significant improvement in fracture healing & bone pain (suggesting beneficial effect on bone remodeling), improved mineralization, long-term fracture reduction, & improvement in QOL. • Use of teriparatide in hypophosphatasia is off-label; to date, there are no prospective studies or clinical trials. • Teriparatide is contraindicated in children (see • Referral to skilled pain mgmt professionals • NSAIDs • Mgmt per neurologist to prophylactically or prospectively treat seizures & manage myopathy • Seizures may respond to treatment w/vitamin B • Psychological support & social work support • Referral to mental health professionals ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in Hypophosphatasia: Recommended Surveillance In infants: at onset of treatment, ages 3, 6, & 12 mos, then every 6 mos In children/adults: at onset of treatment, 2 weeks, 3, 6, & 12 mos after initiating treatment, then annually Plasma PLP Urine PEA Serum ionized calcium (or serum calcium adjusted for albumin concentration) Serum phosphorus In infants: at onset of treatment, ages 1, 3, 6, & 12 mos, then annually In children/adults: at onset of treatment, 3 mos after initiating treatment, then annually In infants: at onset of treatment, ages 1, 3, 6, & 12 mos, then annually once normal levels reached In children/adults: at onset of treatment, 3, 6, & 12 mos after initiating treatment, then annually once normal levels reached Complete blood count Liver function (bilirubin, ALT, AST) In infants: at onset of treatment, ages 3, 6, 9, & 12 mos, then annually In children/adults: at onset of treatment, 6 mos after initiating treatment, then annually Creatinine, BUN Urine calcium-to-creatinine ratio to assess for nephrocalcinosis In infants: at onset of treatment, then every 3 mos; monitor closely during acute phase until stable In children/adults: at onset of treatment, 6 mos after initiating treatment, then annually ALT = alanine transaminase; AST = aspartate transaminase; BUN = blood urea nitrogen; eGFR = estimated glomerular filtration rate; OT = occupational therapy; PEA = phosphoethanolamine; PLP = pyridoxal 5′-phosphate; PT = physical therapy; PTH = parathyroid hormone • In infants: at onset of treatment, ages 3, 6, & 12 mos, then every 6 mos • In children/adults: at onset of treatment, 2 weeks, 3, 6, & 12 mos after initiating treatment, then annually • Plasma PLP • Urine PEA • Serum ionized calcium (or serum calcium adjusted for albumin concentration) • Serum phosphorus • In infants: at onset of treatment, ages 1, 3, 6, & 12 mos, then annually • In children/adults: at onset of treatment, 3 mos after initiating treatment, then annually • In infants: at onset of treatment, ages 1, 3, 6, & 12 mos, then annually once normal levels reached • In children/adults: at onset of treatment, 3, 6, & 12 mos after initiating treatment, then annually once normal levels reached • Complete blood count • Liver function (bilirubin, ALT, AST) • In infants: at onset of treatment, ages 3, 6, 9, & 12 mos, then annually • In children/adults: at onset of treatment, 6 mos after initiating treatment, then annually • Creatinine, BUN • Urine calcium-to-creatinine ratio to assess for nephrocalcinosis • In infants: at onset of treatment, then every 3 mos; monitor closely during acute phase until stable • In children/adults: at onset of treatment, 6 mos after initiating treatment, then annually ## Agents/Circumstances to Avoid ## 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. Regardless of age, clinically asymptomatic individuals found to have a familial See ## Pregnancy Management The use of asfotase alfa ERT during human pregnancy has not been extensively studied; therefore, any potential risk to the fetus of a pregnant woman is unknown. See ## Therapies Under Investigation Search ## Genetic Counseling Perinatal and infantile hypophosphatasia are typically inherited in an autosomal recessive manner. Milder forms of hypophosphatasia, especially adult hypophosphatasia and odontohypophosphatasia, may be inherited in an autosomal recessive or autosomal dominant manner depending on the effect of the Intrafamilial clinical variability is common, particularly when some affected family members have a heterozygous Reliable assessment of recurrence risk requires identification of the causative pathogenic variant(s) in the proband and molecular genetic testing of the proband's parents to confirm their genetic status. The parents of a child with biallelic Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an If 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 [ Depending on the If both parents are known to be heterozygous for an Sibs who inherit biallelic pathogenic variants tend to have similar disease severity; however, growth differences, nutrition, activity level, and earlier age of diagnosis may all influence phenotype. Sibs with compound heterozygous variants tend to display less intrafamilial clinical variability at the severe end of the spectrum and more variability at the milder end of the spectrum [ Depending on the An individual with autosomal dominant hypophosphatasia may have the disorder as the result of an An individual with autosomal dominant hypophosphatasia may have the disorder as the result of a Recommendations for the evaluation of parents of a proband include review of clinical history and laboratory evaluations for signs of hypophosphatasia. Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: Evaluation of parents may determine that a parent is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the disorder, reduced penetrance, and/or a milder phenotypic presentation. 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 known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Clinical severity is often similar in affected family members but cannot be reliably predicted by family history or molecular genetic testing due to reduced penetrance and variable expressivity. If the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. The American Academy of Pediatrics (AAP) recommends that genetic counseling and reproductive counseling for children with an inherited disease should be introduced in an age-appropriate manner during adolescence. The ACMG includes hypophosphatasia among those disorders for which expanded carrier screening should be offered to all pregnant individuals and individuals planning a pregnancy [ Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The parents of a child with biallelic • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an • If 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 [ • Depending on the • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual 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 who inherit biallelic pathogenic variants tend to have similar disease severity; however, growth differences, nutrition, activity level, and earlier age of diagnosis may all influence phenotype. Sibs with compound heterozygous variants tend to display less intrafamilial clinical variability at the severe end of the spectrum and more variability at the milder end of the spectrum [ • Depending on the • An individual with autosomal dominant hypophosphatasia may have the disorder as the result of an • An individual with autosomal dominant hypophosphatasia may have the disorder as the result of a • Recommendations for the evaluation of parents of a proband include review of clinical history and laboratory evaluations for signs of hypophosphatasia. Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: Evaluation of parents may determine that a parent is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the disorder, reduced penetrance, and/or a milder phenotypic presentation. 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 known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. • Clinical severity is often similar in affected family members but cannot be reliably predicted by family history or molecular genetic testing due to reduced penetrance and variable expressivity. • 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, are heterozygous, or are at risk of being heterozygous. The American Academy of Pediatrics (AAP) recommends that genetic counseling and reproductive counseling for children with an inherited disease should be introduced in an age-appropriate manner during adolescence. • The ACMG includes hypophosphatasia among those disorders for which expanded carrier screening should be offered to all pregnant individuals and individuals planning a pregnancy [ ## Mode of Inheritance Perinatal and infantile hypophosphatasia are typically inherited in an autosomal recessive manner. Milder forms of hypophosphatasia, especially adult hypophosphatasia and odontohypophosphatasia, may be inherited in an autosomal recessive or autosomal dominant manner depending on the effect of the Intrafamilial clinical variability is common, particularly when some affected family members have a heterozygous Reliable assessment of recurrence risk requires identification of the causative pathogenic variant(s) in the proband and molecular genetic testing of the proband's parents to confirm their genetic status. ## Autosomal Recessive Inheritance – Risk to Family Members The parents of a child with biallelic Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for 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 [ Depending on the If both parents are known to be heterozygous for an Sibs who inherit biallelic pathogenic variants tend to have similar disease severity; however, growth differences, nutrition, activity level, and earlier age of diagnosis may all influence phenotype. Sibs with compound heterozygous variants tend to display less intrafamilial clinical variability at the severe end of the spectrum and more variability at the milder end of the spectrum [ Depending on the • The parents of a child with biallelic • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an • If 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 [ • Depending on the • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual 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 who inherit biallelic pathogenic variants tend to have similar disease severity; however, growth differences, nutrition, activity level, and earlier age of diagnosis may all influence phenotype. Sibs with compound heterozygous variants tend to display less intrafamilial clinical variability at the severe end of the spectrum and more variability at the milder end of the spectrum [ • Depending on the ## Autosomal Dominant Inheritance – Risk to Family Members An individual with autosomal dominant hypophosphatasia may have the disorder as the result of an An individual with autosomal dominant hypophosphatasia may have the disorder as the result of a Recommendations for the evaluation of parents of a proband include review of clinical history and laboratory evaluations for signs of hypophosphatasia. Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: Evaluation of parents may determine that a parent is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the disorder, reduced penetrance, and/or a milder phenotypic presentation. 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 known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Clinical severity is often similar in affected family members but cannot be reliably predicted by family history or molecular genetic testing due to reduced penetrance and variable expressivity. If the • An individual with autosomal dominant hypophosphatasia may have the disorder as the result of an • An individual with autosomal dominant hypophosphatasia may have the disorder as the result of a • Recommendations for the evaluation of parents of a proband include review of clinical history and laboratory evaluations for signs of hypophosphatasia. Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: Evaluation of parents may determine that a parent is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the disorder, reduced penetrance, and/or a milder phenotypic presentation. 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 known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. • Clinical severity is often similar in affected family members but cannot be reliably predicted by family history or molecular genetic testing due to reduced penetrance and variable expressivity. • If the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. The American Academy of Pediatrics (AAP) recommends that genetic counseling and reproductive counseling for children with an inherited disease should be introduced in an age-appropriate manner during adolescence. The ACMG includes hypophosphatasia among those disorders for which expanded carrier screening should be offered to all pregnant individuals and individuals planning a pregnancy [ • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. The American Academy of Pediatrics (AAP) recommends that genetic counseling and reproductive counseling for children with an inherited disease should be introduced in an age-appropriate manner during adolescence. • The ACMG includes hypophosphatasia among those disorders for which expanded carrier screening should be offered to all pregnant individuals and individuals planning a pregnancy [ ## Prenatal Testing and Preimplantation Genetic Testing Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources Canada • • • • • • Canada • • • • • • • ## Molecular Genetics Hypophosphatasia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Hypophosphatasia ( The most common Genotype-phenotype correlations have been studied using site-directed mutagenesis and 3D enzyme modeling. These studies have allowed the characterization of severe and moderate alleles (alleles producing significant residual enzymatic activity) and alleles with a dominant-negative effect responsible for autosomal dominant inheritance [ Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis The most common Genotype-phenotype correlations have been studied using site-directed mutagenesis and 3D enzyme modeling. These studies have allowed the characterization of severe and moderate alleles (alleles producing significant residual enzymatic activity) and alleles with a dominant-negative effect responsible for autosomal dominant inheritance [ Variants listed in the table have been provided by the authors. ## Chapter Notes Dr Dahir's professional effort is divided between clinical care for individuals with rare skeletal dysplasias, including hypophosphatasia, X-linked hypophosphatemia, tumor-induced hypophosphatemia, osteogenesis imperfecta, ENPP1 deficiency, and fibrous dysplasia ossificans progressive, and research, in which she leads an independent laboratory. Her research focuses on academic-industrial and patient advocacy partnerships to translate pharmacotherapeutics and other technologies for diagnosing and treating rare skeletal disorders. She also investigates the genetic basis of these diseases using approaches like electronic health records (EHRs) and genomics data from large-scale biobanks, including Vanderbilt's BioVU and the Synthetic Derivative. The See the Michael Whyte, MD, is the foremost authority on hypophosphatasia in all its clinical forms, and his mentorship inspires this chapter. Etienne Mornet, PhD, is the foremost authority on Hypophospatasie Europe sponsored the 5th and 6th International Alkaline Phosphatase and Hypophosphatasia Symposia, which established the patient, clinical, academic, and commercial partnership leading to breakthrough therapy. Soft Bones has continued to expand the collaboration. Kathryn M Dahir, MD (2025-present)Etienne Mornet, PhD; Centre Hospitalier de Versailles (2007-2022)Mark E Nunes, MD (2007-present) 27 March 2025 (sw) Comprehensive update posted live 7 April 2022 (sw) Comprehensive update posted live 4 February 2016 (ha) Comprehensive update posted live 5 August 2010 (me) Comprehensive update posted live 20 November 2007 (me) Review posted live 18 December 2006 (men) Original submission • 27 March 2025 (sw) Comprehensive update posted live • 7 April 2022 (sw) Comprehensive update posted live • 4 February 2016 (ha) Comprehensive update posted live • 5 August 2010 (me) Comprehensive update posted live • 20 November 2007 (me) Review posted live • 18 December 2006 (men) Original submission ## Author Notes Dr Dahir's professional effort is divided between clinical care for individuals with rare skeletal dysplasias, including hypophosphatasia, X-linked hypophosphatemia, tumor-induced hypophosphatemia, osteogenesis imperfecta, ENPP1 deficiency, and fibrous dysplasia ossificans progressive, and research, in which she leads an independent laboratory. Her research focuses on academic-industrial and patient advocacy partnerships to translate pharmacotherapeutics and other technologies for diagnosing and treating rare skeletal disorders. She also investigates the genetic basis of these diseases using approaches like electronic health records (EHRs) and genomics data from large-scale biobanks, including Vanderbilt's BioVU and the Synthetic Derivative. The See the ## Acknowledgments Michael Whyte, MD, is the foremost authority on hypophosphatasia in all its clinical forms, and his mentorship inspires this chapter. Etienne Mornet, PhD, is the foremost authority on Hypophospatasie Europe sponsored the 5th and 6th International Alkaline Phosphatase and Hypophosphatasia Symposia, which established the patient, clinical, academic, and commercial partnership leading to breakthrough therapy. Soft Bones has continued to expand the collaboration. ## Author History Kathryn M Dahir, MD (2025-present)Etienne Mornet, PhD; Centre Hospitalier de Versailles (2007-2022)Mark E Nunes, MD (2007-present) ## Revision History 27 March 2025 (sw) Comprehensive update posted live 7 April 2022 (sw) Comprehensive update posted live 4 February 2016 (ha) Comprehensive update posted live 5 August 2010 (me) Comprehensive update posted live 20 November 2007 (me) Review posted live 18 December 2006 (men) Original submission • 27 March 2025 (sw) Comprehensive update posted live • 7 April 2022 (sw) Comprehensive update posted live • 4 February 2016 (ha) Comprehensive update posted live • 5 August 2010 (me) Comprehensive update posted live • 20 November 2007 (me) Review posted live • 18 December 2006 (men) Original submission ## Key Sections in this ## References ## Literature Cited Lost incisors with and without hypophosphatasia A. Hypophosphatasia: root intact B. Normal: root absorbed Reproduced with permission from Michael Whyte, MD Radiographic signs of hypophosphatasia A. Rachitic rib changes, flail chest, and metaphyseal dysplasia (proximal humerus) in infantile hypophosphatasia B. Alveolar bone loss surrounding molars in childhood (juvenile) hypophosphatasia C. Hypolucent "tongue" mid-metaphysis in childhood (juvenile) hypophosphatasia D. Pseudofracture ("Looser zone") in adult hypophosphatasia Radiograph of treated hypophosphatasia. Individual from Radiograph of left femur in a female age 62 years with hypophosphatasia, showing a transverse fracture of the proximal midshaft of the femur with varus angulation. Radiograph of multiple healed bilateral metatarsal fractures and features of arthritic changes in a female age 56 years with hypophosphatasia. Radiograph of treated adult hypophosphatasia: linear sclerosis in remodeling distal femur and proximal tibia, osteophytes mid-proximal tibia, and chondrocalcinosis medial lateral compartment	[]	20/11/2007	27/3/2025	30/3/2023	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
hos	hos	[ "Heart-Hand Syndrome", "Heart-Hand Syndrome", "T-box transcription factor TBX5", "TBX5", "Holt-Oram Syndrome" ]	Holt-Oram Syndrome	Clémence Vanlerberghe, Florence Petit	Summary Holt-Oram syndrome (HOS) is characterized by the association of upper-limb defects, congenital heart malformations, and cardiac conduction disease. Upper-limb malformations are usually bilateral/asymmetric, rarely unilateral or bilateral/symmetric, and affect the radial ray. They can range from thenar hypoplasia, triphalangeal thumb(s), or absent thumb(s) to radial agenesis/hypoplasia to phocomelia. Deformities of the carpal and thenar bones, abnormalities of the shoulders and/or elbows, and vertebral defects can occur. A congenital heart malformation is present in 90% of individuals with HOS and most commonly involves the septum. Atrial septal defect and ventricular septal defect can vary in number, size, and location. Complex congenital heart malformations can also occur in individuals with HOS. Individuals with HOS with or without a congenital heart malformation are at risk for cardiac conduction disease (30%). While individuals may present at birth with sinus bradycardia and first-degree atrioventricular (AV) block, AV block can progress unpredictably to a higher grade including complete heart block with and without atrial fibrillation. The clinical diagnosis of HOS is established by the presence in a proband of a preaxial radial ray anomaly and a personal or family history of cardiac septation and/or conduction defects. More than 70% of individuals who meet strict clinical diagnostic criteria have an identifiable heterozygous pathogenic variant in HOS is inherited in an autosomal dominant manner. Some individuals diagnosed with HOS have an affected parent; up to 60% of affected individuals represent simplex cases. Significant intrafamilial variability in limb and heart defect severity is observed among affected family members. Offspring of an individual with HOS have a 50% risk for HOS. If the	## Diagnosis Clinical diagnostic criteria for Holt-Oram syndrome (HOS) have been established and validated through molecular genetic testing [ HOS Note: Congenital malformations involving the following structures or organ systems are not typically within the spectrum of HOS and should prompt the clinician to consider alternate diagnoses: ulnar ray only, kidney, craniofacies, auditory system (ear malformations with or without hearing loss), lower limb, anus, and eye. The clinical diagnosis of HOS The molecular diagnosis of HOS Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular testing approaches can include gene-targeted testing ( For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Holt-Oram Syndrome See See Sequence analysis should include coding and noncoding regions and may detect variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Genome sequencing can identify Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 one or more exons or the entire gene was detected in about 2% of individuals with HOS who did not have a pathogenic variant identified by sequence analysis / variant scanning [ Chromosome rearrangements involving 12q24 have been reported in individuals with HOS [ That current molecular analysis fails to identify a heterozygous pathogenic variant in • ## Suggestive Findings HOS Note: Congenital malformations involving the following structures or organ systems are not typically within the spectrum of HOS and should prompt the clinician to consider alternate diagnoses: ulnar ray only, kidney, craniofacies, auditory system (ear malformations with or without hearing loss), lower limb, anus, and eye. • ## Establishing the Diagnosis The clinical diagnosis of HOS The molecular diagnosis of HOS Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular testing approaches can include gene-targeted testing ( For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Holt-Oram Syndrome See See Sequence analysis should include coding and noncoding regions and may detect variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Genome sequencing can identify Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 one or more exons or the entire gene was detected in about 2% of individuals with HOS who did not have a pathogenic variant identified by sequence analysis / variant scanning [ Chromosome rearrangements involving 12q24 have been reported in individuals with HOS [ That current molecular analysis fails to identify a heterozygous pathogenic variant in ## Clinical Diagnosis The clinical diagnosis of HOS ## Molecular Diagnosis The molecular diagnosis of HOS Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular testing approaches can include gene-targeted testing ( For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Holt-Oram Syndrome See See Sequence analysis should include coding and noncoding regions and may detect variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Genome sequencing can identify Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 one or more exons or the entire gene was detected in about 2% of individuals with HOS who did not have a pathogenic variant identified by sequence analysis / variant scanning [ Chromosome rearrangements involving 12q24 have been reported in individuals with HOS [ That current molecular analysis fails to identify a heterozygous pathogenic variant in ## For an introduction to multigene panels click ## For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Holt-Oram Syndrome See See Sequence analysis should include coding and noncoding regions and may detect variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Genome sequencing can identify Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 one or more exons or the entire gene was detected in about 2% of individuals with HOS who did not have a pathogenic variant identified by sequence analysis / variant scanning [ Chromosome rearrangements involving 12q24 have been reported in individuals with HOS [ That current molecular analysis fails to identify a heterozygous pathogenic variant in ## Clinical Characteristics Holt-Oram syndrome (HOS) is characterized by upper-limb defects, congenital heart malformations, and cardiac conduction disease [ While all individuals have an upper-limb defect, the broad range of severity of these findings is such that some individuals with the mildest upper-limb malformations and mild or no congenital heart malformation may escape diagnosis. These individuals may only be diagnosed when a more severely affected relative is born or when symptoms develop in middle age as a result of cardiac abnormalities such as pulmonary hypertension, high-grade atrioventricular (AV) block, and/or atrial fibrillation. Some individuals with severe congenital heart malformation may require surgery early in life to repair significant septal defects [ Other individuals may have complex congenital heart malformations [ Various genotype-phenotype correlations have been suggested: missense variants at the 5' end of the T-box are associated with more serious cardiac defects, whereas missense variants at the 3' end of the T-box are associated with more pronounced limb defects [ In addition, genotypes do not appear to predict the progressive hemodynamic course associated with any particular cardiac septal defect. Penetrance of HOS is most commonly complete, but rare families with reduced penetrance have been reported [ HOS has been referred to as heart-hand syndrome, a nonspecific designation that could apply to any number of conditions with involvement of these structures. HOS is the most common of the heart-hand syndromes. The estimated prevalence of HOS is between 0.7 and 1 in 100,000 births [ ## Clinical Description Holt-Oram syndrome (HOS) is characterized by upper-limb defects, congenital heart malformations, and cardiac conduction disease [ While all individuals have an upper-limb defect, the broad range of severity of these findings is such that some individuals with the mildest upper-limb malformations and mild or no congenital heart malformation may escape diagnosis. These individuals may only be diagnosed when a more severely affected relative is born or when symptoms develop in middle age as a result of cardiac abnormalities such as pulmonary hypertension, high-grade atrioventricular (AV) block, and/or atrial fibrillation. Some individuals with severe congenital heart malformation may require surgery early in life to repair significant septal defects [ Other individuals may have complex congenital heart malformations [ ## Genotype-Phenotype Correlations Various genotype-phenotype correlations have been suggested: missense variants at the 5' end of the T-box are associated with more serious cardiac defects, whereas missense variants at the 3' end of the T-box are associated with more pronounced limb defects [ In addition, genotypes do not appear to predict the progressive hemodynamic course associated with any particular cardiac septal defect. ## Penetrance Penetrance of HOS is most commonly complete, but rare families with reduced penetrance have been reported [ ## Nomenclature HOS has been referred to as heart-hand syndrome, a nonspecific designation that could apply to any number of conditions with involvement of these structures. ## Prevalence HOS is the most common of the heart-hand syndromes. The estimated prevalence of HOS is between 0.7 and 1 in 100,000 births [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this Variants in ## Differential Diagnosis Diagnoses summarized in Note: Disorders of Known Genetic Cause of Interest in the Differential Diagnosis of Holt-Oram Syndrome Radial ray malformations can include thenar hypoplasia &/or hypoplasia or aplasia of thumbs, triphalangeal thumbs, hypoplasia or aplasia of radii, & shortening & radial deviation of forearms CHD (in 15% of affected persons) Thumb duplication Duane anomaly; renal anomalies Sensorineural hearing loss Hypoplastic thumbs, triphalangeal thumbs, hypoplastic radius CHD (in 6% of affected persons) Preaxial polydactyly Microcephaly; scoliosis, hemivertebrae, rib anomalies; clubfeet, toe syndactyly; abnormal skin pigmentation Pancytopenia due to progressive bone marrow failure Growth deficiency ↑ risk for malignancy Thumb duplication Feet malformations Triphalangeal thumbs, rarely thumb hypoplasia CHD (in 20% of affected persons) Thumb duplication Imperforate anus or anal stenosis; dysplastic ears; foot malformations; genitourinary malformations; renal malformations Impaired kidney function Hearing impairment Bilateral absence of radii CHD Phocomelia of upper limbs Preserved thumbs Lower-limb malformations: hip/patellar dislocations, patella absence, varus/valgus anomalies; ribs & vertebrae defects (rare); CAKUT Thrombocytopenia (<50 platelets/nL), generally transient Cow's milk allergy Thumb hypoplasia, radioulnar synostosis Congenital heart defects (15%) Lower-limb malformations; mandibulofacial dysostosis; ear malformations; cleft palate Deafness Thumb duplication; involvement of other digits Lacrimal duct atresia; ear malformations; teeth agenesis or hypoplasia Deafness Radial hypoplasia/aplasia Radioulnar synostosis Thumb hypoplasia/aplasia; triphalangeal thumbs CHD Thumb duplication Mandibulofacial dysostosis; genitourinary malformations Growth deficiency Profound normochromic & usually macrocytic anemia Risk of malignancy Hypomelia/phocomelia, wrist/elbow synostosis, oligodactyly/brachydactyly involving thumb CHD Lower-limb involvement: phocomelia, knee/ankle synostosis, talipes equinovarus Brachycephaly, microcephaly; cleft lip/palate; midfacial capillary hemangioma; urogenital malformations; hypertelorism, exophthalmos, underdeveloped alae nasi; micrognathia; ear malformations Intrauterine & postnatal growth deficiency Mild-to-severe ID is common. Early mortality is common among severely affected pregnancies & newborns. Radial hypoplasia Thumb hypoplasia Thumb duplication; syndactyly of fingers Feet malformations Ectodermal dysplasia AD = autosomal dominant; AR = autosomal recessive; CAKUT = congenital anomalies of the kidney and urinary tract; CHD = congenital heart defects; HOS = Holt-Oram syndrome; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked Genes/disorders are ordered from greatest to least phenotypic overlap with HOS. 2.. Fanconi anemia (FA) is inherited in an autosomal recessive manner, an autosomal dominant manner ( Thrombocytopenia absent radius (TAR) syndrome is caused by compound heterozygosity for a null allele and an Diamond-Blackfan anemia (DBA) is most often inherited in an autosomal dominant manner; • Radial ray malformations can include thenar hypoplasia &/or hypoplasia or aplasia of thumbs, triphalangeal thumbs, hypoplasia or aplasia of radii, & shortening & radial deviation of forearms • CHD (in 15% of affected persons) • Thumb duplication • Duane anomaly; renal anomalies • Sensorineural hearing loss • Hypoplastic thumbs, triphalangeal thumbs, hypoplastic radius • CHD (in 6% of affected persons) • Preaxial polydactyly • Microcephaly; scoliosis, hemivertebrae, rib anomalies; clubfeet, toe syndactyly; abnormal skin pigmentation • Pancytopenia due to progressive bone marrow failure • Growth deficiency • ↑ risk for malignancy • Thumb duplication • Feet malformations • Triphalangeal thumbs, rarely thumb hypoplasia • CHD (in 20% of affected persons) • Thumb duplication • Imperforate anus or anal stenosis; dysplastic ears; foot malformations; genitourinary malformations; renal malformations • Impaired kidney function • Hearing impairment • Bilateral absence of radii • CHD • Phocomelia of upper limbs • Preserved thumbs • Lower-limb malformations: hip/patellar dislocations, patella absence, varus/valgus anomalies; ribs & vertebrae defects (rare); CAKUT • Thrombocytopenia (<50 platelets/nL), generally transient • Cow's milk allergy • Thumb hypoplasia, radioulnar synostosis • Congenital heart defects (15%) • Lower-limb malformations; mandibulofacial dysostosis; ear malformations; cleft palate • Deafness • Thumb duplication; involvement of other digits • Lacrimal duct atresia; ear malformations; teeth agenesis or hypoplasia • Deafness • Radial hypoplasia/aplasia • Radioulnar synostosis • Thumb hypoplasia/aplasia; triphalangeal thumbs • CHD • Thumb duplication • Mandibulofacial dysostosis; genitourinary malformations • Growth deficiency • Profound normochromic & usually macrocytic anemia • Risk of malignancy • Hypomelia/phocomelia, wrist/elbow synostosis, oligodactyly/brachydactyly involving thumb • CHD • Lower-limb involvement: phocomelia, knee/ankle synostosis, talipes equinovarus • Brachycephaly, microcephaly; cleft lip/palate; midfacial capillary hemangioma; urogenital malformations; hypertelorism, exophthalmos, underdeveloped alae nasi; micrognathia; ear malformations • Intrauterine & postnatal growth deficiency • Mild-to-severe ID is common. • Early mortality is common among severely affected pregnancies & newborns. • Radial hypoplasia • Thumb hypoplasia • Thumb duplication; syndactyly of fingers • Feet malformations • Ectodermal dysplasia ## Disorders of Known Genetic Cause of Interest in the Differential Diagnosis of HOS Diagnoses summarized in Note: Disorders of Known Genetic Cause of Interest in the Differential Diagnosis of Holt-Oram Syndrome Radial ray malformations can include thenar hypoplasia &/or hypoplasia or aplasia of thumbs, triphalangeal thumbs, hypoplasia or aplasia of radii, & shortening & radial deviation of forearms CHD (in 15% of affected persons) Thumb duplication Duane anomaly; renal anomalies Sensorineural hearing loss Hypoplastic thumbs, triphalangeal thumbs, hypoplastic radius CHD (in 6% of affected persons) Preaxial polydactyly Microcephaly; scoliosis, hemivertebrae, rib anomalies; clubfeet, toe syndactyly; abnormal skin pigmentation Pancytopenia due to progressive bone marrow failure Growth deficiency ↑ risk for malignancy Thumb duplication Feet malformations Triphalangeal thumbs, rarely thumb hypoplasia CHD (in 20% of affected persons) Thumb duplication Imperforate anus or anal stenosis; dysplastic ears; foot malformations; genitourinary malformations; renal malformations Impaired kidney function Hearing impairment Bilateral absence of radii CHD Phocomelia of upper limbs Preserved thumbs Lower-limb malformations: hip/patellar dislocations, patella absence, varus/valgus anomalies; ribs & vertebrae defects (rare); CAKUT Thrombocytopenia (<50 platelets/nL), generally transient Cow's milk allergy Thumb hypoplasia, radioulnar synostosis Congenital heart defects (15%) Lower-limb malformations; mandibulofacial dysostosis; ear malformations; cleft palate Deafness Thumb duplication; involvement of other digits Lacrimal duct atresia; ear malformations; teeth agenesis or hypoplasia Deafness Radial hypoplasia/aplasia Radioulnar synostosis Thumb hypoplasia/aplasia; triphalangeal thumbs CHD Thumb duplication Mandibulofacial dysostosis; genitourinary malformations Growth deficiency Profound normochromic & usually macrocytic anemia Risk of malignancy Hypomelia/phocomelia, wrist/elbow synostosis, oligodactyly/brachydactyly involving thumb CHD Lower-limb involvement: phocomelia, knee/ankle synostosis, talipes equinovarus Brachycephaly, microcephaly; cleft lip/palate; midfacial capillary hemangioma; urogenital malformations; hypertelorism, exophthalmos, underdeveloped alae nasi; micrognathia; ear malformations Intrauterine & postnatal growth deficiency Mild-to-severe ID is common. Early mortality is common among severely affected pregnancies & newborns. Radial hypoplasia Thumb hypoplasia Thumb duplication; syndactyly of fingers Feet malformations Ectodermal dysplasia AD = autosomal dominant; AR = autosomal recessive; CAKUT = congenital anomalies of the kidney and urinary tract; CHD = congenital heart defects; HOS = Holt-Oram syndrome; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked Genes/disorders are ordered from greatest to least phenotypic overlap with HOS. 2.. Fanconi anemia (FA) is inherited in an autosomal recessive manner, an autosomal dominant manner ( Thrombocytopenia absent radius (TAR) syndrome is caused by compound heterozygosity for a null allele and an Diamond-Blackfan anemia (DBA) is most often inherited in an autosomal dominant manner; • Radial ray malformations can include thenar hypoplasia &/or hypoplasia or aplasia of thumbs, triphalangeal thumbs, hypoplasia or aplasia of radii, & shortening & radial deviation of forearms • CHD (in 15% of affected persons) • Thumb duplication • Duane anomaly; renal anomalies • Sensorineural hearing loss • Hypoplastic thumbs, triphalangeal thumbs, hypoplastic radius • CHD (in 6% of affected persons) • Preaxial polydactyly • Microcephaly; scoliosis, hemivertebrae, rib anomalies; clubfeet, toe syndactyly; abnormal skin pigmentation • Pancytopenia due to progressive bone marrow failure • Growth deficiency • ↑ risk for malignancy • Thumb duplication • Feet malformations • Triphalangeal thumbs, rarely thumb hypoplasia • CHD (in 20% of affected persons) • Thumb duplication • Imperforate anus or anal stenosis; dysplastic ears; foot malformations; genitourinary malformations; renal malformations • Impaired kidney function • Hearing impairment • Bilateral absence of radii • CHD • Phocomelia of upper limbs • Preserved thumbs • Lower-limb malformations: hip/patellar dislocations, patella absence, varus/valgus anomalies; ribs & vertebrae defects (rare); CAKUT • Thrombocytopenia (<50 platelets/nL), generally transient • Cow's milk allergy • Thumb hypoplasia, radioulnar synostosis • Congenital heart defects (15%) • Lower-limb malformations; mandibulofacial dysostosis; ear malformations; cleft palate • Deafness • Thumb duplication; involvement of other digits • Lacrimal duct atresia; ear malformations; teeth agenesis or hypoplasia • Deafness • Radial hypoplasia/aplasia • Radioulnar synostosis • Thumb hypoplasia/aplasia; triphalangeal thumbs • CHD • Thumb duplication • Mandibulofacial dysostosis; genitourinary malformations • Growth deficiency • Profound normochromic & usually macrocytic anemia • Risk of malignancy • Hypomelia/phocomelia, wrist/elbow synostosis, oligodactyly/brachydactyly involving thumb • CHD • Lower-limb involvement: phocomelia, knee/ankle synostosis, talipes equinovarus • Brachycephaly, microcephaly; cleft lip/palate; midfacial capillary hemangioma; urogenital malformations; hypertelorism, exophthalmos, underdeveloped alae nasi; micrognathia; ear malformations • Intrauterine & postnatal growth deficiency • Mild-to-severe ID is common. • Early mortality is common among severely affected pregnancies & newborns. • Radial hypoplasia • Thumb hypoplasia • Thumb duplication; syndactyly of fingers • Feet malformations • Ectodermal dysplasia ## Other Diagnoses to Consider in the Differential Diagnosis of HOS ## Management No clinical practice guidelines for Holt-Oram syndrome (HOS) 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 HOS, the evaluations summarized in Holt-Oram Syndrome: Recommended Evaluations Following Initial Diagnosis HOS = Holt-Oram syndrome; MOI = mode of inheritance Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) The management of individuals with HOS optimally involves a multidisciplinary team approach with specialists in medical genetics, cardiology, and orthopedics, including a specialist in hand surgery (see Holt-Oram Syndrome: Treatment of Manifestations Surgery for improved upper-limb & hand function PT & OT Prostheses (in those w/severe limb shortening) Antiarrhythmic medications Surgery Pacemaker implantation in those w/severe heart block OT = occupational therapy; PT = physical therapy To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Recommended Surveillance for Individuals with Holt-Oram Syndrome As recommended by managing cardiologist depending on nature & significance of potential septal defects & history of heart surgery Every 5 yrs in absence of congenital malformations (rare cardiomyopathy) ADL = activities of daily living; OT = occupational therapy/therapist; PT = physical therapy/therapist Certain medications may be contraindicated in individuals with arrhythmias, cardiomyopathy, and/or pulmonary hypertension. People with such disorders require individual assessment by a cardiologist. 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 appropriate cardiac management. Evaluations can include: Molecular genetic testing if the Echocardiography, EKG, and hand radiographs (anteroposterior view) if the pathogenic variant in the family is not known. See Pregnant women with HOS who have a known history of a structural cardiac defect or cardiac conduction abnormality should be followed by a multidisciplinary team (including a cardiologist) during pregnancy. Affected women who have not undergone cardiac evaluation should do so prior to pregnancy if possible, or as soon as the pregnancy is recognized. See Search • Surgery for improved upper-limb & hand function • PT & OT • Prostheses (in those w/severe limb shortening) • Antiarrhythmic medications • Surgery • Pacemaker implantation in those w/severe heart block • As recommended by managing cardiologist depending on nature & significance of potential septal defects & history of heart surgery • Every 5 yrs in absence of congenital malformations (rare cardiomyopathy) • Molecular genetic testing if the • Echocardiography, EKG, and hand radiographs (anteroposterior view) 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 HOS, the evaluations summarized in Holt-Oram Syndrome: Recommended Evaluations Following Initial Diagnosis HOS = Holt-Oram syndrome; MOI = mode of inheritance Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) ## Treatment of Manifestations The management of individuals with HOS optimally involves a multidisciplinary team approach with specialists in medical genetics, cardiology, and orthopedics, including a specialist in hand surgery (see Holt-Oram Syndrome: Treatment of Manifestations Surgery for improved upper-limb & hand function PT & OT Prostheses (in those w/severe limb shortening) Antiarrhythmic medications Surgery Pacemaker implantation in those w/severe heart block OT = occupational therapy; PT = physical therapy • Surgery for improved upper-limb & hand function • PT & OT • Prostheses (in those w/severe limb shortening) • Antiarrhythmic medications • Surgery • Pacemaker implantation in those w/severe heart block ## 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 Holt-Oram Syndrome As recommended by managing cardiologist depending on nature & significance of potential septal defects & history of heart surgery Every 5 yrs in absence of congenital malformations (rare cardiomyopathy) ADL = activities of daily living; OT = occupational therapy/therapist; PT = physical therapy/therapist • As recommended by managing cardiologist depending on nature & significance of potential septal defects & history of heart surgery • Every 5 yrs in absence of congenital malformations (rare cardiomyopathy) ## Agents/Circumstances to Avoid Certain medications may be contraindicated in individuals with arrhythmias, cardiomyopathy, and/or pulmonary hypertension. People with such disorders require individual assessment by a cardiologist. ## 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 appropriate cardiac management. Evaluations can include: Molecular genetic testing if the Echocardiography, EKG, and hand radiographs (anteroposterior view) if the pathogenic variant in the family is not known. See • Molecular genetic testing if the • Echocardiography, EKG, and hand radiographs (anteroposterior view) if the pathogenic variant in the family is not known. ## Pregnancy Management Pregnant women with HOS who have a known history of a structural cardiac defect or cardiac conduction abnormality should be followed by a multidisciplinary team (including a cardiologist) during pregnancy. Affected women who have not undergone cardiac evaluation should do so prior to pregnancy if possible, or as soon as the pregnancy is recognized. See ## Therapies Under Investigation Search ## Genetic Counseling Holt-Oram syndrome (HOS) is inherited in an autosomal dominant manner. Some individuals diagnosed with HOS have an affected parent [ Up to 60% of individuals with HOS represent simplex cases (i.e., the only family member known to be affected) [ Evaluation of the parents of a proband who appears to be the only affected family member (i.e., a simplex case) is recommended in order to determine the clinical status of the parents and inform recurrence risk assessment. Evaluations include: Echocardiography, EKG, and hand radiographs (anteroposterior view); Molecular genetic testing if a If a molecular diagnosis has been established in the proband, the The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [ * A parent with somatic and gonadal mosaicism for a If a parent of the proband is affected and/or is known to have the If the parents are clinically unaffected and the proband has a known If the parents are clinically unaffected (based on appropriate clinical evaluation) 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. Offspring of a proband are at 50% risk for HOS. Because of the significant variability in limb and heart defect severity observed in individuals with HOS, both among and within families with the same 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. If the If the pathogenic variant in the family is not known, US examination evaluating for characteristic limb and cardiac manifestations (including fetal echocardiogram) is recommended. Note: A normal US examination does not eliminate the possibility of HOS in the fetus. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • Some individuals diagnosed with HOS have an affected parent [ • Up to 60% of individuals with HOS represent simplex cases (i.e., the only family member known to be affected) [ • Evaluation of the parents of a proband who appears to be the only affected family member (i.e., a simplex case) is recommended in order to determine the clinical status of the parents and inform recurrence risk assessment. Evaluations include: • Echocardiography, EKG, and hand radiographs (anteroposterior view); • Molecular genetic testing if a • Echocardiography, EKG, and hand radiographs (anteroposterior view); • Molecular genetic testing if a • If a molecular diagnosis has been established in the proband, the • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [ • * A parent with somatic and gonadal mosaicism for a • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [ • * A parent with somatic and gonadal mosaicism for a • Echocardiography, EKG, and hand radiographs (anteroposterior view); • Molecular genetic testing if a • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [ • * A parent with somatic and gonadal mosaicism for a • If a parent of the proband is affected and/or is known to have the • If the parents are clinically unaffected and the proband has a known • If the parents are clinically unaffected (based on appropriate clinical evaluation) 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. • Offspring of a proband are at 50% risk for HOS. • Because of the significant variability in limb and heart defect severity observed in individuals with HOS, both among and within families with 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 Holt-Oram syndrome (HOS) is inherited in an autosomal dominant manner. ## Risk to Family Members Some individuals diagnosed with HOS have an affected parent [ Up to 60% of individuals with HOS represent simplex cases (i.e., the only family member known to be affected) [ Evaluation of the parents of a proband who appears to be the only affected family member (i.e., a simplex case) is recommended in order to determine the clinical status of the parents and inform recurrence risk assessment. Evaluations include: Echocardiography, EKG, and hand radiographs (anteroposterior view); Molecular genetic testing if a If a molecular diagnosis has been established in the proband, the The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [ * A parent with somatic and gonadal mosaicism for a If a parent of the proband is affected and/or is known to have the If the parents are clinically unaffected and the proband has a known If the parents are clinically unaffected (based on appropriate clinical evaluation) 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. Offspring of a proband are at 50% risk for HOS. Because of the significant variability in limb and heart defect severity observed in individuals with HOS, both among and within families with the same • Some individuals diagnosed with HOS have an affected parent [ • Up to 60% of individuals with HOS represent simplex cases (i.e., the only family member known to be affected) [ • Evaluation of the parents of a proband who appears to be the only affected family member (i.e., a simplex case) is recommended in order to determine the clinical status of the parents and inform recurrence risk assessment. Evaluations include: • Echocardiography, EKG, and hand radiographs (anteroposterior view); • Molecular genetic testing if a • Echocardiography, EKG, and hand radiographs (anteroposterior view); • Molecular genetic testing if a • If a molecular diagnosis has been established in the proband, the • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [ • * A parent with somatic and gonadal mosaicism for a • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [ • * A parent with somatic and gonadal mosaicism for a • Echocardiography, EKG, and hand radiographs (anteroposterior view); • Molecular genetic testing if a • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [ • * A parent with somatic and gonadal mosaicism for a • If a parent of the proband is affected and/or is known to have the • If the parents are clinically unaffected and the proband has a known • If the parents are clinically unaffected (based on appropriate clinical evaluation) 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. • Offspring of a proband are at 50% risk for HOS. • Because of the significant variability in limb and heart defect severity observed in individuals with HOS, both among and within families with the same ## 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 If the If the pathogenic variant in the family is not known, US examination evaluating for characteristic limb and cardiac manifestations (including fetal echocardiogram) is recommended. Note: A normal US examination does not eliminate the possibility of HOS in the fetus. 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 Holt-Oram Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Holt-Oram Syndrome ( T-box transcription factor TBX5 functions as a transcription factor that has an important role in both cardiogenesis and limb development. TBX5 can interact with other transcription factors including It is hypothesized that most nonsense, frameshift, and splice site pathogenic variants lead to mutated Note: ## Molecular Pathogenesis T-box transcription factor TBX5 functions as a transcription factor that has an important role in both cardiogenesis and limb development. TBX5 can interact with other transcription factors including It is hypothesized that most nonsense, frameshift, and splice site pathogenic variants lead to mutated Note: ## Chapter Notes Dr Vanlerberghe ( Dr Vanlerberghe is also interested in hearing from clinicians treating families affected by radial defects 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 Brunelle to inquire about review of To Prof Florence Petit and Dr Perrine Brunelle, clinical and molecular geneticists, respectively, for their expertise and contribution to this work, and the research team RADEME at Lille University. Craig T Basson, MD, PhD; Novartis Institutes for BioMedical Research (2004-2025)Jamie C Fong, MS, CGC; University of California, San Francisco (2004-2025)Deborah A McDermott, MS, CGC; Consultant, Human Genetics and Genetic Counseling (2004-2025)Florence Petit, MD, PhD (2025-present)Clémence Vanlerberghe, MD, PhD (2025-present) 31 July 2025 (sw) Comprehensive update posted live 23 May 2019 (sw) Comprehensive update posted live 8 October 2015 (me) Comprehensive update posted live 4 April 2013 (me) Comprehensive update posted live 4 January 2011 (me) Comprehensive update posted live 21 September 2006 (me) Comprehensive update posted live 20 July 2004 (me) Review posted live 23 December 2003 (cb) Original submission • 31 July 2025 (sw) Comprehensive update posted live • 23 May 2019 (sw) Comprehensive update posted live • 8 October 2015 (me) Comprehensive update posted live • 4 April 2013 (me) Comprehensive update posted live • 4 January 2011 (me) Comprehensive update posted live • 21 September 2006 (me) Comprehensive update posted live • 20 July 2004 (me) Review posted live • 23 December 2003 (cb) Original submission ## Author Notes Dr Vanlerberghe ( Dr Vanlerberghe is also interested in hearing from clinicians treating families affected by radial defects 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 Brunelle to inquire about review of ## Acknowledgments To Prof Florence Petit and Dr Perrine Brunelle, clinical and molecular geneticists, respectively, for their expertise and contribution to this work, and the research team RADEME at Lille University. ## Author History Craig T Basson, MD, PhD; Novartis Institutes for BioMedical Research (2004-2025)Jamie C Fong, MS, CGC; University of California, San Francisco (2004-2025)Deborah A McDermott, MS, CGC; Consultant, Human Genetics and Genetic Counseling (2004-2025)Florence Petit, MD, PhD (2025-present)Clémence Vanlerberghe, MD, PhD (2025-present) ## Revision History 31 July 2025 (sw) Comprehensive update posted live 23 May 2019 (sw) Comprehensive update posted live 8 October 2015 (me) Comprehensive update posted live 4 April 2013 (me) Comprehensive update posted live 4 January 2011 (me) Comprehensive update posted live 21 September 2006 (me) Comprehensive update posted live 20 July 2004 (me) Review posted live 23 December 2003 (cb) Original submission • 31 July 2025 (sw) Comprehensive update posted live • 23 May 2019 (sw) Comprehensive update posted live • 8 October 2015 (me) Comprehensive update posted live • 4 April 2013 (me) Comprehensive update posted live • 4 January 2011 (me) Comprehensive update posted live • 21 September 2006 (me) Comprehensive update posted live • 20 July 2004 (me) Review posted live • 23 December 2003 (cb) Original submission ## References ## Literature Cited	[]	20/7/2004	31/7/2025	22/11/2006	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
hoxa1-dis	hoxa1-dis	[ "Athabaskan Brain Stem Dysgenesis Syndrome (ABDS)", "Bosley-Salih-Alorainy Syndrome (BSAS)", "Homeobox protein Hox-A1", "HOXA1", "HOXA1-Related Disorders" ]		Prince Jacob, Venkatraman Bhat, Siddaramappa J Patil	Summary The diagnosis of a	Bosley-Salih-Alorainy syndrome (BSAS) Athabascan brain stem dysgenesis syndrome (ABDS) For synonyms and outdated names, see • Bosley-Salih-Alorainy syndrome (BSAS) • Athabascan brain stem dysgenesis syndrome (ABDS) ## Diagnosis Ocular motility disorder: horizontal gaze palsy with or without Duane syndrome (also referred to as Duane retraction syndrome) Bilateral sensorineural deafness Developmental delay Intellectual disability Central hypoventilation while awake or asleep requiring supplemental oxygen and/or mechanical ventilatory support Congenital heart malformations, cerebrovascular malformations Facial paresis, vocal cord paresis, and swallowing dysfunction leading to recurrent aspiration and pneumonia Seizure disorder Neurobehavioral/psychiatric manifestations Cerebrovascular malformations often involving the carotid arteries Abnormalities of inner ear structures Variable absence of cranial nerves VI-XII, most commonly cranial nerve VI (abducens nerve) Small petrous bones, likely due to absent carotid canal and inner ear structural abnormalities with patulous Meckel caves Generalized cerebral atrophy Normal brain stem Abnormalities of the cerebrovascular system Abnormalities of inner ear structures Variable absence of cranial nerves VI-XII The diagnosis of a Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Note: Targeted analysis for a founder pathogenic variant can be performed first in individuals of Saudi Arabian ancestry (c.175dupG [p.Val59GlyfsTer119]) and individuals of Navajo and/or Apache ancestry (c.76C>T [p.Arg26Ter]) (see For an introduction to multigene panels click When the diagnosis of a For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. To date, no large intragenic deletions/duplications have been reported in individuals with • Ocular motility disorder: horizontal gaze palsy with or without Duane syndrome (also referred to as Duane retraction syndrome) • Bilateral sensorineural deafness • Developmental delay • Intellectual disability • Central hypoventilation while awake or asleep requiring supplemental oxygen and/or mechanical ventilatory support • Congenital heart malformations, cerebrovascular malformations • Facial paresis, vocal cord paresis, and swallowing dysfunction leading to recurrent aspiration and pneumonia • Seizure disorder • Neurobehavioral/psychiatric manifestations • Cerebrovascular malformations often involving the carotid arteries • Abnormalities of inner ear structures • Variable absence of cranial nerves VI-XII, most commonly cranial nerve VI (abducens nerve) • Small petrous bones, likely due to absent carotid canal and inner ear structural abnormalities with patulous Meckel caves • Cerebrovascular malformations often involving the carotid arteries • Abnormalities of inner ear structures • Variable absence of cranial nerves VI-XII, most commonly cranial nerve VI (abducens nerve) • Small petrous bones, likely due to absent carotid canal and inner ear structural abnormalities with patulous Meckel caves • • Generalized cerebral atrophy • Normal brain stem • Abnormalities of the cerebrovascular system • Abnormalities of inner ear structures • Variable absence of cranial nerves VI-XII • Generalized cerebral atrophy • Normal brain stem • Abnormalities of the cerebrovascular system • Abnormalities of inner ear structures • Variable absence of cranial nerves VI-XII • Cerebrovascular malformations often involving the carotid arteries • Abnormalities of inner ear structures • Variable absence of cranial nerves VI-XII, most commonly cranial nerve VI (abducens nerve) • Small petrous bones, likely due to absent carotid canal and inner ear structural abnormalities with patulous Meckel caves • Generalized cerebral atrophy • Normal brain stem • Abnormalities of the cerebrovascular system • Abnormalities of inner ear structures • Variable absence of cranial nerves VI-XII ## Suggestive Findings Ocular motility disorder: horizontal gaze palsy with or without Duane syndrome (also referred to as Duane retraction syndrome) Bilateral sensorineural deafness Developmental delay Intellectual disability Central hypoventilation while awake or asleep requiring supplemental oxygen and/or mechanical ventilatory support Congenital heart malformations, cerebrovascular malformations Facial paresis, vocal cord paresis, and swallowing dysfunction leading to recurrent aspiration and pneumonia Seizure disorder Neurobehavioral/psychiatric manifestations Cerebrovascular malformations often involving the carotid arteries Abnormalities of inner ear structures Variable absence of cranial nerves VI-XII, most commonly cranial nerve VI (abducens nerve) Small petrous bones, likely due to absent carotid canal and inner ear structural abnormalities with patulous Meckel caves Generalized cerebral atrophy Normal brain stem Abnormalities of the cerebrovascular system Abnormalities of inner ear structures Variable absence of cranial nerves VI-XII • Ocular motility disorder: horizontal gaze palsy with or without Duane syndrome (also referred to as Duane retraction syndrome) • Bilateral sensorineural deafness • Developmental delay • Intellectual disability • Central hypoventilation while awake or asleep requiring supplemental oxygen and/or mechanical ventilatory support • Congenital heart malformations, cerebrovascular malformations • Facial paresis, vocal cord paresis, and swallowing dysfunction leading to recurrent aspiration and pneumonia • Seizure disorder • Neurobehavioral/psychiatric manifestations • Cerebrovascular malformations often involving the carotid arteries • Abnormalities of inner ear structures • Variable absence of cranial nerves VI-XII, most commonly cranial nerve VI (abducens nerve) • Small petrous bones, likely due to absent carotid canal and inner ear structural abnormalities with patulous Meckel caves • Cerebrovascular malformations often involving the carotid arteries • Abnormalities of inner ear structures • Variable absence of cranial nerves VI-XII, most commonly cranial nerve VI (abducens nerve) • Small petrous bones, likely due to absent carotid canal and inner ear structural abnormalities with patulous Meckel caves • • Generalized cerebral atrophy • Normal brain stem • Abnormalities of the cerebrovascular system • Abnormalities of inner ear structures • Variable absence of cranial nerves VI-XII • Generalized cerebral atrophy • Normal brain stem • Abnormalities of the cerebrovascular system • Abnormalities of inner ear structures • Variable absence of cranial nerves VI-XII • Cerebrovascular malformations often involving the carotid arteries • Abnormalities of inner ear structures • Variable absence of cranial nerves VI-XII, most commonly cranial nerve VI (abducens nerve) • Small petrous bones, likely due to absent carotid canal and inner ear structural abnormalities with patulous Meckel caves • Generalized cerebral atrophy • Normal brain stem • Abnormalities of the cerebrovascular system • Abnormalities of inner ear structures • Variable absence of cranial nerves VI-XII ## Establishing the Diagnosis The diagnosis of a Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Note: Targeted analysis for a founder pathogenic variant can be performed first in individuals of Saudi Arabian ancestry (c.175dupG [p.Val59GlyfsTer119]) and individuals of Navajo and/or Apache ancestry (c.76C>T [p.Arg26Ter]) (see For an introduction to multigene panels click When the diagnosis of a For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. To date, no large intragenic deletions/duplications have been reported in individuals with ## Option 1 Note: Targeted analysis for a founder pathogenic variant can be performed first in individuals of Saudi Arabian ancestry (c.175dupG [p.Val59GlyfsTer119]) and individuals of Navajo and/or Apache ancestry (c.76C>T [p.Arg26Ter]) (see For an introduction to multigene panels click ## Option 2 When the diagnosis of a For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. To date, no large intragenic deletions/duplications have been reported in individuals with ## Clinical Characteristics Based on ABDS = Athabascan brain stem dysgenesis syndrome; BSAS = Bosley-Salih-Alorainy syndrome; NA = not applicable Denominator indicates number of appropriately evaluated individuals. Individuals with BSAS are reported to have variable developmental abilities and cognitive function ranging from isolated motor delay, learning difficulties, or behavioral issues to global developmental delay and autism spectrum disorder. Often neurologic assessment is confounded by the presence of profound sensorineural deafness and speech issues. Normal neurologic function has been reported in seven of 20 individuals with BSAS [ None of the individuals with BSAS have central hypoventilation. Some individuals with BSAS also have congenital heart disease including double outlet left ventricle, tetralogy of Fallot, and ventricular septal defect. One individual with BSAS was reported to have apparently isolated congenital heart disease without ocular motility disorder or hearing impairment [ External ear minor malformations (e.g., flattened ear helix, low-set ears) in four individuals with BSAS Clubfoot in three individuals Chronic constipation in two individuals with BSAS Frequent grimacing in two individuals with BSAS Facial asymmetry in one individual with BSAS and one individual with ABDS Multiple lentigines, hypertrichosis, polydactyly, brachydactyly, and duplex ureteral system with urethral stricture (1 individual each) No genotype-phenotype correlations have been identified. Central hypoventilation has only been reported in individuals with ABDS, and high altitude is a suspected contributing factor [ ABDS was previously referred to as "Navajo brain stem syndrome." To date, 34 individuals have been reported with biallelic variants in ABDS is prevalent in individuals of Navajo and Apache descent due to the BSAS has been reported in individuals from Middle Eastern populations including Saudi Arabia and Turkey due to the • External ear minor malformations (e.g., flattened ear helix, low-set ears) in four individuals with BSAS • Clubfoot in three individuals • Chronic constipation in two individuals with BSAS • Frequent grimacing in two individuals with BSAS • Facial asymmetry in one individual with BSAS and one individual with ABDS • Multiple lentigines, hypertrichosis, polydactyly, brachydactyly, and duplex ureteral system with urethral stricture (1 individual each) ## Clinical Description Based on ABDS = Athabascan brain stem dysgenesis syndrome; BSAS = Bosley-Salih-Alorainy syndrome; NA = not applicable Denominator indicates number of appropriately evaluated individuals. Individuals with BSAS are reported to have variable developmental abilities and cognitive function ranging from isolated motor delay, learning difficulties, or behavioral issues to global developmental delay and autism spectrum disorder. Often neurologic assessment is confounded by the presence of profound sensorineural deafness and speech issues. Normal neurologic function has been reported in seven of 20 individuals with BSAS [ None of the individuals with BSAS have central hypoventilation. Some individuals with BSAS also have congenital heart disease including double outlet left ventricle, tetralogy of Fallot, and ventricular septal defect. One individual with BSAS was reported to have apparently isolated congenital heart disease without ocular motility disorder or hearing impairment [ External ear minor malformations (e.g., flattened ear helix, low-set ears) in four individuals with BSAS Clubfoot in three individuals Chronic constipation in two individuals with BSAS Frequent grimacing in two individuals with BSAS Facial asymmetry in one individual with BSAS and one individual with ABDS Multiple lentigines, hypertrichosis, polydactyly, brachydactyly, and duplex ureteral system with urethral stricture (1 individual each) • External ear minor malformations (e.g., flattened ear helix, low-set ears) in four individuals with BSAS • Clubfoot in three individuals • Chronic constipation in two individuals with BSAS • Frequent grimacing in two individuals with BSAS • Facial asymmetry in one individual with BSAS and one individual with ABDS • Multiple lentigines, hypertrichosis, polydactyly, brachydactyly, and duplex ureteral system with urethral stricture (1 individual each) ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been identified. Central hypoventilation has only been reported in individuals with ABDS, and high altitude is a suspected contributing factor [ ## Nomenclature ABDS was previously referred to as "Navajo brain stem syndrome." ## Prevalence To date, 34 individuals have been reported with biallelic variants in ABDS is prevalent in individuals of Navajo and Apache descent due to the BSAS has been reported in individuals from Middle Eastern populations including Saudi Arabia and Turkey due to the ## 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; AR = autosomal recessive; CFEOM = congenital fibrosis of the extraocular muscles; MOI = mode of inheritance Congenital central hypoventilation syndrome (CCHS) is typically inherited in an autosomal dominant manner (CCHS caused by biallelic reduced-penetrance Both genetic and environmental etiologies have been proposed. Additionally, prenatal exposure to misoprostol and other agents has been known to cause a Moebius syndrome phenotype. Heterozygous ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with a Complete neuro-ophthalmologic & orthoptic exams Binocular vision tests Neurologic exam Brain MRI To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Awake pulse oximetry Sleep study Arterial blood gases EKG Echocardiogram Bronchoscopy Swallow study Community or Social work involvement for parental support Home nursing referral ASD = autism spectrum disorder; MOI = mode of inheritance; TOF = time-of-flight Medical geneticist, certified genetic counselor, certified advanced genetic nurse There is no cure for Orthoptic exercises Botulinum toxin injection Surgery in those w/severe manifestations Treatment approach depends on severity & impact on visual function. Surgical intervention may be considered if non-surgical options are insufficient. Hearing aids Cochlear implants Speech therapy Consider educational support & accommodations. Mgmt per cardiovascular specialist Treatment may incl medications (e.g., antiplatelets, anticoagulants) or surgical intervention (e.g., angioplasty, stenting, surgical revascularization). Mechanical ventilation (e.g., positive pressure ventilation) w/aminophylline Continuous monitoring of respiratory function Medications (e.g., diuretics, beta-blockers) Surgical intervention (e.g., repair of structural defects) Cardiac rehab Medications (e.g., anticonvulsants, muscle relaxants) Botulinum toxin injection Physical therapy Tracheostomy Gastrostomy tube feeding Pharmacologic therapies for gastroesophageal reflux Often these issues complicate central hypoventilation in children w/ABDS. Usually these manifestations improve w/age (after infancy), allowing removal of gastrostomy tube & closure of tracheostomy. 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 ABDS = Athabascan brain stem dysgenesis syndrome The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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 Assessment of visual acuity & ocular alignment Orthoptic eval (if applicable) Fundoscopic exam Audiologic assessment Assessment of hearing function & speech development Monitor for signs of hearing loss or auditory processing deficits. Developmental assessment incl assessment of motor development & musculoskeletal function Physical therapy eval Assess for need for early intervention services. Assess for need for educational support & accommodations. Monitor for signs of intellectual disability. Assess for signs of central hypoventilation. Monitor for respiratory manifestations or complications. Neurologic exam for facial twitching or facial paresis Assess for development of seizures. It seems prudent to avoid high altitude, especially among individuals with ABDS, based on a few case studies [ Avoid risk factors leading to stroke (lifestyle and drugs). It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of surveillance and treatment. See Search • Complete neuro-ophthalmologic & orthoptic exams • Binocular vision tests • Neurologic exam • Brain MRI • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Awake pulse oximetry • Sleep study • Arterial blood gases • EKG • Echocardiogram • Bronchoscopy • Swallow study • Community or • Social work involvement for parental support • Home nursing referral • Orthoptic exercises • Botulinum toxin injection • Surgery in those w/severe manifestations • Treatment approach depends on severity & impact on visual function. • Surgical intervention may be considered if non-surgical options are insufficient. • Hearing aids • Cochlear implants • Speech therapy • Consider educational support & accommodations. • Mgmt per cardiovascular specialist • Treatment may incl medications (e.g., antiplatelets, anticoagulants) or surgical intervention (e.g., angioplasty, stenting, surgical revascularization). • Mechanical ventilation (e.g., positive pressure ventilation) w/aminophylline • Continuous monitoring of respiratory function • Medications (e.g., diuretics, beta-blockers) • Surgical intervention (e.g., repair of structural defects) • Cardiac rehab • Medications (e.g., anticonvulsants, muscle relaxants) • Botulinum toxin injection • Physical therapy • Tracheostomy • Gastrostomy tube feeding • Pharmacologic therapies for gastroesophageal reflux • Often these issues complicate central hypoventilation in children w/ABDS. • Usually these manifestations improve w/age (after infancy), allowing removal of gastrostomy tube & closure of tracheostomy. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox • Assessment of visual acuity & ocular alignment • Orthoptic eval (if applicable) • Fundoscopic exam • Audiologic assessment • Assessment of hearing function & speech development • Monitor for signs of hearing loss or auditory processing deficits. • Developmental assessment incl assessment of motor development & musculoskeletal function • Physical therapy eval • Assess for need for early intervention services. • Assess for need for educational support & accommodations. • Monitor for signs of intellectual disability. • Assess for signs of central hypoventilation. • Monitor for respiratory manifestations or complications. • Neurologic exam for facial twitching or facial paresis • Assess for development of seizures. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with a Complete neuro-ophthalmologic & orthoptic exams Binocular vision tests Neurologic exam Brain MRI To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Awake pulse oximetry Sleep study Arterial blood gases EKG Echocardiogram Bronchoscopy Swallow study Community or Social work involvement for parental support Home nursing referral ASD = autism spectrum disorder; MOI = mode of inheritance; TOF = time-of-flight Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Complete neuro-ophthalmologic & orthoptic exams • Binocular vision tests • Neurologic exam • Brain MRI • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Awake pulse oximetry • Sleep study • Arterial blood gases • EKG • Echocardiogram • Bronchoscopy • Swallow study • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations There is no cure for Orthoptic exercises Botulinum toxin injection Surgery in those w/severe manifestations Treatment approach depends on severity & impact on visual function. Surgical intervention may be considered if non-surgical options are insufficient. Hearing aids Cochlear implants Speech therapy Consider educational support & accommodations. Mgmt per cardiovascular specialist Treatment may incl medications (e.g., antiplatelets, anticoagulants) or surgical intervention (e.g., angioplasty, stenting, surgical revascularization). Mechanical ventilation (e.g., positive pressure ventilation) w/aminophylline Continuous monitoring of respiratory function Medications (e.g., diuretics, beta-blockers) Surgical intervention (e.g., repair of structural defects) Cardiac rehab Medications (e.g., anticonvulsants, muscle relaxants) Botulinum toxin injection Physical therapy Tracheostomy Gastrostomy tube feeding Pharmacologic therapies for gastroesophageal reflux Often these issues complicate central hypoventilation in children w/ABDS. Usually these manifestations improve w/age (after infancy), allowing removal of gastrostomy tube & closure of tracheostomy. 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 ABDS = Athabascan brain stem dysgenesis syndrome The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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. • Orthoptic exercises • Botulinum toxin injection • Surgery in those w/severe manifestations • Treatment approach depends on severity & impact on visual function. • Surgical intervention may be considered if non-surgical options are insufficient. • Hearing aids • Cochlear implants • Speech therapy • Consider educational support & accommodations. • Mgmt per cardiovascular specialist • Treatment may incl medications (e.g., antiplatelets, anticoagulants) or surgical intervention (e.g., angioplasty, stenting, surgical revascularization). • Mechanical ventilation (e.g., positive pressure ventilation) w/aminophylline • Continuous monitoring of respiratory function • Medications (e.g., diuretics, beta-blockers) • Surgical intervention (e.g., repair of structural defects) • Cardiac rehab • Medications (e.g., anticonvulsants, muscle relaxants) • Botulinum toxin injection • Physical therapy • Tracheostomy • Gastrostomy tube feeding • Pharmacologic therapies for gastroesophageal reflux • Often these issues complicate central hypoventilation in children w/ABDS. • Usually these manifestations improve w/age (after infancy), allowing removal of gastrostomy tube & closure of tracheostomy. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Motor Dysfunction Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## Neurobehavioral/Psychiatric Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Assessment of visual acuity & ocular alignment Orthoptic eval (if applicable) Fundoscopic exam Audiologic assessment Assessment of hearing function & speech development Monitor for signs of hearing loss or auditory processing deficits. Developmental assessment incl assessment of motor development & musculoskeletal function Physical therapy eval Assess for need for early intervention services. Assess for need for educational support & accommodations. Monitor for signs of intellectual disability. Assess for signs of central hypoventilation. Monitor for respiratory manifestations or complications. Neurologic exam for facial twitching or facial paresis Assess for development of seizures. • Assessment of visual acuity & ocular alignment • Orthoptic eval (if applicable) • Fundoscopic exam • Audiologic assessment • Assessment of hearing function & speech development • Monitor for signs of hearing loss or auditory processing deficits. • Developmental assessment incl assessment of motor development & musculoskeletal function • Physical therapy eval • Assess for need for early intervention services. • Assess for need for educational support & accommodations. • Monitor for signs of intellectual disability. • Assess for signs of central hypoventilation. • Monitor for respiratory manifestations or complications. • Neurologic exam for facial twitching or facial paresis • Assess for development of seizures. ## Agents/Circumstances to Avoid It seems prudent to avoid high altitude, especially among individuals with ABDS, based on a few case studies [ Avoid risk factors leading to stroke (lifestyle and drugs). ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of surveillance and treatment. See ## Therapies Under Investigation Search ## Genetic Counseling The parents of an affected individual are presumed to be heterozygous for a Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Carrier testing for at-risk relatives requires prior identification of the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Carrier testing should be considered for the reproductive partners of individuals affected with a Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected individual are presumed to be heterozygous for a • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • Carrier testing should be considered for the reproductive partners of individuals affected with a ## Mode of Inheritance ## Risk to Family Members The parents of an affected individual are presumed to be heterozygous for a Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The parents of an affected individual are presumed to be heterozygous for a • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Carrier testing should be considered for the reproductive partners of individuals affected with a • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • Carrier testing should be considered for the reproductive partners of individuals affected with a ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • ## Molecular Genetics HOXA1-Related Disorders: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for HOXA1-Related Disorders ( Homeobox (HOX) genes occur in four clusters (A-D), located on different chromosomes. In each cluster, 3' HOX genes are expressed earlier and more anteriorly than 5' HOX genes [ To date, the reported biallelic pathogenic variants in Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis Homeobox (HOX) genes occur in four clusters (A-D), located on different chromosomes. In each cluster, 3' HOX genes are expressed earlier and more anteriorly than 5' HOX genes [ To date, the reported biallelic pathogenic variants in Variants listed in the table have been provided by the authors. ## Chapter Notes Dr Siddaramappa J Patil ( Dr Patil and Dr Jacob are actively involved in clinical research regarding individuals with Dr Patil is also interested in hearing from clinicians treating families affected by inherited cardiovascular malformations 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 Patil and Dr Jacob to inquire about review of We are thankful to Narayana Hrudayalaya Hospital / Mazumdar Shaw Medical Center and JSS Academy of Higher Research (JSSAHER) for providing the support and resources for conducting the study. 14 November 2024 (sw) Review posted live 22 April 2024 (sp) Original submission • 14 November 2024 (sw) Review posted live • 22 April 2024 (sp) Original submission ## Author Notes Dr Siddaramappa J Patil ( Dr Patil and Dr Jacob are actively involved in clinical research regarding individuals with Dr Patil is also interested in hearing from clinicians treating families affected by inherited cardiovascular malformations 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 Patil and Dr Jacob to inquire about review of ## Acknowledgments We are thankful to Narayana Hrudayalaya Hospital / Mazumdar Shaw Medical Center and JSS Academy of Higher Research (JSSAHER) for providing the support and resources for conducting the study. ## Revision History 14 November 2024 (sw) Review posted live 22 April 2024 (sp) Original submission • 14 November 2024 (sw) Review posted live • 22 April 2024 (sp) Original submission ## References ## Literature Cited Reproduced with permission from	[]	14/11/2024			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
hpe-overview	hpe-overview	[ "CCR4-NOT transcription complex subunit 1", "Cell adhesion molecule-related/down-regulated by oncogenes", "Cohesin subunit SA-2", "Delta-like protein 1", "Double-strand-break repair protein rad21 homolog", "Fibroblast growth factor 8", "Fibroblast growth factor receptor 1", "Histone-lysine N-methyltransferase 2D", "Homeobox protein SIX3", "Homeobox protein TGIF1", "Protein dispatched homolog 1", "Protein phosphatase 1 regulatory subunit 12A", "SCL-interrupting locus protein", "Sonic hedgehog protein", "Structural maintenance of chromosomes protein 1A", "Structural maintenance of chromosomes protein 3", "Zinc finger protein GLI2", "Zinc finger protein ZIC 2", "CDON", "CNOT1", "DISP1", "DLL1", "FGF8", "FGFR1", "GLI2", "KMT2D", "PPP1R12A", "RAD21", "SHH", "SIX3", "SMC1A", "SMC3", "STAG2", "STIL", "TGIF1", "ZIC2", "Holoprosencephaly", "Overview" ]	Holoprosencephaly Overview	Cedrik Tekendo-Ngongang, Maximilian Muenke, Paul Kruszka	Summary The purpose of this overview is to: Describe the Review the Provide an Inform	## Clinical Characteristics of Holoprosencephaly Holoprosencephaly (HPE), the most common malformation of the forebrain in humans, is a structural anomaly of the brain resulting from failed or incomplete forebrain division in the third to fourth weeks of gestation; the forebrain (prosencephalon) incompletely cleaves into right and left hemispheres, deep brain structures, and the olfactory and optic bulbs and tracts [ While HPE is often first identified on prenatal ultrasound examination [ Imaging of the brain by CT scan or MRI defines the type of HPE and identifies associated CNS anomalies [ HPE, a continuum of brain malformations, is traditionally divided into the following types (in decreasing order of severity) (reviewed in Cyclopia: single eye or partially divided eye in single orbit with a proboscis above the eye Cyclopia without proboscis Ethmocephaly: extremely closely spaced eyes but separate orbits with proboscis between the eyes Cebocephaly: closely spaced eyes with single-nostril nose Closely spaced eyes Anophthalmia or microophthalmia Premaxillary agenesis with median cleft lip, closely spaced eyes, depressed nasal ridge Bilateral cleft lip Relatively normal facial appearance (especially in persons with pathogenic variants in Closely spaced eyes Anophthalmia/microophthalmia Depressed nasal ridge Absent nasal septum Flat nasal tip Bilateral cleft lip with median process representing the philtrum-premaxilla anlage Midline cleft (lip and/or palate) Relatively normal facial appearance Bilateral cleft lip with median process Closely spaced eyes Depressed nasal ridge Relatively normal facial appearance The range of findings includes: Closely spaced eyes Depressed nasal bridge Narrow nasal bridge Relatively normal facial appearance Microcephaly [ Single central maxillary incisor [ Closely spaced eyes Anosmia/hyposmia (resulting from absence of olfactory tracts and bulbs) A broad range of ophthalmologic anomalies, including refractive errors, ptosis, microcornea, and coloboma [ Sharp, narrow nasal bridge [ Absent superior labial frenulum Midface retrusion Congenital nasal pyriform aperture stenosis [ Developmental delay (variably present). Of note, individuals with classic HPE-spectrum facial features and pathogenic variants seen in severely affected relatives may be intellectually gifted [ Other structural CNS findings that may occur with but are not specific to HPE: Anomalies of midline structures: undivided thalami, agenesis of the corpus callosum (OMIM Macrocephaly secondary to hydrocephalus Dandy-Walker malformation Neuronal migration anomalies Abnormal circle of Willis Caudal dysgenesis The continuum of craniofacial anomalies, present in approximately 80% of individuals with HPE, includes cyclopia, synophthalmia, or a proboscis at the severe end and normal facies in individuals who have, but are not expressing, an HPE pathogenic variant inherited in an autosomal dominant manner. Common subtle facial features in individuals without obvious craniofacial findings include microcephaly (although hydrocephalus can result in macrocephaly), closely spaced eyes (also known as hypotelorism; potentially severe), depressed nasal ridge, and cleft lip and/or palate. A single maxillary central incisor may be present; although a nonspecific finding, it is a distinctive microform in autosomal dominant HPE [ Of note, subtle facial anomalies in mildly affected family members can be easily overlooked [ Malformations of the nose include complete absence, agenesis of the nasal cartridge, and proboscis (flat nose with a single central nostril without nasal bones). Palatal anomalies include various midline and lateral clefts, midline palatal ridge, bifid uvula, high-arched palate, and absence of the superior labial frenulum [ The extremely variable phenotypic expression occurs both in simplex HPE (i.e., a single occurrence in a family) and among members of the same family with an inherited form of HPE. Clinical manifestations (reviewed in The longer survival may be on account of recent advances in diagnostic methods, including brain imaging methods that allow for early detection of both severe and mild malformations. Improvement in the management of HPE over time may have also contributed to longer survival [ The distribution of HPE subtypes appears to be similar among children, adolescents, and adults, with semilobar HPE representing approximately 50% of HPE in both children and adults. The exception is alobar HPE, which appears to be less frequent in adults than children [ Among affected individuals with abnormal chromosome complement, an inverse relationship exists between the severity of the facial phenotype and length of survival. Infants with cyclopia or ethmocephaly generally do not survive beyond age one week. Approximately 85% of adults with HPE have a mild or nonclassic facial phenotype [ Among affected adolescents and adults, sensorineural hearing loss is found in approximately 30% and cortical vision impairment in approximately 20% [ Of note, 60% of adolescent and adult survivors have severe involvement: they are nonambulatory and nonverbal with minimal hand function, and full dependence on caregivers [ • Cyclopia: single eye or partially divided eye in single orbit with a proboscis above the eye • Cyclopia without proboscis • Ethmocephaly: extremely closely spaced eyes but separate orbits with proboscis between the eyes • Cebocephaly: closely spaced eyes with single-nostril nose • Closely spaced eyes • Anophthalmia or microophthalmia • Premaxillary agenesis with median cleft lip, closely spaced eyes, depressed nasal ridge • Bilateral cleft lip • Relatively normal facial appearance (especially in persons with pathogenic variants in • Closely spaced eyes • Anophthalmia/microophthalmia • Depressed nasal ridge • Absent nasal septum • Flat nasal tip • Bilateral cleft lip with median process representing the philtrum-premaxilla anlage • Midline cleft (lip and/or palate) • Relatively normal facial appearance • Bilateral cleft lip with median process • Closely spaced eyes • Depressed nasal ridge • Relatively normal facial appearance • Closely spaced eyes • Depressed nasal bridge • Narrow nasal bridge • Relatively normal facial appearance • Microcephaly [ • Single central maxillary incisor [ • Closely spaced eyes • Anosmia/hyposmia (resulting from absence of olfactory tracts and bulbs) • A broad range of ophthalmologic anomalies, including refractive errors, ptosis, microcornea, and coloboma [ • Sharp, narrow nasal bridge [ • Absent superior labial frenulum • Midface retrusion • Congenital nasal pyriform aperture stenosis [ • Developmental delay (variably present). Of note, individuals with classic HPE-spectrum facial features and pathogenic variants seen in severely affected relatives may be intellectually gifted [ • Anomalies of midline structures: undivided thalami, agenesis of the corpus callosum (OMIM • Macrocephaly secondary to hydrocephalus • Dandy-Walker malformation • Neuronal migration anomalies • Abnormal circle of Willis • Caudal dysgenesis • Infants with cyclopia or ethmocephaly generally do not survive beyond age one week. • Approximately 85% of adults with HPE have a mild or nonclassic facial phenotype [ ## Types of HPE HPE, a continuum of brain malformations, is traditionally divided into the following types (in decreasing order of severity) (reviewed in Cyclopia: single eye or partially divided eye in single orbit with a proboscis above the eye Cyclopia without proboscis Ethmocephaly: extremely closely spaced eyes but separate orbits with proboscis between the eyes Cebocephaly: closely spaced eyes with single-nostril nose Closely spaced eyes Anophthalmia or microophthalmia Premaxillary agenesis with median cleft lip, closely spaced eyes, depressed nasal ridge Bilateral cleft lip Relatively normal facial appearance (especially in persons with pathogenic variants in Closely spaced eyes Anophthalmia/microophthalmia Depressed nasal ridge Absent nasal septum Flat nasal tip Bilateral cleft lip with median process representing the philtrum-premaxilla anlage Midline cleft (lip and/or palate) Relatively normal facial appearance Bilateral cleft lip with median process Closely spaced eyes Depressed nasal ridge Relatively normal facial appearance The range of findings includes: Closely spaced eyes Depressed nasal bridge Narrow nasal bridge Relatively normal facial appearance Microcephaly [ Single central maxillary incisor [ Closely spaced eyes Anosmia/hyposmia (resulting from absence of olfactory tracts and bulbs) A broad range of ophthalmologic anomalies, including refractive errors, ptosis, microcornea, and coloboma [ Sharp, narrow nasal bridge [ Absent superior labial frenulum Midface retrusion Congenital nasal pyriform aperture stenosis [ Developmental delay (variably present). Of note, individuals with classic HPE-spectrum facial features and pathogenic variants seen in severely affected relatives may be intellectually gifted [ Other structural CNS findings that may occur with but are not specific to HPE: Anomalies of midline structures: undivided thalami, agenesis of the corpus callosum (OMIM Macrocephaly secondary to hydrocephalus Dandy-Walker malformation Neuronal migration anomalies Abnormal circle of Willis Caudal dysgenesis The continuum of craniofacial anomalies, present in approximately 80% of individuals with HPE, includes cyclopia, synophthalmia, or a proboscis at the severe end and normal facies in individuals who have, but are not expressing, an HPE pathogenic variant inherited in an autosomal dominant manner. Common subtle facial features in individuals without obvious craniofacial findings include microcephaly (although hydrocephalus can result in macrocephaly), closely spaced eyes (also known as hypotelorism; potentially severe), depressed nasal ridge, and cleft lip and/or palate. A single maxillary central incisor may be present; although a nonspecific finding, it is a distinctive microform in autosomal dominant HPE [ Of note, subtle facial anomalies in mildly affected family members can be easily overlooked [ Malformations of the nose include complete absence, agenesis of the nasal cartridge, and proboscis (flat nose with a single central nostril without nasal bones). Palatal anomalies include various midline and lateral clefts, midline palatal ridge, bifid uvula, high-arched palate, and absence of the superior labial frenulum [ The extremely variable phenotypic expression occurs both in simplex HPE (i.e., a single occurrence in a family) and among members of the same family with an inherited form of HPE. • Cyclopia: single eye or partially divided eye in single orbit with a proboscis above the eye • Cyclopia without proboscis • Ethmocephaly: extremely closely spaced eyes but separate orbits with proboscis between the eyes • Cebocephaly: closely spaced eyes with single-nostril nose • Closely spaced eyes • Anophthalmia or microophthalmia • Premaxillary agenesis with median cleft lip, closely spaced eyes, depressed nasal ridge • Bilateral cleft lip • Relatively normal facial appearance (especially in persons with pathogenic variants in • Closely spaced eyes • Anophthalmia/microophthalmia • Depressed nasal ridge • Absent nasal septum • Flat nasal tip • Bilateral cleft lip with median process representing the philtrum-premaxilla anlage • Midline cleft (lip and/or palate) • Relatively normal facial appearance • Bilateral cleft lip with median process • Closely spaced eyes • Depressed nasal ridge • Relatively normal facial appearance • Closely spaced eyes • Depressed nasal bridge • Narrow nasal bridge • Relatively normal facial appearance • Microcephaly [ • Single central maxillary incisor [ • Closely spaced eyes • Anosmia/hyposmia (resulting from absence of olfactory tracts and bulbs) • A broad range of ophthalmologic anomalies, including refractive errors, ptosis, microcornea, and coloboma [ • Sharp, narrow nasal bridge [ • Absent superior labial frenulum • Midface retrusion • Congenital nasal pyriform aperture stenosis [ • Developmental delay (variably present). Of note, individuals with classic HPE-spectrum facial features and pathogenic variants seen in severely affected relatives may be intellectually gifted [ • Anomalies of midline structures: undivided thalami, agenesis of the corpus callosum (OMIM • Macrocephaly secondary to hydrocephalus • Dandy-Walker malformation • Neuronal migration anomalies • Abnormal circle of Willis • Caudal dysgenesis ## Other Structural CNS Findings Other structural CNS findings that may occur with but are not specific to HPE: Anomalies of midline structures: undivided thalami, agenesis of the corpus callosum (OMIM Macrocephaly secondary to hydrocephalus Dandy-Walker malformation Neuronal migration anomalies Abnormal circle of Willis Caudal dysgenesis • Anomalies of midline structures: undivided thalami, agenesis of the corpus callosum (OMIM • Macrocephaly secondary to hydrocephalus • Dandy-Walker malformation • Neuronal migration anomalies • Abnormal circle of Willis • Caudal dysgenesis ## Craniofacial Anomalies The continuum of craniofacial anomalies, present in approximately 80% of individuals with HPE, includes cyclopia, synophthalmia, or a proboscis at the severe end and normal facies in individuals who have, but are not expressing, an HPE pathogenic variant inherited in an autosomal dominant manner. Common subtle facial features in individuals without obvious craniofacial findings include microcephaly (although hydrocephalus can result in macrocephaly), closely spaced eyes (also known as hypotelorism; potentially severe), depressed nasal ridge, and cleft lip and/or palate. A single maxillary central incisor may be present; although a nonspecific finding, it is a distinctive microform in autosomal dominant HPE [ Of note, subtle facial anomalies in mildly affected family members can be easily overlooked [ Malformations of the nose include complete absence, agenesis of the nasal cartridge, and proboscis (flat nose with a single central nostril without nasal bones). Palatal anomalies include various midline and lateral clefts, midline palatal ridge, bifid uvula, high-arched palate, and absence of the superior labial frenulum [ The extremely variable phenotypic expression occurs both in simplex HPE (i.e., a single occurrence in a family) and among members of the same family with an inherited form of HPE. ## Clinical Manifestations of HPE Clinical manifestations (reviewed in The longer survival may be on account of recent advances in diagnostic methods, including brain imaging methods that allow for early detection of both severe and mild malformations. Improvement in the management of HPE over time may have also contributed to longer survival [ The distribution of HPE subtypes appears to be similar among children, adolescents, and adults, with semilobar HPE representing approximately 50% of HPE in both children and adults. The exception is alobar HPE, which appears to be less frequent in adults than children [ Among affected individuals with abnormal chromosome complement, an inverse relationship exists between the severity of the facial phenotype and length of survival. Infants with cyclopia or ethmocephaly generally do not survive beyond age one week. Approximately 85% of adults with HPE have a mild or nonclassic facial phenotype [ Among affected adolescents and adults, sensorineural hearing loss is found in approximately 30% and cortical vision impairment in approximately 20% [ Of note, 60% of adolescent and adult survivors have severe involvement: they are nonambulatory and nonverbal with minimal hand function, and full dependence on caregivers [ • Infants with cyclopia or ethmocephaly generally do not survive beyond age one week. • Approximately 85% of adults with HPE have a mild or nonclassic facial phenotype [ ## Genetic Causes of Holoprosencephaly Approximately 25%-50% of individuals with HPE have a chromosome abnormality. Chromosome abnormalities are nonspecific and either numeric or structural, and can involve any chromosome [ Individuals with HPE and a normal chromosome complement cannot be distinguished from those with an abnormal chromosome complement based on craniofacial abnormality or HPE subtype; however, individuals with HPE caused by a chromosome abnormality are more likely to have other organ system involvement, resulting in a more severe clinical course in most. The other common aneuploidies associated with HPE include trisomy 18 and triploidy. Various other aneuploidies have been reported [ Approximately 18%-25% of individuals with HPE have a pathogenic variant in a single gene causing syndromic HPE. At least 25 different conditions in which HPE is an occasional finding have been described; the majority of these disorders are rare. Some of the more common are summarized in Syndromes with Holoprosencephaly as an Occasional Finding: Monogenic Causes AD = autosomal dominant; AR = autosomal recessive; CHD = congenital heart disease; HPE = holoprosencephaly; MOI = mode of inheritance The nonsyndromic forms of HPE best understood at a molecular genetic level are inherited in an autosomal dominant manner (see The phenotype of individuals with pathogenic variants in genes associated with nonsyndromic HPE is extremely variable even within the same family, ranging from alobar HPE with cyclopia to clinically normal [ In the majority of individuals with HPE, a correlation exists between the facial anomalies and the gene involved and/or type of pathogenic variant (see Nonsyndromic Holoprosencephaly: Most Common Monogenic Causes Affected persons may be part of large kindreds segregating the variant; many of these families are not identified until ascertainment of the severely affected proband. Renal/urinary anomalies may be more common than in those w/pathogenic variants in other HPE genes. Renal/urinary anomalies may be more common than in those w/pathogenic variants in other HPE genes. Pathogenic variants are more frequently Affected persons may be part of large kindreds segregating the variant; many of these families are not identified until ascertainment of the severely affected proband. May be assoc w/more severe types of HPE AD = autosomal dominant; AR = autosomal recessive; CHD = congenital heart disease; DD = developmental delay; HPE = holoprosencephaly; LOF = loss of function; MOI = mode of inheritance Genes are listed in order of most commonly involved. Nonsyndromic Holoprosencephaly: Less Common Monogenic Causes Semilobar HPE described in 2 unrelated persons Neonatal diabetes mellitus requiring insulin may be a feature. Pancreatic exocrine insufficiency may be present. May be assoc w/sensorineural & conductive hearing loss w/ossicle anomalies Range of HPE-spectrum features described in 5 unrelated persons. May be assoc w/mild forms of HPE May present w/a range of classic HPE-spectrum features AR inheritance in all reported persons AR = autosomal recessive; DD = developmental delay; HPE = holoprosencephaly Genes are listed in alphabetic order. Variants in other candidate genes including Although Caudal dysgenesis (OMIM Pseudotrisomy 13 (OMIM Genoa syndrome (OMIM Brachial amelia, cleft lip, and holoprosencephaly (OMIM • Affected persons may be part of large kindreds segregating the variant; many of these families are not identified until ascertainment of the severely affected proband. • Renal/urinary anomalies may be more common than in those w/pathogenic variants in other HPE genes. • Renal/urinary anomalies may be more common than in those w/pathogenic variants in other HPE genes. • Pathogenic variants are more frequently • Affected persons may be part of large kindreds segregating the variant; many of these families are not identified until ascertainment of the severely affected proband. • May be assoc w/more severe types of HPE • Semilobar HPE described in 2 unrelated persons • Neonatal diabetes mellitus requiring insulin may be a feature. • Pancreatic exocrine insufficiency may be present. • May be assoc w/sensorineural & conductive hearing loss w/ossicle anomalies • Range of HPE-spectrum features described in 5 unrelated persons. • May be assoc w/mild forms of HPE • May present w/a range of classic HPE-spectrum features • AR inheritance in all reported persons • Caudal dysgenesis (OMIM • Pseudotrisomy 13 (OMIM • Genoa syndrome (OMIM • Brachial amelia, cleft lip, and holoprosencephaly (OMIM ## Chromosome Abnormalities with Holoprosencephaly Approximately 25%-50% of individuals with HPE have a chromosome abnormality. Chromosome abnormalities are nonspecific and either numeric or structural, and can involve any chromosome [ Individuals with HPE and a normal chromosome complement cannot be distinguished from those with an abnormal chromosome complement based on craniofacial abnormality or HPE subtype; however, individuals with HPE caused by a chromosome abnormality are more likely to have other organ system involvement, resulting in a more severe clinical course in most. The other common aneuploidies associated with HPE include trisomy 18 and triploidy. Various other aneuploidies have been reported [ ## Monogenic Syndromes with Holoprosencephaly as an Occasional Finding Approximately 18%-25% of individuals with HPE have a pathogenic variant in a single gene causing syndromic HPE. At least 25 different conditions in which HPE is an occasional finding have been described; the majority of these disorders are rare. Some of the more common are summarized in Syndromes with Holoprosencephaly as an Occasional Finding: Monogenic Causes AD = autosomal dominant; AR = autosomal recessive; CHD = congenital heart disease; HPE = holoprosencephaly; MOI = mode of inheritance ## Single-Gene Disorders with Isolated (Nonsyndromic) Holoprosencephaly The nonsyndromic forms of HPE best understood at a molecular genetic level are inherited in an autosomal dominant manner (see The phenotype of individuals with pathogenic variants in genes associated with nonsyndromic HPE is extremely variable even within the same family, ranging from alobar HPE with cyclopia to clinically normal [ In the majority of individuals with HPE, a correlation exists between the facial anomalies and the gene involved and/or type of pathogenic variant (see Nonsyndromic Holoprosencephaly: Most Common Monogenic Causes Affected persons may be part of large kindreds segregating the variant; many of these families are not identified until ascertainment of the severely affected proband. Renal/urinary anomalies may be more common than in those w/pathogenic variants in other HPE genes. Renal/urinary anomalies may be more common than in those w/pathogenic variants in other HPE genes. Pathogenic variants are more frequently Affected persons may be part of large kindreds segregating the variant; many of these families are not identified until ascertainment of the severely affected proband. May be assoc w/more severe types of HPE AD = autosomal dominant; AR = autosomal recessive; CHD = congenital heart disease; DD = developmental delay; HPE = holoprosencephaly; LOF = loss of function; MOI = mode of inheritance Genes are listed in order of most commonly involved. Nonsyndromic Holoprosencephaly: Less Common Monogenic Causes Semilobar HPE described in 2 unrelated persons Neonatal diabetes mellitus requiring insulin may be a feature. Pancreatic exocrine insufficiency may be present. May be assoc w/sensorineural & conductive hearing loss w/ossicle anomalies Range of HPE-spectrum features described in 5 unrelated persons. May be assoc w/mild forms of HPE May present w/a range of classic HPE-spectrum features AR inheritance in all reported persons AR = autosomal recessive; DD = developmental delay; HPE = holoprosencephaly Genes are listed in alphabetic order. Variants in other candidate genes including Although • Affected persons may be part of large kindreds segregating the variant; many of these families are not identified until ascertainment of the severely affected proband. • Renal/urinary anomalies may be more common than in those w/pathogenic variants in other HPE genes. • Renal/urinary anomalies may be more common than in those w/pathogenic variants in other HPE genes. • Pathogenic variants are more frequently • Affected persons may be part of large kindreds segregating the variant; many of these families are not identified until ascertainment of the severely affected proband. • May be assoc w/more severe types of HPE • Semilobar HPE described in 2 unrelated persons • Neonatal diabetes mellitus requiring insulin may be a feature. • Pancreatic exocrine insufficiency may be present. • May be assoc w/sensorineural & conductive hearing loss w/ossicle anomalies • Range of HPE-spectrum features described in 5 unrelated persons. • May be assoc w/mild forms of HPE • May present w/a range of classic HPE-spectrum features • AR inheritance in all reported persons ## Holoprosencephaly of Unknown Cause Caudal dysgenesis (OMIM Pseudotrisomy 13 (OMIM Genoa syndrome (OMIM Brachial amelia, cleft lip, and holoprosencephaly (OMIM • Caudal dysgenesis (OMIM • Pseudotrisomy 13 (OMIM • Genoa syndrome (OMIM • Brachial amelia, cleft lip, and holoprosencephaly (OMIM ## Evaluation Strategies to Identify the Genetic Cause of Holoprosencephaly in a Proband Establishing a specific genetic cause of holoprosencephaly (HPE) can aid in discussions of prognosis (which are beyond the scope of this Evaluations to determine a specific genetic cause of holoprosencephaly usually involve the following. For an introduction to multigene panels click For an introduction to comprehensive genomic testing click • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Genetic Counseling If a genetic etiology (chromosome abnormality, monogenic condition, or pathogenic variant in a HPE-associated gene) is established in a proband with HPE, specific counseling for recurrence risk is indicated [ Parents of a child with a numeric chromosome abnormality (e.g., trisomy or triploidy) are expected to be chromosomally and phenotypically normal. Parents of a child with a structural unbalanced chromosome rearrangement (e.g., deletion, duplication) are at risk of having a balanced chromosome rearrangement and should be offered chromosome analysis. Sibs of a child with a numeric chromosome abnormality are at a slightly increased risk of having a similar chromosome abnormality (depending on the specific abnormality and the age of the mother) with a similar or different phenotype. The risk to the sibs of a child with a structural unbalanced chromosome rearrangement depends on the chromosome status of the parents: If neither parent has a structural rearrangement, the risk to sibs is negligible. If a parent has a balanced structural rearrangement, the risk is increased and depends on the specific rearrangement and possibly other variables. Many individuals diagnosed with autosomal dominant nonsyndromic HPE ( Some individuals with autosomal dominant nonsyndromic HPE may have the disorder as the result of a Molecular genetic testing is recommended for the parents of a proband with an apparent If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a * Misattributed parentage can also be explored as an alternative explanation for an apparent The family history of some individuals diagnosed with HPE may appear to be negative because of reduced penetrance and failure to recognize the disorder in family members; this is particularly true for families with HPE caused by pathogenic variants in If a parent is affected or has an HPE pathogenic variant (with or without clinical manifestations), the risk to sibs of inheriting the variant is 50%. Empiric studies indicate that sibs who inherit a pathogenic variant have a 20% risk for HPE, 15% risk for an HPE microform, and a 15% likelihood of a normal phenotype. If the proband has a known HPE pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is low, but slightly greater than that of the general population because of the possibility of parental germline mosaicism [ If the parents have not been tested for the HPE pathogenic variant in the proband but are clinically unaffected and the family history is negative, the risk to the sibs of the proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for HPE because of the possibility of reduced penetrance in a parent or parental germline mosaicism. Every child of an individual with a pathogenic variant for autosomal dominant nonsyndromic HPE has a 50% chance of inheriting the pathogenic variant. Although severely affected individuals do not reproduce, individuals with mild forms and microforms of autosomal dominant HPE may do so. The clinical manifestations and severity in offspring may range from mild to severe. The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a Heterozygotes (carriers) are asymptomatic. If both parents are known to be heterozygous for a Heterozygotes (carriers) are asymptomatic. A female proband with X-linked HPE caused by a pathogenic variant in To date, the majority of individuals with X-linked HPE are female, represent simplex cases (i.e., a single occurrence in the family), and have the disorder as the result of a Molecular genetic testing is recommended for both parents of a female proband. If the Note: The mother of a proband who is found to be heterozygous for a If a male is the only affected family member (i.e., a simplex case), the mother may be heterozygous or the affected male may have a Molecular genetic testing is recommended for the mother of a male proband. The father of an affected male will not have the disorder nor will he be hemizygous for an X-linked HPE-causing pathogenic variant; therefore, he does not require further evaluation/testing. If the mother of the proband has a Females who inherit the pathogenic variant are at high risk of developing HPE, although skewed X inactivation may result in variable phenotypic expression. Because the large majority of individuals affected with X-linked HPE identified to date are females, it is very likely that males who inherit If the father of the proband has a If the proband represents a simplex case and if the 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 Each child of a female proband with X-linked HPE has a 50% chance of inheriting the Each daughter of a male proband with X-linked HPE has a 50% chance of inheriting the Lobar HPE can be recognized in utero with ultrasound. However, a specific diagnosis is often difficult and relies on qualitative evaluation of the morphology of the ventricles. Though not specific, antenatal demonstration of an echogenic linear structure running anterior-posterior within the third ventricle is highly suggestive of lobar HPE, and can assist this difficult diagnosis. Fetal MRI is routinely used as a second-line investigation in several centers to evaluate CNS structure when ultrasound studies have suggested the presence of an anomaly [ When HPE is found on routine prenatal ultrasound examination in a fetus not known to be at increased risk for HPE, an extensive fetal examination, preferably using high-resolution ultrasound examination (e.g., examination with 3D ultrasound) to determine the presence of additional structural anomalies is indicated [ Fetal karyotype to detect numeric and structural chromosome abnormalities. Fetal karyotype is usually the first test ordered in the context of low-risk pregnancies. CMA if the karyotype is normal (or instead of karyotype) to detect pathogenic deletions or duplications (and aneuploidies if no previous karyotype) in the genes known to cause HPE (see Multigene panel sequencing including at least the three following genes: It is essential to bear in mind that if the fetus has HPE identified by ultrasound examination, medical and parental decision making about the pregnancy may occur independent of a specific genetic diagnosis. • Parents of a child with a numeric chromosome abnormality (e.g., trisomy or triploidy) are expected to be chromosomally and phenotypically normal. • Parents of a child with a structural unbalanced chromosome rearrangement (e.g., deletion, duplication) are at risk of having a balanced chromosome rearrangement and should be offered chromosome analysis. • Sibs of a child with a numeric chromosome abnormality are at a slightly increased risk of having a similar chromosome abnormality (depending on the specific abnormality and the age of the mother) with a similar or different phenotype. • The risk to the sibs of a child with a structural unbalanced chromosome rearrangement depends on the chromosome status of the parents: • If neither parent has a structural rearrangement, the risk to sibs is negligible. • If a parent has a balanced structural rearrangement, the risk is increased and depends on the specific rearrangement and possibly other variables. • If neither parent has a structural rearrangement, the risk to sibs is negligible. • If a parent has a balanced structural rearrangement, the risk is increased and depends on the specific rearrangement and possibly other variables. • If neither parent has a structural rearrangement, the risk to sibs is negligible. • If a parent has a balanced structural rearrangement, the risk is increased and depends on the specific rearrangement and possibly other variables. • Many individuals diagnosed with autosomal dominant nonsyndromic HPE ( • Some individuals with autosomal dominant nonsyndromic HPE may have the disorder as the result of a • Molecular genetic testing is recommended for the parents of a proband with an apparent • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a • * Misattributed parentage can also be explored as an alternative explanation for an apparent • The family history of some individuals diagnosed with HPE may appear to be negative because of reduced penetrance and failure to recognize the disorder in family members; this is particularly true for families with HPE caused by pathogenic variants in • If a parent is affected or has an HPE pathogenic variant (with or without clinical manifestations), the risk to sibs of inheriting the variant is 50%. Empiric studies indicate that sibs who inherit a pathogenic variant have a 20% risk for HPE, 15% risk for an HPE microform, and a 15% likelihood of a normal phenotype. • If the proband has a known HPE pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is low, but slightly greater than that of the general population because of the possibility of parental germline mosaicism [ • If the parents have not been tested for the HPE pathogenic variant in the proband but are clinically unaffected and the family history is negative, the risk to the sibs of the proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for HPE because of the possibility of reduced penetrance in a parent or parental germline mosaicism. • Every child of an individual with a pathogenic variant for autosomal dominant nonsyndromic HPE has a 50% chance of inheriting the pathogenic variant. • Although severely affected individuals do not reproduce, individuals with mild forms and microforms of autosomal dominant HPE may do so. The clinical manifestations and severity in offspring may range from mild to severe. • The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • Heterozygotes (carriers) are asymptomatic. • If both parents are known to be heterozygous for a • Heterozygotes (carriers) are asymptomatic. • A female proband with X-linked HPE caused by a pathogenic variant in • To date, the majority of individuals with X-linked HPE are female, represent simplex cases (i.e., a single occurrence in the family), and have the disorder as the result of a • Molecular genetic testing is recommended for both parents of a female proband. • If the • Note: The mother of a proband who is found to be heterozygous for a • If a male is the only affected family member (i.e., a simplex case), the mother may be heterozygous or the affected male may have a • Molecular genetic testing is recommended for the mother of a male proband. • The father of an affected male will not have the disorder nor will he be hemizygous for an X-linked HPE-causing pathogenic variant; therefore, he does not require further evaluation/testing. • If the mother of the proband has a • Females who inherit the pathogenic variant are at high risk of developing HPE, although skewed X inactivation may result in variable phenotypic expression. • Because the large majority of individuals affected with X-linked HPE identified to date are females, it is very likely that males who inherit • Females who inherit the pathogenic variant are at high risk of developing HPE, although skewed X inactivation may result in variable phenotypic expression. • Because the large majority of individuals affected with X-linked HPE identified to date are females, it is very likely that males who inherit • If the father of the proband has a • If the proband represents a simplex case and if the • Females who inherit the pathogenic variant are at high risk of developing HPE, although skewed X inactivation may result in variable phenotypic expression. • Because the large majority of individuals affected with X-linked HPE identified to date are females, it is very likely that males who inherit • 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 • Each child of a female proband with X-linked HPE has a 50% chance of inheriting the • Each daughter of a male proband with X-linked HPE has a 50% chance of inheriting the • Fetal karyotype to detect numeric and structural chromosome abnormalities. Fetal karyotype is usually the first test ordered in the context of low-risk pregnancies. • CMA if the karyotype is normal (or instead of karyotype) to detect pathogenic deletions or duplications (and aneuploidies if no previous karyotype) in the genes known to cause HPE (see • Multigene panel sequencing including at least the three following genes: ## Chromosome Abnormality – Risk to Family Members Parents of a child with a numeric chromosome abnormality (e.g., trisomy or triploidy) are expected to be chromosomally and phenotypically normal. Parents of a child with a structural unbalanced chromosome rearrangement (e.g., deletion, duplication) are at risk of having a balanced chromosome rearrangement and should be offered chromosome analysis. Sibs of a child with a numeric chromosome abnormality are at a slightly increased risk of having a similar chromosome abnormality (depending on the specific abnormality and the age of the mother) with a similar or different phenotype. The risk to the sibs of a child with a structural unbalanced chromosome rearrangement depends on the chromosome status of the parents: If neither parent has a structural rearrangement, the risk to sibs is negligible. If a parent has a balanced structural rearrangement, the risk is increased and depends on the specific rearrangement and possibly other variables. • Parents of a child with a numeric chromosome abnormality (e.g., trisomy or triploidy) are expected to be chromosomally and phenotypically normal. • Parents of a child with a structural unbalanced chromosome rearrangement (e.g., deletion, duplication) are at risk of having a balanced chromosome rearrangement and should be offered chromosome analysis. • Sibs of a child with a numeric chromosome abnormality are at a slightly increased risk of having a similar chromosome abnormality (depending on the specific abnormality and the age of the mother) with a similar or different phenotype. • The risk to the sibs of a child with a structural unbalanced chromosome rearrangement depends on the chromosome status of the parents: • If neither parent has a structural rearrangement, the risk to sibs is negligible. • If a parent has a balanced structural rearrangement, the risk is increased and depends on the specific rearrangement and possibly other variables. • If neither parent has a structural rearrangement, the risk to sibs is negligible. • If a parent has a balanced structural rearrangement, the risk is increased and depends on the specific rearrangement and possibly other variables. • If neither parent has a structural rearrangement, the risk to sibs is negligible. • If a parent has a balanced structural rearrangement, the risk is increased and depends on the specific rearrangement and possibly other variables. ## Autosomal Dominant Inheritance – Risk to Family Members Many individuals diagnosed with autosomal dominant nonsyndromic HPE ( Some individuals with autosomal dominant nonsyndromic HPE may have the disorder as the result of a Molecular genetic testing is recommended for the parents of a proband with an apparent If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a * Misattributed parentage can also be explored as an alternative explanation for an apparent The family history of some individuals diagnosed with HPE may appear to be negative because of reduced penetrance and failure to recognize the disorder in family members; this is particularly true for families with HPE caused by pathogenic variants in If a parent is affected or has an HPE pathogenic variant (with or without clinical manifestations), the risk to sibs of inheriting the variant is 50%. Empiric studies indicate that sibs who inherit a pathogenic variant have a 20% risk for HPE, 15% risk for an HPE microform, and a 15% likelihood of a normal phenotype. If the proband has a known HPE pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is low, but slightly greater than that of the general population because of the possibility of parental germline mosaicism [ If the parents have not been tested for the HPE pathogenic variant in the proband but are clinically unaffected and the family history is negative, the risk to the sibs of the proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for HPE because of the possibility of reduced penetrance in a parent or parental germline mosaicism. Every child of an individual with a pathogenic variant for autosomal dominant nonsyndromic HPE has a 50% chance of inheriting the pathogenic variant. Although severely affected individuals do not reproduce, individuals with mild forms and microforms of autosomal dominant HPE may do so. The clinical manifestations and severity in offspring may range from mild to severe. • Many individuals diagnosed with autosomal dominant nonsyndromic HPE ( • Some individuals with autosomal dominant nonsyndromic HPE may have the disorder as the result of a • Molecular genetic testing is recommended for the parents of a proband with an apparent • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a • * Misattributed parentage can also be explored as an alternative explanation for an apparent • The family history of some individuals diagnosed with HPE may appear to be negative because of reduced penetrance and failure to recognize the disorder in family members; this is particularly true for families with HPE caused by pathogenic variants in • If a parent is affected or has an HPE pathogenic variant (with or without clinical manifestations), the risk to sibs of inheriting the variant is 50%. Empiric studies indicate that sibs who inherit a pathogenic variant have a 20% risk for HPE, 15% risk for an HPE microform, and a 15% likelihood of a normal phenotype. • If the proband has a known HPE pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is low, but slightly greater than that of the general population because of the possibility of parental germline mosaicism [ • If the parents have not been tested for the HPE pathogenic variant in the proband but are clinically unaffected and the family history is negative, the risk to the sibs of the proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for HPE because of the possibility of reduced penetrance in a parent or parental germline mosaicism. • Every child of an individual with a pathogenic variant for autosomal dominant nonsyndromic HPE has a 50% chance of inheriting the pathogenic variant. • Although severely affected individuals do not reproduce, individuals with mild forms and microforms of autosomal dominant HPE may do so. The clinical manifestations and severity in offspring may range from mild to severe. ## Autosomal Recessive Inheritance – Risk to Family Members The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a Heterozygotes (carriers) are asymptomatic. If both parents are known to be heterozygous for a Heterozygotes (carriers) are asymptomatic. • The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • Heterozygotes (carriers) are asymptomatic. • If both parents are known to be heterozygous for a • Heterozygotes (carriers) are asymptomatic. ## X-Linked Inheritance – Risk to Family Members A female proband with X-linked HPE caused by a pathogenic variant in To date, the majority of individuals with X-linked HPE are female, represent simplex cases (i.e., a single occurrence in the family), and have the disorder as the result of a Molecular genetic testing is recommended for both parents of a female proband. If the Note: The mother of a proband who is found to be heterozygous for a If a male is the only affected family member (i.e., a simplex case), the mother may be heterozygous or the affected male may have a Molecular genetic testing is recommended for the mother of a male proband. The father of an affected male will not have the disorder nor will he be hemizygous for an X-linked HPE-causing pathogenic variant; therefore, he does not require further evaluation/testing. If the mother of the proband has a Females who inherit the pathogenic variant are at high risk of developing HPE, although skewed X inactivation may result in variable phenotypic expression. Because the large majority of individuals affected with X-linked HPE identified to date are females, it is very likely that males who inherit If the father of the proband has a If the proband represents a simplex case and if the 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 Each child of a female proband with X-linked HPE has a 50% chance of inheriting the Each daughter of a male proband with X-linked HPE has a 50% chance of inheriting the • A female proband with X-linked HPE caused by a pathogenic variant in • To date, the majority of individuals with X-linked HPE are female, represent simplex cases (i.e., a single occurrence in the family), and have the disorder as the result of a • Molecular genetic testing is recommended for both parents of a female proband. • If the • Note: The mother of a proband who is found to be heterozygous for a • If a male is the only affected family member (i.e., a simplex case), the mother may be heterozygous or the affected male may have a • Molecular genetic testing is recommended for the mother of a male proband. • The father of an affected male will not have the disorder nor will he be hemizygous for an X-linked HPE-causing pathogenic variant; therefore, he does not require further evaluation/testing. • If the mother of the proband has a • Females who inherit the pathogenic variant are at high risk of developing HPE, although skewed X inactivation may result in variable phenotypic expression. • Because the large majority of individuals affected with X-linked HPE identified to date are females, it is very likely that males who inherit • Females who inherit the pathogenic variant are at high risk of developing HPE, although skewed X inactivation may result in variable phenotypic expression. • Because the large majority of individuals affected with X-linked HPE identified to date are females, it is very likely that males who inherit • If the father of the proband has a • If the proband represents a simplex case and if the • Females who inherit the pathogenic variant are at high risk of developing HPE, although skewed X inactivation may result in variable phenotypic expression. • Because the large majority of individuals affected with X-linked HPE identified to date are females, it is very likely that males who inherit • 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 • Each child of a female proband with X-linked HPE has a 50% chance of inheriting the • Each daughter of a male proband with X-linked HPE has a 50% chance of inheriting the ## Prenatal Testing and Preimplantation Genetic Testing Lobar HPE can be recognized in utero with ultrasound. However, a specific diagnosis is often difficult and relies on qualitative evaluation of the morphology of the ventricles. Though not specific, antenatal demonstration of an echogenic linear structure running anterior-posterior within the third ventricle is highly suggestive of lobar HPE, and can assist this difficult diagnosis. Fetal MRI is routinely used as a second-line investigation in several centers to evaluate CNS structure when ultrasound studies have suggested the presence of an anomaly [ When HPE is found on routine prenatal ultrasound examination in a fetus not known to be at increased risk for HPE, an extensive fetal examination, preferably using high-resolution ultrasound examination (e.g., examination with 3D ultrasound) to determine the presence of additional structural anomalies is indicated [ Fetal karyotype to detect numeric and structural chromosome abnormalities. Fetal karyotype is usually the first test ordered in the context of low-risk pregnancies. CMA if the karyotype is normal (or instead of karyotype) to detect pathogenic deletions or duplications (and aneuploidies if no previous karyotype) in the genes known to cause HPE (see Multigene panel sequencing including at least the three following genes: It is essential to bear in mind that if the fetus has HPE identified by ultrasound examination, medical and parental decision making about the pregnancy may occur independent of a specific genetic diagnosis. • Fetal karyotype to detect numeric and structural chromosome abnormalities. Fetal karyotype is usually the first test ordered in the context of low-risk pregnancies. • CMA if the karyotype is normal (or instead of karyotype) to detect pathogenic deletions or duplications (and aneuploidies if no previous karyotype) in the genes known to cause HPE (see • Multigene panel sequencing including at least the three following genes: ## High-Risk Pregnancies Lobar HPE can be recognized in utero with ultrasound. However, a specific diagnosis is often difficult and relies on qualitative evaluation of the morphology of the ventricles. Though not specific, antenatal demonstration of an echogenic linear structure running anterior-posterior within the third ventricle is highly suggestive of lobar HPE, and can assist this difficult diagnosis. Fetal MRI is routinely used as a second-line investigation in several centers to evaluate CNS structure when ultrasound studies have suggested the presence of an anomaly [ ## Low-Risk Pregnancies When HPE is found on routine prenatal ultrasound examination in a fetus not known to be at increased risk for HPE, an extensive fetal examination, preferably using high-resolution ultrasound examination (e.g., examination with 3D ultrasound) to determine the presence of additional structural anomalies is indicated [ Fetal karyotype to detect numeric and structural chromosome abnormalities. Fetal karyotype is usually the first test ordered in the context of low-risk pregnancies. CMA if the karyotype is normal (or instead of karyotype) to detect pathogenic deletions or duplications (and aneuploidies if no previous karyotype) in the genes known to cause HPE (see Multigene panel sequencing including at least the three following genes: It is essential to bear in mind that if the fetus has HPE identified by ultrasound examination, medical and parental decision making about the pregnancy may occur independent of a specific genetic diagnosis. • Fetal karyotype to detect numeric and structural chromosome abnormalities. Fetal karyotype is usually the first test ordered in the context of low-risk pregnancies. • CMA if the karyotype is normal (or instead of karyotype) to detect pathogenic deletions or duplications (and aneuploidies if no previous karyotype) in the genes known to cause HPE (see • Multigene panel sequencing including at least the three following genes: ## Resources 1219 North Wittfield Street Indianapolis IN 46229 PO Box 5801 Bethesda MD 20824 • • 1219 North Wittfield Street • Indianapolis IN 46229 • • • • • • • PO Box 5801 • Bethesda MD 20824 • • • ## Chapter Notes Andrea L Gropman, MD, FAAP, FACMG; Children's National Health System (2000-2020)Paul Kruszka, MD, MPH (2020-present)Maximilian Muenke, MD, FACMG (2000-present)Benjamin D Solomon, MD; National Human Genome Research Institute (2010-2020)Cedrik Tekendo-Ngongang, MD (2020-present) 5 March 2020 (bp) Comprehensive update posted live 29 August 2013 (me) Comprehensive update posted live 30 March 2010 (me) Comprehensive update posted live 5 March 2008 (me) Comprehensive update posted live 11 March 2005 (me) Comprehensive update posted live 27 January 2003 (me) Comprehensive update posted live 27 December 2000 (pb) Overview posted live August 2000 (mm) Original submission • 5 March 2020 (bp) Comprehensive update posted live • 29 August 2013 (me) Comprehensive update posted live • 30 March 2010 (me) Comprehensive update posted live • 5 March 2008 (me) Comprehensive update posted live • 11 March 2005 (me) Comprehensive update posted live • 27 January 2003 (me) Comprehensive update posted live • 27 December 2000 (pb) Overview posted live • August 2000 (mm) Original submission ## Author History Andrea L Gropman, MD, FAAP, FACMG; Children's National Health System (2000-2020)Paul Kruszka, MD, MPH (2020-present)Maximilian Muenke, MD, FACMG (2000-present)Benjamin D Solomon, MD; National Human Genome Research Institute (2010-2020)Cedrik Tekendo-Ngongang, MD (2020-present) ## Revision History 5 March 2020 (bp) Comprehensive update posted live 29 August 2013 (me) Comprehensive update posted live 30 March 2010 (me) Comprehensive update posted live 5 March 2008 (me) Comprehensive update posted live 11 March 2005 (me) Comprehensive update posted live 27 January 2003 (me) Comprehensive update posted live 27 December 2000 (pb) Overview posted live August 2000 (mm) Original submission • 5 March 2020 (bp) Comprehensive update posted live • 29 August 2013 (me) Comprehensive update posted live • 30 March 2010 (me) Comprehensive update posted live • 5 March 2008 (me) Comprehensive update posted live • 11 March 2005 (me) Comprehensive update posted live • 27 January 2003 (me) Comprehensive update posted live • 27 December 2000 (pb) Overview posted live • August 2000 (mm) Original submission ## References ## Literature Cited Alobar HPE A. MRI of alobar holoprosencephaly (HPE), the most severe form of HPE, characterized by an enlarged midline monoventricle (holoventricle, red/thin arrow) with fusion of the frontal lobes and the midline gray matter structures (thalami and basal ganglia, blue/thick arrow). Typically, the corpus callosum and the third ventricle are absent. B. Facial features seen in the alobar HPE spectrum, characterized by a single eye-like structure (cyclopia, red/thin arrow) and an overriding nose-like structure (proboscis, blue/thick arrow) Semilobar HPE A. MRI showing semilobar HPE. Note fusion of the frontal lobes, but presence of some septation posteriorly with presence of a falx and interhemispheric fissure (red/thin arrow). The splenium of the corpus callosum is present but more anterior portions are usually absent. A small, partially formed third ventricle is seen. More significant fusion of anterior brain structures (cortex, basal ganglia, thalamus) persists in this variant (blue/thick arrows). A dorsal cyst may be seen. In mild cases, lack of frontal horn development distinguishes this from the lobar type. B. Note microcephaly, closely spaced eyes, depressed nasal ridge with cleft lip. Lobar HPE A. MRI in axial plane depicting lobar HPE, the least severe of the major types of HPE. The cerebral hemispheres are separated (blue/thick arrows); the ventricles are misshapen as a result of absence of the septum pellucidum. The posterior portion of the corpus callosum may be normally formed. There is a varying degree of fusion of the midline gray structures (thalami, basal ganglia, red/thin arrow). B. Relatively normal facial appearance of a child with lobar HPE resulting from a pathogenic variant in Middle interhemispheric fusion (MIHF) A. MRI in axial plane depicting middle interhemispheric variant of HPE in which the anterior portions of the frontal lobes and the occipital lobes are well separated. The sylvian fissures are oriented nearly vertically and are abnormally connected across the midline over the vertex of the brain (red/thin arrows). The genu and splenium of the corpus callosum appear normally formed, but the callosal body is typically absent. The hypothalamus and lentiform nuclei are normally separated; however, the caudate nuclei and the thalami remain incompletely separated. B. The facial appearance is usually normal. Microforms of holoprosencephaly (HPE) spectrum with milder craniofacial anomalies in the absence of neurologic findings A. Premaxillary agenesis with repaired bilateral clefts of the lip B. Absence of nasal bones and cartilage with a narrow nasal bridge C. Single central maxillary incisor D. Premaxillary agenesis, repaired unilateral cleft of the lip, and bilateral iris coloboma E. Close-up showing single central maxillary incisor F. This woman has a child with HPE. She has closely spaced eyes and narrow nasal bridge as her only manifestations. G. Single central incisor H. Prominent midline palatal ridge I. Premaxillary agenesis with bilateral cleft lip and palate in a child with pituitary hypoplasia and growth hormone deficiency J. Sagittal T Facial findings in holoprosencephaly (HPE) A. Alobar HPE with cyclopia and proboscis above the single eye B. Alobar HPE with cebocephaly and closely spaced eyes C. Semilobar HPE with microcephaly, premaxillary agenesis, and midline cleft lip and palate D. Semilobar HPE with closely spaced eyes, midface retrusion, and mild dysmorphism	[]	27/12/2000	5/3/2020	3/11/2011	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
hpp	hpp	[ "HOKPP", "HypoPP", "HOKPP", "HypoPP", "Sodium channel protein type 4 subunit alpha", "Voltage-dependent L-type calcium channel subunit alpha-1S", "CACNA1S", "SCN4A", "Hypokalemic Periodic Paralysis" ]	Hypokalemic Periodic Paralysis	Frank Weber, Frank Lehmann-Horn	Summary Hypokalemic periodic paralysis (hypoPP) is a condition in which affected individuals may experience paralytic episodes with concomitant hypokalemia (serum potassium <3.5 mmol/L). The paralytic attacks are characterized by decreased muscle tone (flaccidity) more marked proximally than distally with normal to decreased deep tendon reflexes. The episodes develop over minutes to hours and last several minutes to several days with spontaneous recovery. Some individuals have only one episode in a lifetime; more commonly, crises occur repeatedly: daily, weekly, monthly, or less often. The major triggering factors are cessation of effort following strenuous exercise and carbohydrate-rich evening meals. Additional triggers can include cold, stress/excitement/fear, salt intake, prolonged immobility, use of glucosteroids or alcohol, and anesthetic procedures. The age of onset of the first attack ranges from two to 30 years; the duration of paralytic episodes ranges from one to 72 hours with an average of nearly 24 hours. Long-lasting interictal muscle weakness may occur in some affected individuals and in some stages of the disease and in myopathic muscle changes. A myopathy may occur independent of paralytic symptoms and may be the sole manifestation of hypoPP. The diagnosis of hypoPP is established in a proband who meets the consensus diagnostic criteria based on a history of attacks of muscle weakness associated with documented serum potassium <3.5 mmol/L during attacks and/or the identification of a heterozygous pathogenic variant in In the case of long-lasting interictal flaccid muscle weakness, imaging techniques can inform on the pathogenesis, potential therapy, and prognosis. Muscle ultrasound and muscle 1H-MRI are reliable image techniques with high accuracy for the disease. The weakness can be caused by edemas, fatty muscle degeneration, and muscle atrophy or a combination of these pathologies. HypoPP is inherited in an autosomal dominant manner. Most individuals diagnosed with hypoPP have an affected parent. The proportion of cases caused by a	## Diagnosis Hypokalemic periodic paralysis (hypoPP) can be a primary condition or a symptom of an overarching syndrome or disease (see HypoPP Decreased muscle tone (flaccidity) Bilateral, symmetric, ascending (lower limbs affected before upper limbs) paralysis that is more marked in proximal than in distal muscles with sparing of the cranial muscles Deep tendon reflexes that are normal or decreased and plantar reflexes that are normal (downward movement of toes) Concomitant hypokalemia that is usually pronounced (0.9-3.5 mmol/L) The typical evolution of symptoms is as follows: Rapid installation (over minutes or over hours) Duration of several minutes to several days Spontaneous recovery Symptoms tend to occur under the following circumstances: At rest after strong physical exertion With fever At times of mental stress On awakening after a carbohydrate-rich meal the previous evening After prolonged immobility (e.g., with long-distance travel) Suspicion for hypoPP is also raised in individuals who have A familial history of paralytic attack in earlier generations (father or mother, grandfather or grandmother) and in sibs; A personal history of previous spontaneously regressive episodes of paralysis or acute muscle weakness with the above-mentioned characteristics; Long-lasting flaccid weakness, especially if the weakness is only moderate and is prevalent in the family. The diagnosis of hypoPP Two or more attacks of muscle weakness with documented serum potassium <3.5 mEq/L OR One attack of muscle weakness in the proband and one attack of weakness in one relative with documented serum potassium <3.5 mEq/L OR Three or more of the following six clinical/laboratory features: Onset in the first or second decade Duration of attack (muscle weakness involving ≥1 limbs) longer than two hours The presence of triggers (previous carbohydrate rich meal, symptom onset during rest after exercise, stress) Improvement in symptoms with potassium intake A family history of the condition or genetically confirmed skeletal calcium or sodium channel mutation Positive long exercise test (see AND Exclusion of other causes of hypokalemia (renal, adrenal, thyroid dysfunction; renal tubular acidosis; diuretic and laxative abuse) In individuals who have had one or more paralytic episodes, several tests can be used to differentiate between primary hypoPP and the other possible causes. See 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 hypoPP is broad, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of hypoPP, the recommended approach is the use of a A multigene panel that includes For an introduction to multigene panels click When the diagnosis of hypoPP is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Hypokalemic Periodic Paralysis 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. No data on detection rate of gene-targeted deletion/duplication analysis are available. Author, personal observation • Decreased muscle tone (flaccidity) • Bilateral, symmetric, ascending (lower limbs affected before upper limbs) paralysis that is more marked in proximal than in distal muscles with sparing of the cranial muscles • Deep tendon reflexes that are normal or decreased and plantar reflexes that are normal (downward movement of toes) • Concomitant hypokalemia that is usually pronounced (0.9-3.5 mmol/L) • Rapid installation (over minutes or over hours) • Duration of several minutes to several days • Spontaneous recovery • At rest after strong physical exertion • With fever • At times of mental stress • On awakening after a carbohydrate-rich meal the previous evening • After prolonged immobility (e.g., with long-distance travel) • A familial history of paralytic attack in earlier generations (father or mother, grandfather or grandmother) and in sibs; • A personal history of previous spontaneously regressive episodes of paralysis or acute muscle weakness with the above-mentioned characteristics; • Long-lasting flaccid weakness, especially if the weakness is only moderate and is prevalent in the family. • Two or more attacks of muscle weakness with documented serum potassium <3.5 mEq/L • OR • One attack of muscle weakness in the proband and one attack of weakness in one relative with documented serum potassium <3.5 mEq/L • OR • Three or more of the following six clinical/laboratory features: • Onset in the first or second decade • Duration of attack (muscle weakness involving ≥1 limbs) longer than two hours • The presence of triggers (previous carbohydrate rich meal, symptom onset during rest after exercise, stress) • Improvement in symptoms with potassium intake • A family history of the condition or genetically confirmed skeletal calcium or sodium channel mutation • Positive long exercise test (see • AND • Onset in the first or second decade • Duration of attack (muscle weakness involving ≥1 limbs) longer than two hours • The presence of triggers (previous carbohydrate rich meal, symptom onset during rest after exercise, stress) • Improvement in symptoms with potassium intake • A family history of the condition or genetically confirmed skeletal calcium or sodium channel mutation • Positive long exercise test (see • Exclusion of other causes of hypokalemia (renal, adrenal, thyroid dysfunction; renal tubular acidosis; diuretic and laxative abuse) • Onset in the first or second decade • Duration of attack (muscle weakness involving ≥1 limbs) longer than two hours • The presence of triggers (previous carbohydrate rich meal, symptom onset during rest after exercise, stress) • Improvement in symptoms with potassium intake • A family history of the condition or genetically confirmed skeletal calcium or sodium channel mutation • Positive long exercise test (see ## Suggestive Findings HypoPP Decreased muscle tone (flaccidity) Bilateral, symmetric, ascending (lower limbs affected before upper limbs) paralysis that is more marked in proximal than in distal muscles with sparing of the cranial muscles Deep tendon reflexes that are normal or decreased and plantar reflexes that are normal (downward movement of toes) Concomitant hypokalemia that is usually pronounced (0.9-3.5 mmol/L) The typical evolution of symptoms is as follows: Rapid installation (over minutes or over hours) Duration of several minutes to several days Spontaneous recovery Symptoms tend to occur under the following circumstances: At rest after strong physical exertion With fever At times of mental stress On awakening after a carbohydrate-rich meal the previous evening After prolonged immobility (e.g., with long-distance travel) Suspicion for hypoPP is also raised in individuals who have A familial history of paralytic attack in earlier generations (father or mother, grandfather or grandmother) and in sibs; A personal history of previous spontaneously regressive episodes of paralysis or acute muscle weakness with the above-mentioned characteristics; Long-lasting flaccid weakness, especially if the weakness is only moderate and is prevalent in the family. • Decreased muscle tone (flaccidity) • Bilateral, symmetric, ascending (lower limbs affected before upper limbs) paralysis that is more marked in proximal than in distal muscles with sparing of the cranial muscles • Deep tendon reflexes that are normal or decreased and plantar reflexes that are normal (downward movement of toes) • Concomitant hypokalemia that is usually pronounced (0.9-3.5 mmol/L) • Rapid installation (over minutes or over hours) • Duration of several minutes to several days • Spontaneous recovery • At rest after strong physical exertion • With fever • At times of mental stress • On awakening after a carbohydrate-rich meal the previous evening • After prolonged immobility (e.g., with long-distance travel) • A familial history of paralytic attack in earlier generations (father or mother, grandfather or grandmother) and in sibs; • A personal history of previous spontaneously regressive episodes of paralysis or acute muscle weakness with the above-mentioned characteristics; • Long-lasting flaccid weakness, especially if the weakness is only moderate and is prevalent in the family. ## Establishing the Diagnosis The diagnosis of hypoPP Two or more attacks of muscle weakness with documented serum potassium <3.5 mEq/L OR One attack of muscle weakness in the proband and one attack of weakness in one relative with documented serum potassium <3.5 mEq/L OR Three or more of the following six clinical/laboratory features: Onset in the first or second decade Duration of attack (muscle weakness involving ≥1 limbs) longer than two hours The presence of triggers (previous carbohydrate rich meal, symptom onset during rest after exercise, stress) Improvement in symptoms with potassium intake A family history of the condition or genetically confirmed skeletal calcium or sodium channel mutation Positive long exercise test (see AND Exclusion of other causes of hypokalemia (renal, adrenal, thyroid dysfunction; renal tubular acidosis; diuretic and laxative abuse) In individuals who have had one or more paralytic episodes, several tests can be used to differentiate between primary hypoPP and the other possible causes. See 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 hypoPP is broad, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of hypoPP, the recommended approach is the use of a A multigene panel that includes For an introduction to multigene panels click When the diagnosis of hypoPP is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Hypokalemic Periodic Paralysis 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. No data on detection rate of gene-targeted deletion/duplication analysis are available. Author, personal observation • Two or more attacks of muscle weakness with documented serum potassium <3.5 mEq/L • OR • One attack of muscle weakness in the proband and one attack of weakness in one relative with documented serum potassium <3.5 mEq/L • OR • Three or more of the following six clinical/laboratory features: • Onset in the first or second decade • Duration of attack (muscle weakness involving ≥1 limbs) longer than two hours • The presence of triggers (previous carbohydrate rich meal, symptom onset during rest after exercise, stress) • Improvement in symptoms with potassium intake • A family history of the condition or genetically confirmed skeletal calcium or sodium channel mutation • Positive long exercise test (see • AND • Onset in the first or second decade • Duration of attack (muscle weakness involving ≥1 limbs) longer than two hours • The presence of triggers (previous carbohydrate rich meal, symptom onset during rest after exercise, stress) • Improvement in symptoms with potassium intake • A family history of the condition or genetically confirmed skeletal calcium or sodium channel mutation • Positive long exercise test (see • Exclusion of other causes of hypokalemia (renal, adrenal, thyroid dysfunction; renal tubular acidosis; diuretic and laxative abuse) • Onset in the first or second decade • Duration of attack (muscle weakness involving ≥1 limbs) longer than two hours • The presence of triggers (previous carbohydrate rich meal, symptom onset during rest after exercise, stress) • Improvement in symptoms with potassium intake • A family history of the condition or genetically confirmed skeletal calcium or sodium channel mutation • Positive long exercise test (see ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of hypoPP, the recommended approach is the use of a A multigene panel that includes For an introduction to multigene panels click ## Option 2 When the diagnosis of hypoPP is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Hypokalemic Periodic Paralysis 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. No data on detection rate of gene-targeted deletion/duplication analysis are available. Author, personal observation ## Clinical Characteristics Large-scale studies of the natural history of primary hypokalemic periodic paralysis (hypoPP) have not been performed. Thus, knowledge of the natural history relies largely on personal observations and on individual cases that have been published with a retrospective description of the individual disease history. The age of the first paralytic attack in affected individuals who develop repetitive attacks ranges from age two years to 30 years, with a mean age of onset of 14 years. Occasionally, clinical manifestations can be present at birth [ Disease onset is not likely after age 30 years. Age of symptom onset is correlated with sex (younger age of onset for girls than for boys). In a cohort study by It was formerly assumed that the frequency of attacks peaks and then decreases with age, but in a recent survey only 21% of the patients reported decreased frequency with age [ In the cohort study by Paralytic episodes may be followed by a period of weakness, obscuring the precise resolution of the attack. The mean level of serum potassium during attacks was reported as 1.8 mmol/L in a cohort study by Occasionally, normal potassium values are noted. The ictal potassium level depends on the pathogenic variant (see Hypokalemia leading to possible cardiac dysrhythmia Weakness or paralysis of respiratory muscles leading to acute respiratory insufficiency Inability to move that can lead to death if it occurs in a hostile environment (i.e., drowning if the paralytic attack occurs in a swimming pool) The frequency of long-lasting interictal muscle weakness is not known with certainty. It was present in all 11 affected individuals from the same family ranging from age 33 to 74 years [ From a survey in which participants were recruited by a patient support group, As no longitudinal prospective study has been performed, the risk for long-lasting interictal muscle weakness as it pertains to age and the particular pathogenic variant present is unknown. In the case of long-lasting interictal flaccid muscle weakness, imaging techniques can inform on the pathogenesis, potential therapy, and prognosis. Muscle ultrasound and muscle 1H-MRI are reliable image techniques with high accuracy for the disease. The weakness can be caused by edemas, fatty muscle degeneration, and muscle atrophy or a combination of these pathologies. Pain (by some reports, more commonly associated with sodium-triggered episodes) Cramps Among the 30% of people who appear to have hypoPP but do not have pathogenic variants in either of the genes known to be associated with hypoPP, the following are often noted: Migraines Heart rhythm abnormalities Attention deficit disorder (ADD, ADHD) Relative insensitivity to the local anesthetic lidocaine and "dental anxiety" Severe premenstrual syndrome There are no clear cut genotype-phenotype correlations for either of the genes known to be associated with hypoPP. In general, the penetrance of this disorder is high (≥90%) in males and reduced in females. An exception to this occurs with pathogenic variants with an arginine-to-glycine substitution for which high penetrance in males and females is noted [ Names for hypokalemic periodic paralysis no longer in use include the following: Cavaré-Romberg syndrome Cavaré-Westphal syndrome Cavaré-Romberg-Westphal syndrome Westphal's disease Westphal's neurosis Hypokalemic periodic paralysis was formerly most often known as Westphal's disease, as Karl Friedrich Otto Westphal (1833-1890) first described extensively and convincingly the main characteristics of the disease, which had previously been described as "periodic palsy" by Musgrave in 1727, Cavaré in 1853, and Romberg in 1857. Hartwig reported a case of palsy with muscle inexcitability provoked by rest after exercise in 1875. Westphal described a simplex case (i.e., single occurrence in a family); it was not until 1887 that a dominant pedigree was described by Cousot. The prevalence of hypoPP is unknown but thought to be approximately 1:100,000 [ • The age of the first paralytic attack in affected individuals who develop repetitive attacks ranges from age two years to 30 years, with a mean age of onset of 14 years. Occasionally, clinical manifestations can be present at birth [ • Disease onset is not likely after age 30 years. • Age of symptom onset is correlated with sex (younger age of onset for girls than for boys). • In a cohort study by • It was formerly assumed that the frequency of attacks peaks and then decreases with age, but in a recent survey only 21% of the patients reported decreased frequency with age [ • In the cohort study by • Paralytic episodes may be followed by a period of weakness, obscuring the precise resolution of the attack. • The mean level of serum potassium during attacks was reported as 1.8 mmol/L in a cohort study by • Occasionally, normal potassium values are noted. The ictal potassium level depends on the pathogenic variant (see • Hypokalemia leading to possible cardiac dysrhythmia • Weakness or paralysis of respiratory muscles leading to acute respiratory insufficiency • Inability to move that can lead to death if it occurs in a hostile environment (i.e., drowning if the paralytic attack occurs in a swimming pool) • The frequency of long-lasting interictal muscle weakness is not known with certainty. It was present in all 11 affected individuals from the same family ranging from age 33 to 74 years [ • From a survey in which participants were recruited by a patient support group, • As no longitudinal prospective study has been performed, the risk for long-lasting interictal muscle weakness as it pertains to age and the particular pathogenic variant present is unknown. • Pain (by some reports, more commonly associated with sodium-triggered episodes) • Cramps • Migraines • Heart rhythm abnormalities • Attention deficit disorder (ADD, ADHD) • Relative insensitivity to the local anesthetic lidocaine and "dental anxiety" • Severe premenstrual syndrome • Cavaré-Romberg syndrome • Cavaré-Westphal syndrome • Cavaré-Romberg-Westphal syndrome • Westphal's disease • Westphal's neurosis ## Clinical Description Large-scale studies of the natural history of primary hypokalemic periodic paralysis (hypoPP) have not been performed. Thus, knowledge of the natural history relies largely on personal observations and on individual cases that have been published with a retrospective description of the individual disease history. The age of the first paralytic attack in affected individuals who develop repetitive attacks ranges from age two years to 30 years, with a mean age of onset of 14 years. Occasionally, clinical manifestations can be present at birth [ Disease onset is not likely after age 30 years. Age of symptom onset is correlated with sex (younger age of onset for girls than for boys). In a cohort study by It was formerly assumed that the frequency of attacks peaks and then decreases with age, but in a recent survey only 21% of the patients reported decreased frequency with age [ In the cohort study by Paralytic episodes may be followed by a period of weakness, obscuring the precise resolution of the attack. The mean level of serum potassium during attacks was reported as 1.8 mmol/L in a cohort study by Occasionally, normal potassium values are noted. The ictal potassium level depends on the pathogenic variant (see Hypokalemia leading to possible cardiac dysrhythmia Weakness or paralysis of respiratory muscles leading to acute respiratory insufficiency Inability to move that can lead to death if it occurs in a hostile environment (i.e., drowning if the paralytic attack occurs in a swimming pool) The frequency of long-lasting interictal muscle weakness is not known with certainty. It was present in all 11 affected individuals from the same family ranging from age 33 to 74 years [ From a survey in which participants were recruited by a patient support group, As no longitudinal prospective study has been performed, the risk for long-lasting interictal muscle weakness as it pertains to age and the particular pathogenic variant present is unknown. In the case of long-lasting interictal flaccid muscle weakness, imaging techniques can inform on the pathogenesis, potential therapy, and prognosis. Muscle ultrasound and muscle 1H-MRI are reliable image techniques with high accuracy for the disease. The weakness can be caused by edemas, fatty muscle degeneration, and muscle atrophy or a combination of these pathologies. Pain (by some reports, more commonly associated with sodium-triggered episodes) Cramps Among the 30% of people who appear to have hypoPP but do not have pathogenic variants in either of the genes known to be associated with hypoPP, the following are often noted: Migraines Heart rhythm abnormalities Attention deficit disorder (ADD, ADHD) Relative insensitivity to the local anesthetic lidocaine and "dental anxiety" Severe premenstrual syndrome • The age of the first paralytic attack in affected individuals who develop repetitive attacks ranges from age two years to 30 years, with a mean age of onset of 14 years. Occasionally, clinical manifestations can be present at birth [ • Disease onset is not likely after age 30 years. • Age of symptom onset is correlated with sex (younger age of onset for girls than for boys). • In a cohort study by • It was formerly assumed that the frequency of attacks peaks and then decreases with age, but in a recent survey only 21% of the patients reported decreased frequency with age [ • In the cohort study by • Paralytic episodes may be followed by a period of weakness, obscuring the precise resolution of the attack. • The mean level of serum potassium during attacks was reported as 1.8 mmol/L in a cohort study by • Occasionally, normal potassium values are noted. The ictal potassium level depends on the pathogenic variant (see • Hypokalemia leading to possible cardiac dysrhythmia • Weakness or paralysis of respiratory muscles leading to acute respiratory insufficiency • Inability to move that can lead to death if it occurs in a hostile environment (i.e., drowning if the paralytic attack occurs in a swimming pool) • The frequency of long-lasting interictal muscle weakness is not known with certainty. It was present in all 11 affected individuals from the same family ranging from age 33 to 74 years [ • From a survey in which participants were recruited by a patient support group, • As no longitudinal prospective study has been performed, the risk for long-lasting interictal muscle weakness as it pertains to age and the particular pathogenic variant present is unknown. • Pain (by some reports, more commonly associated with sodium-triggered episodes) • Cramps • Migraines • Heart rhythm abnormalities • Attention deficit disorder (ADD, ADHD) • Relative insensitivity to the local anesthetic lidocaine and "dental anxiety" • Severe premenstrual syndrome ## Genotype-Phenotype Correlations There are no clear cut genotype-phenotype correlations for either of the genes known to be associated with hypoPP. ## Penetrance In general, the penetrance of this disorder is high (≥90%) in males and reduced in females. An exception to this occurs with pathogenic variants with an arginine-to-glycine substitution for which high penetrance in males and females is noted [ ## Nomenclature Names for hypokalemic periodic paralysis no longer in use include the following: Cavaré-Romberg syndrome Cavaré-Westphal syndrome Cavaré-Romberg-Westphal syndrome Westphal's disease Westphal's neurosis Hypokalemic periodic paralysis was formerly most often known as Westphal's disease, as Karl Friedrich Otto Westphal (1833-1890) first described extensively and convincingly the main characteristics of the disease, which had previously been described as "periodic palsy" by Musgrave in 1727, Cavaré in 1853, and Romberg in 1857. Hartwig reported a case of palsy with muscle inexcitability provoked by rest after exercise in 1875. Westphal described a simplex case (i.e., single occurrence in a family); it was not until 1887 that a dominant pedigree was described by Cousot. • Cavaré-Romberg syndrome • Cavaré-Westphal syndrome • Cavaré-Romberg-Westphal syndrome • Westphal's disease • Westphal's neurosis ## Prevalence The prevalence of hypoPP is unknown but thought to be approximately 1:100,000 [ ## Genetically Related (Allelic) Disorders Main Phenotypes Related to Pathogenic Variants in See Complex allele c.4468_4479del12insCTCCTGGTCATA reported as p.Ile1490Leu-p.Met1493Ile [ p.Gly1306Glu: Glu causes myotonia permanens with neonatal laryngospasms; also other SCM-causing variants (e.g., p.Gly1306Ala) may be responsible for neonatal respiratory insufficiency (i.e. myotonia fluctuans). ## Differential Diagnosis The following signs and symptoms suggest a diagnosis other than hypokalemic periodic paralysis (hypoPP): Associated sensory symptoms, including pain or tenderness Sensory loss could suggest polyneuropathy such as Guillain-Barré syndrome. Pain could suggest myositis; however, some individuals with hypoPP report paralytic episodes as painful. Urinary retention or constipation, which may be observed in other causes of acute or subacute paralysis, but can occur rarely in hypoPP Associated symptoms that suggest myasthenia or involvement of the neuromuscular junction, including: Ptosis Diplopia Dysphagia Dysarthria Alteration or loss of consciousness Abnormal movement History of fever days before an attack, which could suggest poliomyelitis or other virus-caused paralysis History of back pain days before an attack, which could suggest acute transverse myelitis History of tick bite, which could suggest tick paralysis HypoPP is the most common cause of periodic paralysis. The four major differential diagnoses are normokalemic potassium-sensitive periodic paralysis (normoPP), The Different Categories of Periodic Paralyses (PP) with Membrane Excitability Disorder and Associated Findings ACZ = acetazolamide; CMAP = compound muscle action potential; DCP = dichlorphenamide; LET = long exercise test; SET = short exercise test OMIM ATS anomalies include low-set ears, widely spaced eyes, small mandible, fifth-digit clinodactyly, syndactyly, short stature, and scoliosis. Serum concentration of potassium during the paralytic attacks is normal or elevated. Some triggering factors for hypoPP attacks (e.g., carbohydrate-rich meals) are not found. Age of onset of paralytic attacks is lower. Duration of attacks is assumed to be shorter. However, this is questionable, according to surveys of affected individuals. Electromyography shows myotonic discharges in most individuals between attacks; however, the response patterns for short exercise test (SET) and long exercise test (LET) may be indiscernible; i.e., pattern IV or V defined by In normokalemic PP, the reaction to oral potassium administration may be different than for hypoPP – anything from amelioration to worsening of the weakness [ Usually, the distinction between hypoPP and normo/hyperPP can be made on the basis of clinical, biologic (i.e., kalemia during an attack), and EMG findings and confirmed by molecular genetic testing [ Although TPP is not usually caused by classic hypoPP-causing pathogenic variants [ Because thyrotoxicosis may be a precipitating factor of genetically defined hypokalemic or normokalemic periodic paralysis [ Plasma thyroid-stimulating hormone (TSH) (reference range: 0.45-4.5 µU/mL) Free thyroxine (FT4) (reference range: 8.0-20.0 pg/mL) Free triiodothyronine (FT3) (reference range: 1.4-4.0 pg/mL) Note: (1) Low TSH together with high FT3 and FT4 are diagnostic of hyperthyroidism. Treatment of hyperthyroidism cures TPP. (2) TPP is distinct from hypokalemic periodic paralysis (hypoPP); however, at least two instances of genetically diagnosed familial hypoPP for which hyperthyroidism was an additional trigger for hypokalemic paralytic episodes have been reported [ See also Identifying the Cause of Secondary Hypokalemia Primary or secondary inappropriate (pseudo) hyperaldosteronism Secondary hyperaldosteronism (↑ renin blood concentration): renin secreting tumor, renal artery stenosis, malignant hypertension Hyperglucocorticism (normal renin blood concentration) Licorice (normal renin blood concentration) Gastrointestinal losses Insufficient potassium intake Vomiting Present treatment w/diuretics Bartter syndrome (tubulopathy w/normo- or hypercalcuria, normomagnesemia) Gitelman syndrome (tubulopathy w/hypocalciuria, hypomagnesemia) Distal tubular acidosis type 1, 2 (but not 4, in which there is hyperkalemia) Diabetic acidosis • Associated sensory symptoms, including pain or tenderness • Sensory loss could suggest polyneuropathy such as Guillain-Barré syndrome. • Pain could suggest myositis; however, some individuals with hypoPP report paralytic episodes as painful. • Sensory loss could suggest polyneuropathy such as Guillain-Barré syndrome. • Pain could suggest myositis; however, some individuals with hypoPP report paralytic episodes as painful. • Urinary retention or constipation, which may be observed in other causes of acute or subacute paralysis, but can occur rarely in hypoPP • Associated symptoms that suggest myasthenia or involvement of the neuromuscular junction, including: • Ptosis • Diplopia • Dysphagia • Dysarthria • Ptosis • Diplopia • Dysphagia • Dysarthria • Alteration or loss of consciousness • Abnormal movement • History of fever days before an attack, which could suggest poliomyelitis or other virus-caused paralysis • History of back pain days before an attack, which could suggest acute transverse myelitis • History of tick bite, which could suggest tick paralysis • Sensory loss could suggest polyneuropathy such as Guillain-Barré syndrome. • Pain could suggest myositis; however, some individuals with hypoPP report paralytic episodes as painful. • Ptosis • Diplopia • Dysphagia • Dysarthria • Serum concentration of potassium during the paralytic attacks is normal or elevated. • Some triggering factors for hypoPP attacks (e.g., carbohydrate-rich meals) are not found. • Age of onset of paralytic attacks is lower. • Duration of attacks is assumed to be shorter. However, this is questionable, according to surveys of affected individuals. • Electromyography shows myotonic discharges in most individuals between attacks; however, the response patterns for short exercise test (SET) and long exercise test (LET) may be indiscernible; i.e., pattern IV or V defined by • In normokalemic PP, the reaction to oral potassium administration may be different than for hypoPP – anything from amelioration to worsening of the weakness [ • Plasma thyroid-stimulating hormone (TSH) (reference range: 0.45-4.5 µU/mL) • Free thyroxine (FT4) (reference range: 8.0-20.0 pg/mL) • Free triiodothyronine (FT3) (reference range: 1.4-4.0 pg/mL) • Primary or secondary inappropriate (pseudo) hyperaldosteronism • Secondary hyperaldosteronism (↑ renin blood concentration): renin secreting tumor, renal artery stenosis, malignant hypertension • Hyperglucocorticism (normal renin blood concentration) • Licorice (normal renin blood concentration) • Gastrointestinal losses • Insufficient potassium intake • Vomiting • Present treatment w/diuretics • Bartter syndrome (tubulopathy w/normo- or hypercalcuria, normomagnesemia) • Gitelman syndrome (tubulopathy w/hypocalciuria, hypomagnesemia) • Distal tubular acidosis type 1, 2 (but not 4, in which there is hyperkalemia) • Diabetic acidosis ## Management To establish the extent of disease and needs in an individual diagnosed with hypokalemic periodic paralysis (hypoPP), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended. Assessment of respiratory status to detect those individuals who may have early respiratory failure Measurement of serum potassium concentration Cardiac electrophysiologic testing (EKG) to assess for life-threatening cardiac consequences of hypokalemia Assessment for swallowing difficulty Neurologic examination to assess muscle strength in the legs Measurement of the following thyroid functions (see Note): Plasma thyroid-stimulating hormone (TSH) Free thyroxine (FT4) Free triiodothyronine (FT3) In those with long-lasting interictal weakness, consideration of muscle sonography or MRI scan of muscles (e.g. thigh) to evaluate the extent of myopathy [ Consultation with a clinical geneticist and/or genetic counselor Note: (1) Hyperthyroidism may be a trigger for a hypokalemic episode in individuals with hypoPP; (2) thyroid function tests may help to distinguish between hypoPP and TPP in those who have a pathogenic variant in For a comprehensive summary of the management of hypokalemic periodic paralysis, see Principles of Treatment for Individuals with HypoPP Strenuous effort; Prolonged immobility; Carbohydrate-rich diet; High sodium diet. Monitor episodes of weakness noting time of day & specific triggers. Provide dietary review/counseling. Shorten/prevent aggravation of the weakness episode. Normalize kalemia. Provide potassium supplementation (oral, or IV if oral impossible or if potassium very low). Avoid glucose intake. Do not use slow-release forms of potassium. Oral potassium: initially, 1 mEq/kg; add 0.3 mEq/kg after 30 min if no improvement IV potassium: 0.3 mEq/kg/h Avoid corticosteroids if possible. Use alpha- or beta adrenergic drugs w/caution, even in local anesthesia or ophthalmology. Kinesiotherapy in case of long-lasting pelvic deficit Adaptive measures: (1) at school & especially for sports; (2) in work setting During a paralytic attack, there is usually no true potassium depletion in the body (unless there are associated digestive or renal losses from another cause), but there is a reversible transfer of potassium from the extracellular to the intracellular space. The global potassium pool (and especially the intracellular pool of the body) is conserved, and the goal of the treatment is to raise the blood potassium level just enough to trigger the shift to repolarization of skeletal muscle membrane, and the liberation of intracellularly sequestered potassium. Treatment may occur in a familial or non-medical setting if the diagnosis is well-established and the affected individual is able to manage paralytic episodes. Rapid recovery is typically possible with oral intake of chloride potassium salts, either as capsules or liquid-containing vials. Aqueous potassium contained in vials may act more rapidly. An initial intake of 1mEq/kg potassium chloride is often used (60 mEq; i.e., 4.5 g of potassium chloride for a 60-kg person). A response (at least partial) should be seen after 30 minutes. If no improvement occurs after 30 minutes, an additional 0.3 mEq/kg can be administered (20 mEq; i.e., 1.5 g of potassium chloride for a 60 kg person). Note: (1) Slow-release forms of potassium should be avoided during a paralytic attack. (2) Potassium ingesting should be followed by oral intake of water (e.g., 100 mL (4 oz) of water for each 20 mEq of potassium). (3) Liquids containing high sugar or sodium content should be avoided. The total dose of potassium taken over a 24-hr period for the treatment of an acute attack should not exceed 200 mEq. During severe paralytic episodes or attacks associated with respiratory, swallowing, or speaking difficulties, or with signs of arrhythmia, the affected individual must be transferred to hospital. In the case of very low serum potassium and severe symptoms (airway compromise with ictal dysphagia, accessory respiratory muscle paralysis, arrhythmia associated with hypokalemia), intravenous potassium treatment should be initiated. Note the following critical points: The concentration of intravenous potassium chloride solution should not exceed 40 mEq/L because of the risk for thrombophlebitis (the use of a central catheter is rarely necessary). The solution should be given as a continuous infusion that does not exceed 0.3 mEq/kg/h of potassium (i.e., 18 mEq/h for a 60-kg person) because of the high risk for arrhythmia or cardiac arrest associated with faster infusions. The physician should be aware that hyperkalemia may occur, as there is no true potassium depletion; a reverse shift of potassium from the intracellular to the extracellular space occurs during the resolution of paralytic episode. A Y-branched peripheral venous line containing potassium chloride should be branched to a perfusion of mannitol or normal saline (avoid glucose-containing solutions, which may enhance hypokalemia). To prevent cardiac arrhythmias, it is important to monitor the EKG before, during, and after treatment and to perform repeat assessments of blood potassium concentration: A prominent increase in the amplitude of the U wave, triggered by hypokalemia, is associated with a higher susceptibility to the ventricular arrhythmia known as Large and sharp T waves are a marker of hyperkalemia and may occur during and after recovery; they are associated with a risk for cardiac arrest. Monitoring of EKG and blood potassium concentration must be continued some hours after normalization of the serum potassium concentration, in order to detect a relapse of hypokalemia or the development of hyperkalemia secondary to excessive potassium load. Administration of supplemental potassium must be discontinued when the serum potassium concentration is normalized, even if weakness persists. Physiotherapy may help to maintain strength and motor abilities, especially after 40 years of age, when long-lasting muscle weakness is more often seen. The physiotherapist must be aware of the following peculiarity of periodic paralysis: that sustained effort results in exacerbation of weakness. Therefore, self-managed exercise should be preferred to superimposed physiotherapy [ Preventive treatment is intended to decrease the frequency and intensity of paralytic attacks. Triggering factors need to be identified and, if possible, avoided (see Oral intake of potassium salts (10-20 mmol/dose, 3 doses/day) can prevent attacks, especially if the dose of potassium is taken some hours before the usual time of the attack (i.e., a nocturnal dose if crises occur at awakening). For individuals receiving chronic potassium supplementation for hypoPP, magnesium might be added, which can be helpful to promote renal retention of potassium and, therefore, reduce the potassium dose [ However, there is no standardized treatment regimen and no consensus as to when to start treatment with acetazolamide. Typical dosage for acetazolamide in adults is between 125 mg/day and 1000 mg/day (usually 250-500 mg/day), divided into three doses and taken with meals; in children a dose of 5-10 mg/kg/day, divided into three doses and taken with meals, is used. Acetazolamide treatment: Is beneficial in approximately 50% of individuals with hypoPP Has no effect in 30% of affected individuals May exacerbate hypoPP in individuals with who have a pathogenic variant in In some affected persons, long-lasting interictal weakness may be partly reversed and muscle strength may be improved by acetazolamide treatment [ Whether acetazolamide treatment prevents or treats myopathy and the resulting fixed weakness that occurs with age is unknown. Further studies are needed to evaluate the effect of preventive acetazolamide treatment on attack rate, severity-weighted attack rate, long-lasting interictal weakness, and myopathy. Common side effects of carbonic anhydrase inhibitors include paresthesia, fatigue, mild, reversible cognitive disturbances and an increased risk of nephrolithiasis. While randomized controlled trials of dichlorphenamide were performed in adults, the same approach is taken for children; dose adjustments may be required based on age. These studies demonstrated a significant reduction in the frequency and severity of the attacks. During a 52-week extension, in which all remaining participants received open-label dichlorphenamide, continued improvement in outcomes was observed in both placebo and dichlorphenamide groups. The dose of dichlorphenamide was 50 mg twice daily for treatment-naıve patients. Individuals already on dichlorphenamide before the study continued on the same dose during the study. In those taking acetazolamide before the study, the dose of dichlorphenamide was set at 20% of the acetazolamide dose. Dose reduction for tolerability was permitted. The mean dose of dichlorphenamide at week 9 was 82 mg/day. The most common side effects with dichlorphenamide were paresthesias, cognitive disorder, dysgeusia, headache, fatigue, hypoesthesia, and muscle spasms, generally not requiring discontinuation of dichlorphenamide, and reversible with drug discontinuation. In the recent study of diclorphenamide [ Because spironolactone is associated with a long half-life for substrate degradation, the individual can become hyperkalemic and weaker, develop cardiac arrhythmias, and suffer from hair loss. Additionally, spironolactone has androgenic side effects. The modern spironolactone derivate Eplerenone may be preferred because it causes fewer androgenic side effects. In addition, it has a very high repolarizing power, the parameter considered as most relevant for a beneficial effect. For individuals with hypoPP, potassium supplementation and a potassium-sparing diuretic may be used concomitantly, but potassium levels should be routinely monitored. Creating a safe environment, getting help in case of paralytic attack, and preventing falls and accidents are critical [ An affected person experiencing a paralytic attack must have access to potassium as well as physical assistance. Thus, those with hypoPP should inform their companions or acquaintances of their risk for paralytic attack, especially in a sports or school context, so that they can access appropriate help rapidly in case of an attack. Falls and injuries from falls are frequent in those with hypoPP (67% of affected individuals age >40 years report such falls and injuries) [ General guidelines for perioperative care include the following: Strict control of serum potassium concentration Avoidance of large glucose and salt loads Low-carbohydrate diet Maintenance of body temperature and acid-base balance Careful use of neuromuscular blocking agents and no depolarizing muscle relaxants The frequency of consultations needs to be adapted to the individual's signs and symptoms and response to preventive treatment. Neurologic examination with attention to muscle strength in the legs should be performed, in order to detect long-lasting interictal weakness associated with myopathy. For those individuals who take acetazolamide the following parameters should be evaluated every three months: complete blood count, electrolytes, glucose, uric acid, and liver enzyme levels. Renal ultrasound should be performed annually. Avoid anything that can trigger paralytic attacks in the individual case, including the following: Unusually strenuous effort Excess of carbohydrate-rich meals or sweets Cold Stress/excitement/fear High salt intake Prolonged immobility Oral or intravenous glucosteroids Use of cooling, glucose and/or mannitol infusion, excessive sodium- containing fluids and certain anesthetics such as succinylcholine during anesthesia Use of alcohol 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 at risk for unexpected acute paralysis and/or possibly malignant hyperthermia and who would benefit from prompt initiation of treatment and preventive measures. Evaluations include: Molecular genetic testing if the pathogenic variant in the family is known; Detailed history (with attention to full or incomplete paralytic crises in the past and/or adverse response to glucose infusion, surgery, or general anesthesia) and neurologic examination. See In general, there is no increased risk for paretic attacks in pregnancy. While in utero acetazolamide exposure is reported to cause limb defects in rodents, acetazolamide therapy during human pregnancy does not appear to increase the risk for fetal malformations [ See Recent studies in mouse models of hypoPP with both Search • Assessment of respiratory status to detect those individuals who may have early respiratory failure • Measurement of serum potassium concentration • Cardiac electrophysiologic testing (EKG) to assess for life-threatening cardiac consequences of hypokalemia • Assessment for swallowing difficulty • Neurologic examination to assess muscle strength in the legs • Measurement of the following thyroid functions (see Note): • Plasma thyroid-stimulating hormone (TSH) • Free thyroxine (FT4) • Free triiodothyronine (FT3) • Plasma thyroid-stimulating hormone (TSH) • Free thyroxine (FT4) • Free triiodothyronine (FT3) • In those with long-lasting interictal weakness, consideration of muscle sonography or MRI scan of muscles (e.g. thigh) to evaluate the extent of myopathy [ • Consultation with a clinical geneticist and/or genetic counselor • Plasma thyroid-stimulating hormone (TSH) • Free thyroxine (FT4) • Free triiodothyronine (FT3) • Strenuous effort; • Prolonged immobility; • Carbohydrate-rich diet; • High sodium diet. • Monitor episodes of weakness noting time of day & specific triggers. • Provide dietary review/counseling. • Shorten/prevent aggravation of the weakness episode. • Normalize kalemia. • Provide potassium supplementation (oral, or IV if oral impossible or if potassium very low). • Avoid glucose intake. • Do not use slow-release forms of potassium. • Oral potassium: initially, 1 mEq/kg; add 0.3 mEq/kg after 30 min if no improvement • IV potassium: 0.3 mEq/kg/h • Avoid corticosteroids if possible. • Use alpha- or beta adrenergic drugs w/caution, even in local anesthesia or ophthalmology. • Kinesiotherapy in case of long-lasting pelvic deficit • Adaptive measures: (1) at school & especially for sports; (2) in work setting • Treatment may occur in a familial or non-medical setting if the diagnosis is well-established and the affected individual is able to manage paralytic episodes. • Rapid recovery is typically possible with oral intake of chloride potassium salts, either as capsules or liquid-containing vials. Aqueous potassium contained in vials may act more rapidly. • An initial intake of 1mEq/kg potassium chloride is often used (60 mEq; i.e., 4.5 g of potassium chloride for a 60-kg person). • A response (at least partial) should be seen after 30 minutes. If no improvement occurs after 30 minutes, an additional 0.3 mEq/kg can be administered (20 mEq; i.e., 1.5 g of potassium chloride for a 60 kg person). • The total dose of potassium taken over a 24-hr period for the treatment of an acute attack should not exceed 200 mEq. • During severe paralytic episodes or attacks associated with respiratory, swallowing, or speaking difficulties, or with signs of arrhythmia, the affected individual must be transferred to hospital. • In the case of very low serum potassium and severe symptoms (airway compromise with ictal dysphagia, accessory respiratory muscle paralysis, arrhythmia associated with hypokalemia), intravenous potassium treatment should be initiated. Note the following critical points: • The concentration of intravenous potassium chloride solution should not exceed 40 mEq/L because of the risk for thrombophlebitis (the use of a central catheter is rarely necessary). • The solution should be given as a continuous infusion that does not exceed 0.3 mEq/kg/h of potassium (i.e., 18 mEq/h for a 60-kg person) because of the high risk for arrhythmia or cardiac arrest associated with faster infusions. • The physician should be aware that hyperkalemia may occur, as there is no true potassium depletion; a reverse shift of potassium from the intracellular to the extracellular space occurs during the resolution of paralytic episode. • The concentration of intravenous potassium chloride solution should not exceed 40 mEq/L because of the risk for thrombophlebitis (the use of a central catheter is rarely necessary). • The solution should be given as a continuous infusion that does not exceed 0.3 mEq/kg/h of potassium (i.e., 18 mEq/h for a 60-kg person) because of the high risk for arrhythmia or cardiac arrest associated with faster infusions. • The physician should be aware that hyperkalemia may occur, as there is no true potassium depletion; a reverse shift of potassium from the intracellular to the extracellular space occurs during the resolution of paralytic episode. • A Y-branched peripheral venous line containing potassium chloride should be branched to a perfusion of mannitol or normal saline (avoid glucose-containing solutions, which may enhance hypokalemia). • To prevent cardiac arrhythmias, it is important to monitor the EKG before, during, and after treatment and to perform repeat assessments of blood potassium concentration: • A prominent increase in the amplitude of the U wave, triggered by hypokalemia, is associated with a higher susceptibility to the ventricular arrhythmia known as • Large and sharp T waves are a marker of hyperkalemia and may occur during and after recovery; they are associated with a risk for cardiac arrest. • A prominent increase in the amplitude of the U wave, triggered by hypokalemia, is associated with a higher susceptibility to the ventricular arrhythmia known as • Large and sharp T waves are a marker of hyperkalemia and may occur during and after recovery; they are associated with a risk for cardiac arrest. • Monitoring of EKG and blood potassium concentration must be continued some hours after normalization of the serum potassium concentration, in order to detect a relapse of hypokalemia or the development of hyperkalemia secondary to excessive potassium load. • Administration of supplemental potassium must be discontinued when the serum potassium concentration is normalized, even if weakness persists. • The concentration of intravenous potassium chloride solution should not exceed 40 mEq/L because of the risk for thrombophlebitis (the use of a central catheter is rarely necessary). • The solution should be given as a continuous infusion that does not exceed 0.3 mEq/kg/h of potassium (i.e., 18 mEq/h for a 60-kg person) because of the high risk for arrhythmia or cardiac arrest associated with faster infusions. • The physician should be aware that hyperkalemia may occur, as there is no true potassium depletion; a reverse shift of potassium from the intracellular to the extracellular space occurs during the resolution of paralytic episode. • A prominent increase in the amplitude of the U wave, triggered by hypokalemia, is associated with a higher susceptibility to the ventricular arrhythmia known as • Large and sharp T waves are a marker of hyperkalemia and may occur during and after recovery; they are associated with a risk for cardiac arrest. • Physiotherapy may help to maintain strength and motor abilities, especially after 40 years of age, when long-lasting muscle weakness is more often seen. • The physiotherapist must be aware of the following peculiarity of periodic paralysis: that sustained effort results in exacerbation of weakness. Therefore, self-managed exercise should be preferred to superimposed physiotherapy [ • Oral intake of potassium salts (10-20 mmol/dose, 3 doses/day) can prevent attacks, especially if the dose of potassium is taken some hours before the usual time of the attack (i.e., a nocturnal dose if crises occur at awakening). • For individuals receiving chronic potassium supplementation for hypoPP, magnesium might be added, which can be helpful to promote renal retention of potassium and, therefore, reduce the potassium dose [ • Typical dosage for acetazolamide in adults is between 125 mg/day and 1000 mg/day (usually 250-500 mg/day), divided into three doses and taken with meals; in children a dose of 5-10 mg/kg/day, divided into three doses and taken with meals, is used. • Acetazolamide treatment: • Is beneficial in approximately 50% of individuals with hypoPP • Has no effect in 30% of affected individuals • May exacerbate hypoPP in individuals with who have a pathogenic variant in • Is beneficial in approximately 50% of individuals with hypoPP • Has no effect in 30% of affected individuals • May exacerbate hypoPP in individuals with who have a pathogenic variant in • In some affected persons, long-lasting interictal weakness may be partly reversed and muscle strength may be improved by acetazolamide treatment [ • Whether acetazolamide treatment prevents or treats myopathy and the resulting fixed weakness that occurs with age is unknown. • Further studies are needed to evaluate the effect of preventive acetazolamide treatment on attack rate, severity-weighted attack rate, long-lasting interictal weakness, and myopathy. • Whether acetazolamide treatment prevents or treats myopathy and the resulting fixed weakness that occurs with age is unknown. • Further studies are needed to evaluate the effect of preventive acetazolamide treatment on attack rate, severity-weighted attack rate, long-lasting interictal weakness, and myopathy. • Common side effects of carbonic anhydrase inhibitors include paresthesia, fatigue, mild, reversible cognitive disturbances and an increased risk of nephrolithiasis. • Is beneficial in approximately 50% of individuals with hypoPP • Has no effect in 30% of affected individuals • May exacerbate hypoPP in individuals with who have a pathogenic variant in • Whether acetazolamide treatment prevents or treats myopathy and the resulting fixed weakness that occurs with age is unknown. • Further studies are needed to evaluate the effect of preventive acetazolamide treatment on attack rate, severity-weighted attack rate, long-lasting interictal weakness, and myopathy. • The dose of dichlorphenamide was 50 mg twice daily for treatment-naıve patients. • Individuals already on dichlorphenamide before the study continued on the same dose during the study. • In those taking acetazolamide before the study, the dose of dichlorphenamide was set at 20% of the acetazolamide dose. • Dose reduction for tolerability was permitted. • The mean dose of dichlorphenamide at week 9 was 82 mg/day. • The most common side effects with dichlorphenamide were paresthesias, cognitive disorder, dysgeusia, headache, fatigue, hypoesthesia, and muscle spasms, generally not requiring discontinuation of dichlorphenamide, and reversible with drug discontinuation. • Because spironolactone is associated with a long half-life for substrate degradation, the individual can become hyperkalemic and weaker, develop cardiac arrhythmias, and suffer from hair loss. Additionally, spironolactone has androgenic side effects. • The modern spironolactone derivate Eplerenone may be preferred because it causes fewer androgenic side effects. In addition, it has a very high repolarizing power, the parameter considered as most relevant for a beneficial effect. • For individuals with hypoPP, potassium supplementation and a potassium-sparing diuretic may be used concomitantly, but potassium levels should be routinely monitored. • An affected person experiencing a paralytic attack must have access to potassium as well as physical assistance. Thus, those with hypoPP should inform their companions or acquaintances of their risk for paralytic attack, especially in a sports or school context, so that they can access appropriate help rapidly in case of an attack. • Falls and injuries from falls are frequent in those with hypoPP (67% of affected individuals age >40 years report such falls and injuries) [ • Strict control of serum potassium concentration • Avoidance of large glucose and salt loads • Low-carbohydrate diet • Maintenance of body temperature and acid-base balance • Careful use of neuromuscular blocking agents and no depolarizing muscle relaxants • Unusually strenuous effort • Excess of carbohydrate-rich meals or sweets • Cold • Stress/excitement/fear • High salt intake • Prolonged immobility • Oral or intravenous glucosteroids • Use of cooling, glucose and/or mannitol infusion, excessive sodium- containing fluids and certain anesthetics such as succinylcholine during anesthesia • Use of alcohol • Molecular genetic testing if the pathogenic variant in the family is known; • Detailed history (with attention to full or incomplete paralytic crises in the past and/or adverse response to glucose infusion, surgery, or general anesthesia) and neurologic examination. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with hypokalemic periodic paralysis (hypoPP), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended. Assessment of respiratory status to detect those individuals who may have early respiratory failure Measurement of serum potassium concentration Cardiac electrophysiologic testing (EKG) to assess for life-threatening cardiac consequences of hypokalemia Assessment for swallowing difficulty Neurologic examination to assess muscle strength in the legs Measurement of the following thyroid functions (see Note): Plasma thyroid-stimulating hormone (TSH) Free thyroxine (FT4) Free triiodothyronine (FT3) In those with long-lasting interictal weakness, consideration of muscle sonography or MRI scan of muscles (e.g. thigh) to evaluate the extent of myopathy [ Consultation with a clinical geneticist and/or genetic counselor Note: (1) Hyperthyroidism may be a trigger for a hypokalemic episode in individuals with hypoPP; (2) thyroid function tests may help to distinguish between hypoPP and TPP in those who have a pathogenic variant in • Assessment of respiratory status to detect those individuals who may have early respiratory failure • Measurement of serum potassium concentration • Cardiac electrophysiologic testing (EKG) to assess for life-threatening cardiac consequences of hypokalemia • Assessment for swallowing difficulty • Neurologic examination to assess muscle strength in the legs • Measurement of the following thyroid functions (see Note): • Plasma thyroid-stimulating hormone (TSH) • Free thyroxine (FT4) • Free triiodothyronine (FT3) • Plasma thyroid-stimulating hormone (TSH) • Free thyroxine (FT4) • Free triiodothyronine (FT3) • In those with long-lasting interictal weakness, consideration of muscle sonography or MRI scan of muscles (e.g. thigh) to evaluate the extent of myopathy [ • Consultation with a clinical geneticist and/or genetic counselor • Plasma thyroid-stimulating hormone (TSH) • Free thyroxine (FT4) • Free triiodothyronine (FT3) ## Treatment of Manifestations For a comprehensive summary of the management of hypokalemic periodic paralysis, see Principles of Treatment for Individuals with HypoPP Strenuous effort; Prolonged immobility; Carbohydrate-rich diet; High sodium diet. Monitor episodes of weakness noting time of day & specific triggers. Provide dietary review/counseling. Shorten/prevent aggravation of the weakness episode. Normalize kalemia. Provide potassium supplementation (oral, or IV if oral impossible or if potassium very low). Avoid glucose intake. Do not use slow-release forms of potassium. Oral potassium: initially, 1 mEq/kg; add 0.3 mEq/kg after 30 min if no improvement IV potassium: 0.3 mEq/kg/h Avoid corticosteroids if possible. Use alpha- or beta adrenergic drugs w/caution, even in local anesthesia or ophthalmology. Kinesiotherapy in case of long-lasting pelvic deficit Adaptive measures: (1) at school & especially for sports; (2) in work setting During a paralytic attack, there is usually no true potassium depletion in the body (unless there are associated digestive or renal losses from another cause), but there is a reversible transfer of potassium from the extracellular to the intracellular space. The global potassium pool (and especially the intracellular pool of the body) is conserved, and the goal of the treatment is to raise the blood potassium level just enough to trigger the shift to repolarization of skeletal muscle membrane, and the liberation of intracellularly sequestered potassium. Treatment may occur in a familial or non-medical setting if the diagnosis is well-established and the affected individual is able to manage paralytic episodes. Rapid recovery is typically possible with oral intake of chloride potassium salts, either as capsules or liquid-containing vials. Aqueous potassium contained in vials may act more rapidly. An initial intake of 1mEq/kg potassium chloride is often used (60 mEq; i.e., 4.5 g of potassium chloride for a 60-kg person). A response (at least partial) should be seen after 30 minutes. If no improvement occurs after 30 minutes, an additional 0.3 mEq/kg can be administered (20 mEq; i.e., 1.5 g of potassium chloride for a 60 kg person). Note: (1) Slow-release forms of potassium should be avoided during a paralytic attack. (2) Potassium ingesting should be followed by oral intake of water (e.g., 100 mL (4 oz) of water for each 20 mEq of potassium). (3) Liquids containing high sugar or sodium content should be avoided. The total dose of potassium taken over a 24-hr period for the treatment of an acute attack should not exceed 200 mEq. During severe paralytic episodes or attacks associated with respiratory, swallowing, or speaking difficulties, or with signs of arrhythmia, the affected individual must be transferred to hospital. In the case of very low serum potassium and severe symptoms (airway compromise with ictal dysphagia, accessory respiratory muscle paralysis, arrhythmia associated with hypokalemia), intravenous potassium treatment should be initiated. Note the following critical points: The concentration of intravenous potassium chloride solution should not exceed 40 mEq/L because of the risk for thrombophlebitis (the use of a central catheter is rarely necessary). The solution should be given as a continuous infusion that does not exceed 0.3 mEq/kg/h of potassium (i.e., 18 mEq/h for a 60-kg person) because of the high risk for arrhythmia or cardiac arrest associated with faster infusions. The physician should be aware that hyperkalemia may occur, as there is no true potassium depletion; a reverse shift of potassium from the intracellular to the extracellular space occurs during the resolution of paralytic episode. A Y-branched peripheral venous line containing potassium chloride should be branched to a perfusion of mannitol or normal saline (avoid glucose-containing solutions, which may enhance hypokalemia). To prevent cardiac arrhythmias, it is important to monitor the EKG before, during, and after treatment and to perform repeat assessments of blood potassium concentration: A prominent increase in the amplitude of the U wave, triggered by hypokalemia, is associated with a higher susceptibility to the ventricular arrhythmia known as Large and sharp T waves are a marker of hyperkalemia and may occur during and after recovery; they are associated with a risk for cardiac arrest. Monitoring of EKG and blood potassium concentration must be continued some hours after normalization of the serum potassium concentration, in order to detect a relapse of hypokalemia or the development of hyperkalemia secondary to excessive potassium load. Administration of supplemental potassium must be discontinued when the serum potassium concentration is normalized, even if weakness persists. Physiotherapy may help to maintain strength and motor abilities, especially after 40 years of age, when long-lasting muscle weakness is more often seen. The physiotherapist must be aware of the following peculiarity of periodic paralysis: that sustained effort results in exacerbation of weakness. Therefore, self-managed exercise should be preferred to superimposed physiotherapy [ • Strenuous effort; • Prolonged immobility; • Carbohydrate-rich diet; • High sodium diet. • Monitor episodes of weakness noting time of day & specific triggers. • Provide dietary review/counseling. • Shorten/prevent aggravation of the weakness episode. • Normalize kalemia. • Provide potassium supplementation (oral, or IV if oral impossible or if potassium very low). • Avoid glucose intake. • Do not use slow-release forms of potassium. • Oral potassium: initially, 1 mEq/kg; add 0.3 mEq/kg after 30 min if no improvement • IV potassium: 0.3 mEq/kg/h • Avoid corticosteroids if possible. • Use alpha- or beta adrenergic drugs w/caution, even in local anesthesia or ophthalmology. • Kinesiotherapy in case of long-lasting pelvic deficit • Adaptive measures: (1) at school & especially for sports; (2) in work setting • Treatment may occur in a familial or non-medical setting if the diagnosis is well-established and the affected individual is able to manage paralytic episodes. • Rapid recovery is typically possible with oral intake of chloride potassium salts, either as capsules or liquid-containing vials. Aqueous potassium contained in vials may act more rapidly. • An initial intake of 1mEq/kg potassium chloride is often used (60 mEq; i.e., 4.5 g of potassium chloride for a 60-kg person). • A response (at least partial) should be seen after 30 minutes. If no improvement occurs after 30 minutes, an additional 0.3 mEq/kg can be administered (20 mEq; i.e., 1.5 g of potassium chloride for a 60 kg person). • The total dose of potassium taken over a 24-hr period for the treatment of an acute attack should not exceed 200 mEq. • During severe paralytic episodes or attacks associated with respiratory, swallowing, or speaking difficulties, or with signs of arrhythmia, the affected individual must be transferred to hospital. • In the case of very low serum potassium and severe symptoms (airway compromise with ictal dysphagia, accessory respiratory muscle paralysis, arrhythmia associated with hypokalemia), intravenous potassium treatment should be initiated. Note the following critical points: • The concentration of intravenous potassium chloride solution should not exceed 40 mEq/L because of the risk for thrombophlebitis (the use of a central catheter is rarely necessary). • The solution should be given as a continuous infusion that does not exceed 0.3 mEq/kg/h of potassium (i.e., 18 mEq/h for a 60-kg person) because of the high risk for arrhythmia or cardiac arrest associated with faster infusions. • The physician should be aware that hyperkalemia may occur, as there is no true potassium depletion; a reverse shift of potassium from the intracellular to the extracellular space occurs during the resolution of paralytic episode. • The concentration of intravenous potassium chloride solution should not exceed 40 mEq/L because of the risk for thrombophlebitis (the use of a central catheter is rarely necessary). • The solution should be given as a continuous infusion that does not exceed 0.3 mEq/kg/h of potassium (i.e., 18 mEq/h for a 60-kg person) because of the high risk for arrhythmia or cardiac arrest associated with faster infusions. • The physician should be aware that hyperkalemia may occur, as there is no true potassium depletion; a reverse shift of potassium from the intracellular to the extracellular space occurs during the resolution of paralytic episode. • A Y-branched peripheral venous line containing potassium chloride should be branched to a perfusion of mannitol or normal saline (avoid glucose-containing solutions, which may enhance hypokalemia). • To prevent cardiac arrhythmias, it is important to monitor the EKG before, during, and after treatment and to perform repeat assessments of blood potassium concentration: • A prominent increase in the amplitude of the U wave, triggered by hypokalemia, is associated with a higher susceptibility to the ventricular arrhythmia known as • Large and sharp T waves are a marker of hyperkalemia and may occur during and after recovery; they are associated with a risk for cardiac arrest. • A prominent increase in the amplitude of the U wave, triggered by hypokalemia, is associated with a higher susceptibility to the ventricular arrhythmia known as • Large and sharp T waves are a marker of hyperkalemia and may occur during and after recovery; they are associated with a risk for cardiac arrest. • Monitoring of EKG and blood potassium concentration must be continued some hours after normalization of the serum potassium concentration, in order to detect a relapse of hypokalemia or the development of hyperkalemia secondary to excessive potassium load. • Administration of supplemental potassium must be discontinued when the serum potassium concentration is normalized, even if weakness persists. • The concentration of intravenous potassium chloride solution should not exceed 40 mEq/L because of the risk for thrombophlebitis (the use of a central catheter is rarely necessary). • The solution should be given as a continuous infusion that does not exceed 0.3 mEq/kg/h of potassium (i.e., 18 mEq/h for a 60-kg person) because of the high risk for arrhythmia or cardiac arrest associated with faster infusions. • The physician should be aware that hyperkalemia may occur, as there is no true potassium depletion; a reverse shift of potassium from the intracellular to the extracellular space occurs during the resolution of paralytic episode. • A prominent increase in the amplitude of the U wave, triggered by hypokalemia, is associated with a higher susceptibility to the ventricular arrhythmia known as • Large and sharp T waves are a marker of hyperkalemia and may occur during and after recovery; they are associated with a risk for cardiac arrest. • Physiotherapy may help to maintain strength and motor abilities, especially after 40 years of age, when long-lasting muscle weakness is more often seen. • The physiotherapist must be aware of the following peculiarity of periodic paralysis: that sustained effort results in exacerbation of weakness. Therefore, self-managed exercise should be preferred to superimposed physiotherapy [ ## Prevention of Primary Manifestations Preventive treatment is intended to decrease the frequency and intensity of paralytic attacks. Triggering factors need to be identified and, if possible, avoided (see Oral intake of potassium salts (10-20 mmol/dose, 3 doses/day) can prevent attacks, especially if the dose of potassium is taken some hours before the usual time of the attack (i.e., a nocturnal dose if crises occur at awakening). For individuals receiving chronic potassium supplementation for hypoPP, magnesium might be added, which can be helpful to promote renal retention of potassium and, therefore, reduce the potassium dose [ However, there is no standardized treatment regimen and no consensus as to when to start treatment with acetazolamide. Typical dosage for acetazolamide in adults is between 125 mg/day and 1000 mg/day (usually 250-500 mg/day), divided into three doses and taken with meals; in children a dose of 5-10 mg/kg/day, divided into three doses and taken with meals, is used. Acetazolamide treatment: Is beneficial in approximately 50% of individuals with hypoPP Has no effect in 30% of affected individuals May exacerbate hypoPP in individuals with who have a pathogenic variant in In some affected persons, long-lasting interictal weakness may be partly reversed and muscle strength may be improved by acetazolamide treatment [ Whether acetazolamide treatment prevents or treats myopathy and the resulting fixed weakness that occurs with age is unknown. Further studies are needed to evaluate the effect of preventive acetazolamide treatment on attack rate, severity-weighted attack rate, long-lasting interictal weakness, and myopathy. Common side effects of carbonic anhydrase inhibitors include paresthesia, fatigue, mild, reversible cognitive disturbances and an increased risk of nephrolithiasis. While randomized controlled trials of dichlorphenamide were performed in adults, the same approach is taken for children; dose adjustments may be required based on age. These studies demonstrated a significant reduction in the frequency and severity of the attacks. During a 52-week extension, in which all remaining participants received open-label dichlorphenamide, continued improvement in outcomes was observed in both placebo and dichlorphenamide groups. The dose of dichlorphenamide was 50 mg twice daily for treatment-naıve patients. Individuals already on dichlorphenamide before the study continued on the same dose during the study. In those taking acetazolamide before the study, the dose of dichlorphenamide was set at 20% of the acetazolamide dose. Dose reduction for tolerability was permitted. The mean dose of dichlorphenamide at week 9 was 82 mg/day. The most common side effects with dichlorphenamide were paresthesias, cognitive disorder, dysgeusia, headache, fatigue, hypoesthesia, and muscle spasms, generally not requiring discontinuation of dichlorphenamide, and reversible with drug discontinuation. In the recent study of diclorphenamide [ Because spironolactone is associated with a long half-life for substrate degradation, the individual can become hyperkalemic and weaker, develop cardiac arrhythmias, and suffer from hair loss. Additionally, spironolactone has androgenic side effects. The modern spironolactone derivate Eplerenone may be preferred because it causes fewer androgenic side effects. In addition, it has a very high repolarizing power, the parameter considered as most relevant for a beneficial effect. For individuals with hypoPP, potassium supplementation and a potassium-sparing diuretic may be used concomitantly, but potassium levels should be routinely monitored. • Oral intake of potassium salts (10-20 mmol/dose, 3 doses/day) can prevent attacks, especially if the dose of potassium is taken some hours before the usual time of the attack (i.e., a nocturnal dose if crises occur at awakening). • For individuals receiving chronic potassium supplementation for hypoPP, magnesium might be added, which can be helpful to promote renal retention of potassium and, therefore, reduce the potassium dose [ • Typical dosage for acetazolamide in adults is between 125 mg/day and 1000 mg/day (usually 250-500 mg/day), divided into three doses and taken with meals; in children a dose of 5-10 mg/kg/day, divided into three doses and taken with meals, is used. • Acetazolamide treatment: • Is beneficial in approximately 50% of individuals with hypoPP • Has no effect in 30% of affected individuals • May exacerbate hypoPP in individuals with who have a pathogenic variant in • Is beneficial in approximately 50% of individuals with hypoPP • Has no effect in 30% of affected individuals • May exacerbate hypoPP in individuals with who have a pathogenic variant in • In some affected persons, long-lasting interictal weakness may be partly reversed and muscle strength may be improved by acetazolamide treatment [ • Whether acetazolamide treatment prevents or treats myopathy and the resulting fixed weakness that occurs with age is unknown. • Further studies are needed to evaluate the effect of preventive acetazolamide treatment on attack rate, severity-weighted attack rate, long-lasting interictal weakness, and myopathy. • Whether acetazolamide treatment prevents or treats myopathy and the resulting fixed weakness that occurs with age is unknown. • Further studies are needed to evaluate the effect of preventive acetazolamide treatment on attack rate, severity-weighted attack rate, long-lasting interictal weakness, and myopathy. • Common side effects of carbonic anhydrase inhibitors include paresthesia, fatigue, mild, reversible cognitive disturbances and an increased risk of nephrolithiasis. • Is beneficial in approximately 50% of individuals with hypoPP • Has no effect in 30% of affected individuals • May exacerbate hypoPP in individuals with who have a pathogenic variant in • Whether acetazolamide treatment prevents or treats myopathy and the resulting fixed weakness that occurs with age is unknown. • Further studies are needed to evaluate the effect of preventive acetazolamide treatment on attack rate, severity-weighted attack rate, long-lasting interictal weakness, and myopathy. • The dose of dichlorphenamide was 50 mg twice daily for treatment-naıve patients. • Individuals already on dichlorphenamide before the study continued on the same dose during the study. • In those taking acetazolamide before the study, the dose of dichlorphenamide was set at 20% of the acetazolamide dose. • Dose reduction for tolerability was permitted. • The mean dose of dichlorphenamide at week 9 was 82 mg/day. • The most common side effects with dichlorphenamide were paresthesias, cognitive disorder, dysgeusia, headache, fatigue, hypoesthesia, and muscle spasms, generally not requiring discontinuation of dichlorphenamide, and reversible with drug discontinuation. • Because spironolactone is associated with a long half-life for substrate degradation, the individual can become hyperkalemic and weaker, develop cardiac arrhythmias, and suffer from hair loss. Additionally, spironolactone has androgenic side effects. • The modern spironolactone derivate Eplerenone may be preferred because it causes fewer androgenic side effects. In addition, it has a very high repolarizing power, the parameter considered as most relevant for a beneficial effect. • For individuals with hypoPP, potassium supplementation and a potassium-sparing diuretic may be used concomitantly, but potassium levels should be routinely monitored. ## Prevention of Secondary Complications Creating a safe environment, getting help in case of paralytic attack, and preventing falls and accidents are critical [ An affected person experiencing a paralytic attack must have access to potassium as well as physical assistance. Thus, those with hypoPP should inform their companions or acquaintances of their risk for paralytic attack, especially in a sports or school context, so that they can access appropriate help rapidly in case of an attack. Falls and injuries from falls are frequent in those with hypoPP (67% of affected individuals age >40 years report such falls and injuries) [ General guidelines for perioperative care include the following: Strict control of serum potassium concentration Avoidance of large glucose and salt loads Low-carbohydrate diet Maintenance of body temperature and acid-base balance Careful use of neuromuscular blocking agents and no depolarizing muscle relaxants • An affected person experiencing a paralytic attack must have access to potassium as well as physical assistance. Thus, those with hypoPP should inform their companions or acquaintances of their risk for paralytic attack, especially in a sports or school context, so that they can access appropriate help rapidly in case of an attack. • Falls and injuries from falls are frequent in those with hypoPP (67% of affected individuals age >40 years report such falls and injuries) [ • Strict control of serum potassium concentration • Avoidance of large glucose and salt loads • Low-carbohydrate diet • Maintenance of body temperature and acid-base balance • Careful use of neuromuscular blocking agents and no depolarizing muscle relaxants ## Surveillance The frequency of consultations needs to be adapted to the individual's signs and symptoms and response to preventive treatment. Neurologic examination with attention to muscle strength in the legs should be performed, in order to detect long-lasting interictal weakness associated with myopathy. For those individuals who take acetazolamide the following parameters should be evaluated every three months: complete blood count, electrolytes, glucose, uric acid, and liver enzyme levels. Renal ultrasound should be performed annually. ## Agents/Circumstances to Avoid Avoid anything that can trigger paralytic attacks in the individual case, including the following: Unusually strenuous effort Excess of carbohydrate-rich meals or sweets Cold Stress/excitement/fear High salt intake Prolonged immobility Oral or intravenous glucosteroids Use of cooling, glucose and/or mannitol infusion, excessive sodium- containing fluids and certain anesthetics such as succinylcholine during anesthesia Use of alcohol • Unusually strenuous effort • Excess of carbohydrate-rich meals or sweets • Cold • Stress/excitement/fear • High salt intake • Prolonged immobility • Oral or intravenous glucosteroids • Use of cooling, glucose and/or mannitol infusion, excessive sodium- containing fluids and certain anesthetics such as succinylcholine during anesthesia • Use of alcohol ## 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 at risk for unexpected acute paralysis and/or possibly malignant hyperthermia and who would benefit from prompt initiation of treatment and preventive measures. Evaluations include: Molecular genetic testing if the pathogenic variant in the family is known; Detailed history (with attention to full or incomplete paralytic crises in the past and/or adverse response to glucose infusion, surgery, or general anesthesia) and neurologic examination. See • Molecular genetic testing if the pathogenic variant in the family is known; • Detailed history (with attention to full or incomplete paralytic crises in the past and/or adverse response to glucose infusion, surgery, or general anesthesia) and neurologic examination. ## Pregnancy Management In general, there is no increased risk for paretic attacks in pregnancy. While in utero acetazolamide exposure is reported to cause limb defects in rodents, acetazolamide therapy during human pregnancy does not appear to increase the risk for fetal malformations [ See ## Therapies Under Investigation Recent studies in mouse models of hypoPP with both Search ## Genetic Counseling Hypokalemic periodic paralysis (hypoPP) is inherited in an autosomal dominant manner. Most individuals diagnosed with The overall proportion of hypoPP cases caused by a Recommendations for the evaluation of parents of an individual with an apparent A search for a history of full or incomplete paralytic crises in the past and/or adverse response to glucose infusion, surgery, or general anesthesia Neurologic examination with evaluation of muscle strength Molecular genetic testing if the hypoPP-related pathogenic variant has been identified in the proband. If the pathogenic variant found in the proband cannot detected in leukocyte DNA of either parent, possible explanations include a If clinical testing of both parents is inconclusive and predictive molecular genetic testing is not possible (i.e., if a pathogenic variant has not been identified in the proband), both parents may need to be considered at risk for complications, including unexpected acute paralysis and hypokalemia, and possibly malignant hyperthermia associated with anesthesia. If a parent is affected and/or is known to have the pathogenic variant identified in the proband, the risk to each sib of inheriting the If the If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for hypoPP because of the possibility of reduced penetrance in a 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 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. • Most individuals diagnosed with • The overall proportion of hypoPP cases caused by a • Recommendations for the evaluation of parents of an individual with an apparent • A search for a history of full or incomplete paralytic crises in the past and/or adverse response to glucose infusion, surgery, or general anesthesia • Neurologic examination with evaluation of muscle strength • Molecular genetic testing if the hypoPP-related pathogenic variant has been identified in the proband. • A search for a history of full or incomplete paralytic crises in the past and/or adverse response to glucose infusion, surgery, or general anesthesia • Neurologic examination with evaluation of muscle strength • Molecular genetic testing if the hypoPP-related pathogenic variant has been identified in the proband. • If the pathogenic variant found in the proband cannot detected in leukocyte DNA of either parent, possible explanations include a • If clinical testing of both parents is inconclusive and predictive molecular genetic testing is not possible (i.e., if a pathogenic variant has not been identified in the proband), both parents may need to be considered at risk for complications, including unexpected acute paralysis and hypokalemia, and possibly malignant hyperthermia associated with anesthesia. • A search for a history of full or incomplete paralytic crises in the past and/or adverse response to glucose infusion, surgery, or general anesthesia • Neurologic examination with evaluation of muscle strength • Molecular genetic testing if the hypoPP-related pathogenic variant has been identified in the proband. • If a parent is affected and/or is known to have the pathogenic variant identified in the proband, the risk to each sib of inheriting the • If the • If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for hypoPP because of the possibility of reduced penetrance in a 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 Hypokalemic periodic paralysis (hypoPP) is inherited in an autosomal dominant manner. ## Risk to Family Members Most individuals diagnosed with The overall proportion of hypoPP cases caused by a Recommendations for the evaluation of parents of an individual with an apparent A search for a history of full or incomplete paralytic crises in the past and/or adverse response to glucose infusion, surgery, or general anesthesia Neurologic examination with evaluation of muscle strength Molecular genetic testing if the hypoPP-related pathogenic variant has been identified in the proband. If the pathogenic variant found in the proband cannot detected in leukocyte DNA of either parent, possible explanations include a If clinical testing of both parents is inconclusive and predictive molecular genetic testing is not possible (i.e., if a pathogenic variant has not been identified in the proband), both parents may need to be considered at risk for complications, including unexpected acute paralysis and hypokalemia, and possibly malignant hyperthermia associated with anesthesia. If a parent is affected and/or is known to have the pathogenic variant identified in the proband, the risk to each sib of inheriting the If the If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for hypoPP because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism. • Most individuals diagnosed with • The overall proportion of hypoPP cases caused by a • Recommendations for the evaluation of parents of an individual with an apparent • A search for a history of full or incomplete paralytic crises in the past and/or adverse response to glucose infusion, surgery, or general anesthesia • Neurologic examination with evaluation of muscle strength • Molecular genetic testing if the hypoPP-related pathogenic variant has been identified in the proband. • A search for a history of full or incomplete paralytic crises in the past and/or adverse response to glucose infusion, surgery, or general anesthesia • Neurologic examination with evaluation of muscle strength • Molecular genetic testing if the hypoPP-related pathogenic variant has been identified in the proband. • If the pathogenic variant found in the proband cannot detected in leukocyte DNA of either parent, possible explanations include a • If clinical testing of both parents is inconclusive and predictive molecular genetic testing is not possible (i.e., if a pathogenic variant has not been identified in the proband), both parents may need to be considered at risk for complications, including unexpected acute paralysis and hypokalemia, and possibly malignant hyperthermia associated with anesthesia. • A search for a history of full or incomplete paralytic crises in the past and/or adverse response to glucose infusion, surgery, or general anesthesia • Neurologic examination with evaluation of muscle strength • Molecular genetic testing if the hypoPP-related pathogenic variant has been identified in the proband. • If a parent is affected and/or is known to have the pathogenic variant identified in the proband, the risk to each sib of inheriting the • If the • If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for hypoPP because of the possibility of reduced penetrance in a 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 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 Canada c/o DRK-Kliniken Berlin \| Mitte Drontheimer Straße 39 Berlin 13359 Germany Joachim Sproß Im Moos 4 Freiburg Germany United Kingdom • • • • • • Canada • • • c/o DRK-Kliniken Berlin \| Mitte • Drontheimer Straße 39 • Berlin 13359 • Germany • • • Joachim Sproß • Im Moos 4 • Freiburg • Germany • • • • • United Kingdom • ## Molecular Genetics Hypokalemic Periodic Paralysis: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Hypokalemic Periodic Paralysis ( The two genes associated with primary hypoPP, The common etiology for weakness in an episode of hypoPP is a failure to maintain the resting potential in low K In all forms of periodic paralysis, ictal paresis is caused by depolarization of the muscle sarcolemma, which in turn causes sodium channel inactivation and reduced fiber excitability. This depolarization is caused by a pathogenic variant in voltage-gated cation channels, i.e. most often Both hypoPP and normoPP are caused by single pathogenic variants in positively charged residues (i.e., gating charges) in the S4 transmembrane segment of the voltage sensor of Nav 1.4 or Cav 1.1. Pathogenic variants of the outermost gating charges (R1 and R2) cause hypoPP by creating a pathogenic gating pore in the voltage sensor through which cations leak in the resting state. Pathogenic variants of the third gating charge (R3) cause normoPP by a cation leak both in activated and inactivated states (see The protein domain location of pathogenic variants associated with disorders correlates between Cav1.1 and Nav1.4 (see HypoPP Cav1.1: outermost gating charges R1 or R2 of domains II, III, and IV Nav1.4: outer arginine residues of S4 (R1 or R2) in domains I, II, or III NormoPP Cav1.1: one missense corresponds to a Nav1.4 missense deeper in S4 compared to hypoPP variants Nav1.4: deeper in S4 compared to hypoPP variants Variants listed in the table have been provided by the authors. GeneReviews follows the standard naming conventions of the Human Genome Variation Society ( Variants listed in the table have been provided by the authors. HypoPP-causing variants in Nav 1.4 S4 segments create an abnormal gating pore current; i. e., an accessory ionic transmembrane permeation pathway through the aqueous environment of S4 segment [ • HypoPP • Cav1.1: outermost gating charges R1 or R2 of domains II, III, and IV • Nav1.4: outer arginine residues of S4 (R1 or R2) in domains I, II, or III • Cav1.1: outermost gating charges R1 or R2 of domains II, III, and IV • Nav1.4: outer arginine residues of S4 (R1 or R2) in domains I, II, or III • NormoPP • Cav1.1: one missense corresponds to a Nav1.4 missense deeper in S4 compared to hypoPP variants • Nav1.4: deeper in S4 compared to hypoPP variants • Cav1.1: one missense corresponds to a Nav1.4 missense deeper in S4 compared to hypoPP variants • Nav1.4: deeper in S4 compared to hypoPP variants • Cav1.1: outermost gating charges R1 or R2 of domains II, III, and IV • Nav1.4: outer arginine residues of S4 (R1 or R2) in domains I, II, or III • Cav1.1: one missense corresponds to a Nav1.4 missense deeper in S4 compared to hypoPP variants • Nav1.4: deeper in S4 compared to hypoPP variants ## Molecular Pathogenesis The two genes associated with primary hypoPP, The common etiology for weakness in an episode of hypoPP is a failure to maintain the resting potential in low K In all forms of periodic paralysis, ictal paresis is caused by depolarization of the muscle sarcolemma, which in turn causes sodium channel inactivation and reduced fiber excitability. This depolarization is caused by a pathogenic variant in voltage-gated cation channels, i.e. most often Both hypoPP and normoPP are caused by single pathogenic variants in positively charged residues (i.e., gating charges) in the S4 transmembrane segment of the voltage sensor of Nav 1.4 or Cav 1.1. Pathogenic variants of the outermost gating charges (R1 and R2) cause hypoPP by creating a pathogenic gating pore in the voltage sensor through which cations leak in the resting state. Pathogenic variants of the third gating charge (R3) cause normoPP by a cation leak both in activated and inactivated states (see The protein domain location of pathogenic variants associated with disorders correlates between Cav1.1 and Nav1.4 (see HypoPP Cav1.1: outermost gating charges R1 or R2 of domains II, III, and IV Nav1.4: outer arginine residues of S4 (R1 or R2) in domains I, II, or III NormoPP Cav1.1: one missense corresponds to a Nav1.4 missense deeper in S4 compared to hypoPP variants Nav1.4: deeper in S4 compared to hypoPP variants Variants listed in the table have been provided by the authors. GeneReviews follows the standard naming conventions of the Human Genome Variation Society ( Variants listed in the table have been provided by the authors. HypoPP-causing variants in Nav 1.4 S4 segments create an abnormal gating pore current; i. e., an accessory ionic transmembrane permeation pathway through the aqueous environment of S4 segment [ • HypoPP • Cav1.1: outermost gating charges R1 or R2 of domains II, III, and IV • Nav1.4: outer arginine residues of S4 (R1 or R2) in domains I, II, or III • Cav1.1: outermost gating charges R1 or R2 of domains II, III, and IV • Nav1.4: outer arginine residues of S4 (R1 or R2) in domains I, II, or III • NormoPP • Cav1.1: one missense corresponds to a Nav1.4 missense deeper in S4 compared to hypoPP variants • Nav1.4: deeper in S4 compared to hypoPP variants • Cav1.1: one missense corresponds to a Nav1.4 missense deeper in S4 compared to hypoPP variants • Nav1.4: deeper in S4 compared to hypoPP variants • Cav1.1: outermost gating charges R1 or R2 of domains II, III, and IV • Nav1.4: outer arginine residues of S4 (R1 or R2) in domains I, II, or III • Cav1.1: one missense corresponds to a Nav1.4 missense deeper in S4 compared to hypoPP variants • Nav1.4: deeper in S4 compared to hypoPP variants ## Variants listed in the table have been provided by the authors. GeneReviews follows the standard naming conventions of the Human Genome Variation Society ( ## Variants listed in the table have been provided by the authors. HypoPP-causing variants in Nav 1.4 S4 segments create an abnormal gating pore current; i. e., an accessory ionic transmembrane permeation pathway through the aqueous environment of S4 segment [ ## References ## Literature Cited ## Chapter Notes This work was supported by: the German Research Foundation (DFG), a network of the IHP Program funded by the European Community; the non-profit Hertie Foundation; the IonNeurONet of German Ministry of Research (BMBF); the German Muscle Society (DGM); and the Else-Kröner-Fresenius Foundation. Marianne Arzel-Hézode, MD; Groupe Hospitalier Pitié-Salpêtrière (2014-2018)Saïd Bendahhou, PhD; Université Nice Sophia Antipolis (2014-2018)Bertrand Fontaine, MD, PhD; Groupe Hospitalier Pitié-Salpêtrière (2002-2018)Emmanuel Fournier, MD, PhD; Groupe Hospitalier Pitié-Salpêtrière (2014-2018)Jérôme Franques, MD; Hôpital de la Timone (2014-2018)Bernard Hainque, PharmD, PhD; Groupe Hospitalier Pitié-Salpêtrière (2002-2018)Frank Lehmann-Horn, MD, PhD, MS (2018 )Philippe Lory, PhD; Université de Montpellier (2014-2018)Sophie Nicole, PhD; Groupe Hospitalier Pitié-Salpêtrière (2014-2018)Damien Sternberg, MD, PhD; Groupe Hospitalier Pitié-Salpêtrière (2002-2018)Nacira Tabti, MD, PhD; Assistance Publique - Hôpitaux de Paris (2002-2014)Savine Vicart, MD; Groupe Hospitalier Pitié-Salpêtrière (2014-2018)Frank Weber, MD, PhD (2018-present) Professor Lehmann-Horn died in May 2018 after a long illness. 26 July 2018 (ha) Comprehensive update posted live 31 July 2014 (me) Comprehensive update posted live 28 April 2009 (me) Comprehensive updated posted live 4 March 2008 (cd) Revision: mutation scanning for 4 August 2006 (me) Comprehensive update posted live 19 May 2004 (me) Comprehensive update posted live 30 April 2002 (me) Review posted live 20 November 2001 (bf) Original submission • 26 July 2018 (ha) Comprehensive update posted live • 31 July 2014 (me) Comprehensive update posted live • 28 April 2009 (me) Comprehensive updated posted live • 4 March 2008 (cd) Revision: mutation scanning for • 4 August 2006 (me) Comprehensive update posted live • 19 May 2004 (me) Comprehensive update posted live • 30 April 2002 (me) Review posted live • 20 November 2001 (bf) Original submission ## Acknowledgments This work was supported by: the German Research Foundation (DFG), a network of the IHP Program funded by the European Community; the non-profit Hertie Foundation; the IonNeurONet of German Ministry of Research (BMBF); the German Muscle Society (DGM); and the Else-Kröner-Fresenius Foundation. ## Author History Marianne Arzel-Hézode, MD; Groupe Hospitalier Pitié-Salpêtrière (2014-2018)Saïd Bendahhou, PhD; Université Nice Sophia Antipolis (2014-2018)Bertrand Fontaine, MD, PhD; Groupe Hospitalier Pitié-Salpêtrière (2002-2018)Emmanuel Fournier, MD, PhD; Groupe Hospitalier Pitié-Salpêtrière (2014-2018)Jérôme Franques, MD; Hôpital de la Timone (2014-2018)Bernard Hainque, PharmD, PhD; Groupe Hospitalier Pitié-Salpêtrière (2002-2018)Frank Lehmann-Horn, MD, PhD, MS (2018 )Philippe Lory, PhD; Université de Montpellier (2014-2018)Sophie Nicole, PhD; Groupe Hospitalier Pitié-Salpêtrière (2014-2018)Damien Sternberg, MD, PhD; Groupe Hospitalier Pitié-Salpêtrière (2002-2018)Nacira Tabti, MD, PhD; Assistance Publique - Hôpitaux de Paris (2002-2014)Savine Vicart, MD; Groupe Hospitalier Pitié-Salpêtrière (2014-2018)Frank Weber, MD, PhD (2018-present) Professor Lehmann-Horn died in May 2018 after a long illness. ## Revision History 26 July 2018 (ha) Comprehensive update posted live 31 July 2014 (me) Comprehensive update posted live 28 April 2009 (me) Comprehensive updated posted live 4 March 2008 (cd) Revision: mutation scanning for 4 August 2006 (me) Comprehensive update posted live 19 May 2004 (me) Comprehensive update posted live 30 April 2002 (me) Review posted live 20 November 2001 (bf) Original submission • 26 July 2018 (ha) Comprehensive update posted live • 31 July 2014 (me) Comprehensive update posted live • 28 April 2009 (me) Comprehensive updated posted live • 4 March 2008 (cd) Revision: mutation scanning for • 4 August 2006 (me) Comprehensive update posted live • 19 May 2004 (me) Comprehensive update posted live • 30 April 2002 (me) Review posted live • 20 November 2001 (bf) Original submission Cav 1.1 Sketch of the voltage-gated calcium channel of skeletal muscle, Cav1.1 enocoded by Modified from NaV 1.4 The voltage-gated sodium channel of skeletal muscle, NaV1.4 encoded by Modified from	[ "S Bendahhou, TR Cummins, AF Hahn, S Langlois, SG Waxman, LJ Ptácek. A double mutation in families with periodic paralysis defines new aspects of sodium channel slow inactivation.. J Clin Invest 2000;106:431-8", "A Bergareche, M Bednarz, E Sánchez, CE Krebs, J Ruiz-Martinez, P De La Riva, V Makarov, A Gorostidi, K Jurkat-Rott, JF Marti-Masso, C Paisán-Ruiz. SCN4A pore mutation pathogenetically contributes to autosomal dominant essential tremor and may increase susceptibility to epilepsy.. Hum Mol Genet. 2015;24:7111-20", "SC Cannon. An atypical CaV1.1 mutation reveals a common mechanism for hypokalemic periodic paralysis. J Gen Physiol. 2017;149:1061-4", "D Carpenter, C Ringrose, V Leo, A Morris, RL Robinson, PJ Halsall, PM Hopkins, MA Shaw. The role of CACNA1S in predisposition to malignant hyperthermia.. BMC Med Genet. 2009;10:104", "D Cavel-Greant, F Lehmann-Horn, K Jurkat-Rott. The impact of permanent muscle weakness on quality of life in periodic paralysis: a survey of 66 patients.. Acta Myol. 2012;31:126-33", "S Chabrier, N Monnier, J Lunardi. Early onset of hypokalaemic periodic paralysis caused by a novel mutation of the CACNA1S gene.. J Med Genet. 2008;45:686-8", "MR Dias da Silva, JM Cerutti, CH Tengan, GK Furuzawa, TC Vieira, AA Gabbai, RM Maciel. Mutations linked to familial hypokalaemic periodic paralysis in the calcium channel alpha1 subunit gene (Cav1.1) are not associated with thyrotoxic hypokalaemic periodic paralysis.. Clin Endocrinol (Oxf) 2002;56:367-75", "C Fan, F Lehmann-Horn, MA Weber, M Bednarz, JR Groome, MK Jonsson, K Jurkat-Rott. Transient compartment-like syndrome and normokalaemic periodic paralysis due to a Ca(v)1.1 mutation.. Brain. 2013;136:3775-86", "E Fournier, M Arzel, D Sternberg, S Vicart, P Laforet, B Eymard, JC Willer, N Tabti, B Fontaine. Electromyography guides toward subgroups of mutations in muscle channelopathies.. Ann Neurol. 2004;56:650-61", "DG Francis, V Rybalchenko, A Struyk, SC Cannon. Leaky sodium channels from voltage sensor mutations in periodic paralysis, but not paramyotonia.. Neurology. 2011;76:1635-41", "SL Greig. Dichlorphenamide: a review in primary periodic paralyses.. Drugs. 2016;76:501-7", "JR Groome, F Lehmann-Horn, C Fan, M Wolf, V Winston, L Merlini, K Jurkat-Rott. NaV1.4 mutations cause hypokalaemic periodic paralysis by disrupting IIIS4 movement during recovery.. Brain 2014;137:998-1008", "A Horga, DL Raja Rayan, E Matthews, R Sud, D Fialho, SC Durran, JA Burge, S Portaro, MB Davis, A Haworth, MG Hanna. Prevalence study of genetically defined skeletal muscle channelopathies in England.. Neurology. 2013;80:1472-5", "D Jiang, TMG el-Din, C Ing, P Lu, R Pomès, N Zheng, WA Catterall. Structural basis for gating pore current in periodic paralysis.. Nature 2018;557:590-4", "K Jurkat-Rott, J Groome, F Lehmann-Horn. Pathophysiological role of omega pore current in channelopathies.. Front Pharmacol. 2012;3:112", "K Jurkat-Rott, B Holzherr, M Fauler, F Lehmann-Horn. Sodium channelopathies of skeletal muscle result from gain or loss of function.. Pflugers Arch. 2010;460:239-48", "K Jurkat-Rott, F Lehmann-Horn. Human muscle voltage gated ion channels and hereditary disease.. Curr Opin Pharmacol 2001;1:280-7", "K Jurkat-Rott, F Lehmann-Horn. State of the art in hereditary muscle channelopathies.. Acta Myol 2010;29:343-50", "K Jurkat-Rott, N Mitrovic, C Hang, A Kouzmekine, P Iaizzo, J Herzog, H Lerche, S Nicole, J Vale-Santos, D Chauveau, B Fontaine, F Lehmann-Horn. Voltage-sensor sodium channel mutations cause hypokalemic periodic paralysis type 2 by enhanced inactivation and reduced current.. Proc Natl Acad Sci U S A. 2000;97:9549-54", "K Jurkat-Rott, MA Weber, M Fauler, XH Guo, BD Holzherr, A Paczulla, N Nordsborg, W Joechle, F. K Lehmann-Horn. +-dependent paradoxical membrane depolarization and Na+ overload, major and reversible contributors to weakness by ion channel leaks.. Proc Natl Acad Sci U S A. 2009;106:4036-41", "JB Kim, KY Lee, JK Hur. A Korean family of hypokalemic periodic paralysis with mutation in a voltage-gated calcium channel (R1239G).. J Korean Med Sci. 2005;20:162-5", "AW Kung, KS Lau, GC Fong, V Chan. Association of novel single nucleotide polymorphisms in the calcium channel alpha 1 subunit gene (Ca(v)1.1) and thyrotoxic periodic paralysis.. J Clin Endocrinol Metab. 2004;89:1340-5", "A Kuzmenkin, V Muncan, K Jurkat-Rott, C Hang, H Lerche, F Lehmann-Horn, N. Mitrovic. Enhanced inactivation and pH sensitivity of Na(+) channel mutations causing hypokalaemic periodic paralysis type II.. Brain. 2002;125:835-43", "AH Lane, K Markarian, I Braziunene. Thyrotoxic periodic paralysis associated with a mutation in the sodium channel gene SCN4A.. J Pediatr Endocrinol Metab. 2004;17:1679-82", "F Lehmann-Horn, K Jurkat-Rott, R Rudel. Diagnostics and therapy of muscle channelopathies -- guidelines of the Ulm Muscle Centre.. Acta Myol 2008;27:98-113", "JO Levitt. Practical aspects in the management of hypokalemic periodic paralysis.. J Transl Med. 2008;6:18", "TP Links, MJ Zwarts, JT Wilmink, WM Molenaar, HJ Oosterhuis. Permanent muscle weakness in familial hypokalaemic periodic paralysis. Clinical, radiological and pathological aspects.. Brain. 1990;113:1873-89", "E Matthews, MG Hanna. Muscle channelopathies: does the predicted channel gating pore offer new treatment options for hypokalaemic periodic paralysis?. J Physiol 2010;588:1879-86", "E Matthews, S Portaro, Q Ke, R Sud, A Haworth, MB Davis, RC Griggs, MG Hanna. Acetazolamide efficacy in hypokalemic periodic paralysis and the predictive role of genotype.. Neurology. 2011;77:1960-4", "TM Miller, MR Dias da Silva, HA Miller, H Kwiecinski, JR Mendell, R Tawil, P McManis, RC Griggs, C Angelini, S Servidei, J Petajan, MC Dalakas, LP Ranum, YH Fu, LJ Ptacek. Correlating phenotype and genotype in the periodic paralyses.. Neurology 2004;63:1647-55", "WY Ng, KF Lui, AC Thai, JS Cheah. Absence of ion channels CACN1AS and SCN4A mutations in thyrotoxic hypokalemic periodic paralysis.. Thyroid 2004;14:187-90", "A Pirone, J Schredelseker, P Tuluc, E Gravino, G Fortunato, BE Flucher, A Carsana, F Salvatore, M Grabner. Identification and functional characterization of malignant hyperthermia mutation T1354S in the outer pore of the Cavalpha1S-subunit.. Am J Physiol Cell Physiol. 2010;299:C1345-54", "NM Plaster, R Tawil, M Tristani-Firouzi, S Canun, S Bendahhou, A Tsunoda, MR Donaldson, ST Iannaccone, E Brunt, R Barohn, J Clark, F Deymeer, AL George, FA Fish, A Hahn, A Nitu, C Ozdemir, P Serdaroglu, SH Subramony, G Wolfe, YH Fu, LJ Ptácek. Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome.. Cell 2001;105:511-9", "H Poulin, P Gosselin-Badaroudine, S Vicart, K Habbout, D Sternberg, S Giuliano, B Fontaine, S Bendahhou, S Nicole, M. Chahine. Substitutions of the S4DIV R2 residue (R1451) in Nav1.4 lead to complex forms of paramyotonia congenita and periodic paralyses.. Scientific Reports. 2018;8:2041", "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", "DP Ryan, MR da Silva, TW Soong, B Fontaine, MR Donaldson, AW Kung, W Jongjaroenprasert, MC Liang, DH Khoo, JS Cheah, SC Ho, HS Bernstein, RM Maciel, RH Brown, LJ Ptácek. Mutations in potassium channel Kir2.6 cause susceptibility to thyrotoxic hypokalemic periodic paralysis.. Cell. 2010;140:88-98", "VA Sansone, J Burge, MP McDermott, PC Smith, B Herr, R Tawil, S Pandya, J Kissel, E Ciafaloni, P Shieh, JW Ralph, A Amato, SC Cannon, J Trivedi, R Barohn, B Crum, H Mitsumoto, A Pestronk, G Meola, R Conwit, MG Hanna, RC Griggs. Randomized, placebo-controlled trials of dichlorphenamide in periodic paralysis.. Neurology 2016;86:1408-16", "V Sansone, G Meola, TP Links, M Panzeri, MR Rose. Treatment for periodic paralysis.. Cochrane Database Syst Rev. 2008", "V Schartner, NB Romero, S Donkervoort, S Treves, P Munot, TM Pierson, I Dabaj, E Malfatti, IT Zaharieva, F Zorzato, O Abath Neto, G Brochier, X Lornage, B Eymard, AL Taratuto, J Böhm, H Gonorazky, L Ramos-Platt, L Feng, R Phadke, DX Bharucha-Goebel, CJ Sumner, MT Bui, E Lacene, M Beuvin, C Labasse, N Dondaine, R Schneider, J Thompson, A Boland, JF Deleuze, E Matthews, AN Pakleza, CA Sewry, V Biancalana, S Quijano-Roy, F Muntoni, M Fardeau, CG Bönnemann, J Laporte. Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy.. Acta Neuropathol. 2017;133:517-33", "S Sokolov, T Scheuer, WA Catterall. Gating pore current in an inherited ion channelopathy.. Nature 2007;446:76-8", "S Sokolov, T Scheuer, WA Catterall. Ion permeation through a voltage- sensitive gating pore in brain sodium channels having voltage sensor mutations.. Neuron. 2005;47:183-9", "S Sokolov, T Scheuer, WA Catterall. Depolarization-activated gating pore current conducted by mutant sodium channels in potassium-sensitive normokalemic periodic paralysis.. Proc Natl Acad Sci U S A. 2008;105:19980-5", "JM Statland, B Fontaine, MG Hanna, NE Johnson, JT Kissel, VA Sansone, PB Shieh, RN Tawil, J Trivedi, SC Cannon, RC Griggs. Review of the diagnosis and treatment of periodic paralysis.. Muscle Nerve. 2018;57:522-30", "D Sternberg, T Maisonobe, K Jurkat-Rott, S Nicole, E Launay, D Chauveau, N Tabti, F Lehmann-Horn, B Hainque, B Fontaine. Hypokalaemic periodic paralysis type 2 caused by mutations at codon 672 in the muscle sodium channel gene SCN4A.. Brain. 2001;124:1091-9", "AF Struyk, SC Cannon. A Na+ channel mutation linked to hypokalemic periodic paralysis exposes a proton-selective gating pore.. J Gen Physiol 2007;130:11-20", "AF Struyk, VS Markin, D Francis, SC Cannon. Gating pore currents in DIIS4 mutations of NaV1.4 associated with periodic paralysis: saturation of ion flux and implications for disease pathogenesis.. J Gen Physiol. 2008;132:447-64", "AF Struyk, KA Scoggan, DE Bulman, SC Cannon. The human skeletal muscle Na channel mutation R669H associated with hypokalemic periodic paralysis enhances slow inactivation.. J Neurosci. 2000;20:8610-7", "CC Sung, CJ Cheng, YF Lo, MS Lin, SS Yang, YC Hsu, SH Lin. Genotype and phenotype analysis of patients with sporadic periodic paralysis.. Am J Med Sci. 2012;343:281-5", "D Tricarico, M Barbieri, A Mele, G Carbonara, DC Camerino. Carbonic anhydrase inhibitors are specific openers of skeletal muscle BK channel of K1-deficient rats.. FASEB J. 2004;18:760-1", "A Tsujino, C Maertens, K Ohno, XM Shen, T Fukuda, CM Harper, SC Cannon, AG Engel. Myasthenic syndrome caused by mutation of the SCN4A sodium channel.. Proc Natl Acad Sci USA 2003;100:7377-82", "S Vicart, D Sternberg, E Fournier, F Ochsner, P Laforet, T Kuntzer, B Eymard, B Hainque, B Fontaine. New mutations of SCN4A cause a potassium-sensitive normokalemic periodic paralysis.. Neurology. 2004;63:2120-7", "Q Wang, M Liu, C Xu, Z Tang, Y Liao, R Du, W Li, X Wu, X Wang, P Liu, X Zhang, J Zhu, X Ren, T Ke, Q Wang, J Yang. Novel CACNA1S mutation causes autosomal dominant hypokalemic periodic paralysis in a Chinese family.. J Mol Med. 2005;83:203-8", "MA Weber, K Jurkat-Rott, H Lerche, F Lehmann-Horn. Strength and muscle structure preserved during long-term therapy in hypokalemic periodic paralysis (Cav1.1-R1239G).. J Neurol. 2019;266:1623-32", "A Winczewska-Wiktor, B Steinborn, F Lehman-Horn, W Biczysko, M Wiktor, B Gurda, K Jurkat-Rott. Myopathy as the first symptom of hypokalemic periodic paralysis – case report of a girl from a Polish family with CACNA1S (R1239G) mutation.. Adv Med Sci. 2007;52:155-7", "F Wu, W Mi, SC Cannon. Bumetanide prevents transient decreases in muscle force in murine hypokalemic periodic paralysis.. Neurology. 2013;80:1110-6" ]	30/4/2002	26/7/2018		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
hps	hps	[ "AP-3 complex subunit beta-1", "AP-3 complex subunit delta-1", "Biogenesis of lysosome-related organelles complex 1 subunit 3", "Biogenesis of lysosome-related organelles complex 1 subunit 5", "Biogenesis of lysosome-related organelles complex 1 subunit 6", "BLOC-2 complex member HPS3", "BLOC-2 complex member HPS5", "BLOC-2 complex member HPS6", "BLOC-3 complex member HPS1", "BLOC-3 complex member HPS4", "Dysbindin", "AP3B1", "AP3D1", "BLOC1S3", "BLOC1S5", "BLOC1S6", "DTNBP1", "HPS1", "HPS3", "HPS4", "HPS5", "HPS6", "Hermansky-Pudlak Syndrome" ]	Hermansky-Pudlak Syndrome	Wendy J Introne, Marjan Huizing, May Christine V Malicdan, Kevin J O'Brien, William A Gahl	Summary Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, a bleeding diathesis, and, in some individuals, pulmonary fibrosis, granulomatous colitis, and/or immunodeficiency. Ocular findings include nystagmus, reduced iris pigment, reduced retinal pigment, foveal hypoplasia with significant reduction in visual acuity (usually in the range of 20/50 to 20/400), and strabismus in many individuals. Hair color ranges from white to brown; skin color ranges from white to olive and is usually at least a shade lighter than that of other family members. The bleeding diathesis can result in variable degrees of bruising, epistaxis, gingival bleeding, postpartum hemorrhage, colonic bleeding, and prolonged bleeding with menses or after tooth extraction, circumcision, and/or other surgeries. Pulmonary fibrosis, colitis, and/or neutropenia have been reported in individuals with pathogenic variants in some HPS-related genes. Pulmonary fibrosis, a restrictive lung disease, typically causes symptoms in the early 30s and can progress to death within a decade. Granulomatous colitis is severe in about 15% of affected individuals. Neutropenia and/or immune defects occur primarily in individuals with pathogenic variants in The clinical diagnosis of HPS can be established in a proband with hypopigmentation of the skin and hair, characteristic eye findings, and demonstration of absence of platelet delta granules (dense bodies) on electron microscopy. Identification of biallelic pathogenic variants in HPS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an HPS-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the HPS-causing pathogenic variants are identified in an affected family member, carrier testing for at-risk family members, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.	## Diagnosis Hermansky-Pudlak syndrome (HPS) Nystagmus, low vision, photophobia, strabismus Skin and hair color lighter than other family members Increased bruising, epistaxis, gingival bleeding, and prolonged bleeding after minor procedures (e.g., circumcision, tooth extraction) Platelet aggregation testing showing impaired secondary aggregation response Prothrombin time, partial thromboplastin time, and platelet counts typically normal Absence of platelet delta granules (dense bodies) on whole mount electron microscopy The Nystagmus Reduced iris pigment with iris transillumination Reduced retinal pigment on fundoscopic examination Foveal hypoplasia associated with significant reduction in visual acuity The molecular diagnosis of HPS 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 Hermansky-Pudlak Syndrome NA = not applicable See There are approximately 770 individuals with HPS and biallelic HPS-related gene variants reported in the literature (as of January 2023). See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and 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 large intragenic deletions or duplications. Methods used may include a range of techniques such as 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 [ A homozygous chromosome 5 inversion with a breakpoint in A homozygous Homozygosity for the Homozygosity for an This includes 20 individuals of Israeli Bedouin descent homozygous for the • Nystagmus, low vision, photophobia, strabismus • Skin and hair color lighter than other family members • Increased bruising, epistaxis, gingival bleeding, and prolonged bleeding after minor procedures (e.g., circumcision, tooth extraction) • Platelet aggregation testing showing impaired secondary aggregation response • Prothrombin time, partial thromboplastin time, and platelet counts typically normal • Absence of platelet delta granules (dense bodies) on whole mount electron microscopy • Nystagmus • Reduced iris pigment with iris transillumination • Reduced retinal pigment on fundoscopic examination • Foveal hypoplasia associated with significant reduction in visual acuity ## Suggestive Findings Hermansky-Pudlak syndrome (HPS) Nystagmus, low vision, photophobia, strabismus Skin and hair color lighter than other family members Increased bruising, epistaxis, gingival bleeding, and prolonged bleeding after minor procedures (e.g., circumcision, tooth extraction) Platelet aggregation testing showing impaired secondary aggregation response Prothrombin time, partial thromboplastin time, and platelet counts typically normal Absence of platelet delta granules (dense bodies) on whole mount electron microscopy • Nystagmus, low vision, photophobia, strabismus • Skin and hair color lighter than other family members • Increased bruising, epistaxis, gingival bleeding, and prolonged bleeding after minor procedures (e.g., circumcision, tooth extraction) • Platelet aggregation testing showing impaired secondary aggregation response • Prothrombin time, partial thromboplastin time, and platelet counts typically normal • Absence of platelet delta granules (dense bodies) on whole mount electron microscopy ## Establishing the Diagnosis The Nystagmus Reduced iris pigment with iris transillumination Reduced retinal pigment on fundoscopic examination Foveal hypoplasia associated with significant reduction in visual acuity The molecular diagnosis of HPS 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 Hermansky-Pudlak Syndrome NA = not applicable See There are approximately 770 individuals with HPS and biallelic HPS-related gene variants reported in the literature (as of January 2023). See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and 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 large intragenic deletions or duplications. Methods used may include a range of techniques such as 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 [ A homozygous chromosome 5 inversion with a breakpoint in A homozygous Homozygosity for the Homozygosity for an This includes 20 individuals of Israeli Bedouin descent homozygous for the • Nystagmus • Reduced iris pigment with iris transillumination • Reduced retinal pigment on fundoscopic examination • Foveal hypoplasia associated with significant reduction in visual acuity ## Clinical Diagnosis Nystagmus Reduced iris pigment with iris transillumination Reduced retinal pigment on fundoscopic examination Foveal hypoplasia associated with significant reduction in visual acuity • Nystagmus • Reduced iris pigment with iris transillumination • Reduced retinal pigment on fundoscopic examination • Foveal hypoplasia associated with significant reduction in visual acuity ## Molecular Diagnosis The molecular diagnosis of HPS 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 Hermansky-Pudlak Syndrome NA = not applicable See There are approximately 770 individuals with HPS and biallelic HPS-related gene variants reported in the literature (as of January 2023). See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and 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 large intragenic deletions or duplications. Methods used may include a range of techniques such as 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 [ A homozygous chromosome 5 inversion with a breakpoint in A homozygous Homozygosity for the Homozygosity for an This includes 20 individuals of Israeli Bedouin descent homozygous for the ## Clinical Characteristics Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, a bleeding diathesis, and other organ involvement in specific subtypes [ Iris color may remain blue or change to a green/hazel or brown/tan color. Iris transillumination can be complete or can show peripupillary clumps or streaks of pigment in the iris that appear like spokes of a wagon wheel. Fine granular pigment may develop in the retina. Photophobia may accompany severe foveal hypoplasia. Foveal hypoplasia is associated with significant visual acuity loss. Visual acuity, usually between 20/50 and 20/400, is typically 20/200 and usually remains constant after early childhood. Individuals with HPS have increased crossing of the optic nerve fibers. Alternating strabismus is found in many individuals with HPS and is generally not associated with the development of amblyopia. Over many years, exposure of lightly pigmented skin to the sun can result in coarse, rough, thickened skin (pachydermia), solar keratoses (premalignant lesions), and skin cancer. Both basal cell carcinoma and squamous cell carcinoma can develop. Although skin melanocytes are present in individuals with HPS, melanoma is rare. Some affected individuals have solar damage manifesting as actinic keratoses and nevi. Freckles, solar lentigines, and basal cell carcinoma also occur with increased frequency among individuals with HPS. All individuals with HPS exhibit oculocutaneous albinism (as a result of aberrant melanosome formation) and a bleeding diathesis (as a result of absent platelet delta granules). Other clinical features occur per subtype and are listed below; individuals with pathogenic variants in the same HPS protein complex of AP-3, BLOC-1, BLOC-2, or BLOC-3 exhibit similar clinical characteristics [ Individuals with pathogenic variants in Some individuals with Data are insufficient to determine whether individuals with BLOC-1 deficiency are prone to complications besides albinism, a bleeding diathesis, and colitis. BLOC-1-deficient individuals appear to have a silver/blond/gold hair color at birth that may turn darker with age [ Some individuals exhibited additional features that should be monitored in other affected individuals. A female of northern European descent with Individuals with pathogenic variants in Bleeding is also mild, and pulmonary fibrosis has not been observed in individuals with BLOC-2 deficiency. Individuals with BLOC-2 deficiency can go undiagnosed for decades: a new diagnosis of Individuals with BLOC-3 deficiency exhibit a generally severe form of oculocutaneous albinism and bleeding diathesis [ BLOC-3 deficiency is associated with potentially lethal pulmonary fibrosis, a progressive restrictive lung disease. Individuals typically become symptomatic in their 30s and may die within a decade, unless transplanted [ Significant granulomatous colitis occurs primarily in individuals with Correlations between specific HPS-causing variants in any one gene and particular clinical presentations are not convincing. HPS may have been referred to as non-neuronal ceroid-lipofuscinosis to differentiate it from neuronal ceroid lipofuscinosis (Batten disease). In HPS, the nervous system appears to be spared. Individuals with HPS with mild hypopigmentation and a bleeding disorder could be referred to as having "delta storage pool deficiency"; however, individuals with isolated delta storage pool deficiency do not have vision defects. HPS is a rare disorder with an estimated worldwide prevalence of one to nine in 1,000,000 individuals ( The prevalence per subtype can differ because of founder variants. The prevalence of Individuals with HPS have been identified in many other regions, including China, India, the Middle East, South America, and Western and Eastern Europe. ## Clinical Description Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, a bleeding diathesis, and other organ involvement in specific subtypes [ Iris color may remain blue or change to a green/hazel or brown/tan color. Iris transillumination can be complete or can show peripupillary clumps or streaks of pigment in the iris that appear like spokes of a wagon wheel. Fine granular pigment may develop in the retina. Photophobia may accompany severe foveal hypoplasia. Foveal hypoplasia is associated with significant visual acuity loss. Visual acuity, usually between 20/50 and 20/400, is typically 20/200 and usually remains constant after early childhood. Individuals with HPS have increased crossing of the optic nerve fibers. Alternating strabismus is found in many individuals with HPS and is generally not associated with the development of amblyopia. Over many years, exposure of lightly pigmented skin to the sun can result in coarse, rough, thickened skin (pachydermia), solar keratoses (premalignant lesions), and skin cancer. Both basal cell carcinoma and squamous cell carcinoma can develop. Although skin melanocytes are present in individuals with HPS, melanoma is rare. Some affected individuals have solar damage manifesting as actinic keratoses and nevi. Freckles, solar lentigines, and basal cell carcinoma also occur with increased frequency among individuals with HPS. ## Phenotype Correlations by Gene All individuals with HPS exhibit oculocutaneous albinism (as a result of aberrant melanosome formation) and a bleeding diathesis (as a result of absent platelet delta granules). Other clinical features occur per subtype and are listed below; individuals with pathogenic variants in the same HPS protein complex of AP-3, BLOC-1, BLOC-2, or BLOC-3 exhibit similar clinical characteristics [ Individuals with pathogenic variants in Some individuals with Data are insufficient to determine whether individuals with BLOC-1 deficiency are prone to complications besides albinism, a bleeding diathesis, and colitis. BLOC-1-deficient individuals appear to have a silver/blond/gold hair color at birth that may turn darker with age [ Some individuals exhibited additional features that should be monitored in other affected individuals. A female of northern European descent with Individuals with pathogenic variants in Bleeding is also mild, and pulmonary fibrosis has not been observed in individuals with BLOC-2 deficiency. Individuals with BLOC-2 deficiency can go undiagnosed for decades: a new diagnosis of Individuals with BLOC-3 deficiency exhibit a generally severe form of oculocutaneous albinism and bleeding diathesis [ BLOC-3 deficiency is associated with potentially lethal pulmonary fibrosis, a progressive restrictive lung disease. Individuals typically become symptomatic in their 30s and may die within a decade, unless transplanted [ Significant granulomatous colitis occurs primarily in individuals with Individuals with pathogenic variants in Some individuals with Data are insufficient to determine whether individuals with BLOC-1 deficiency are prone to complications besides albinism, a bleeding diathesis, and colitis. BLOC-1-deficient individuals appear to have a silver/blond/gold hair color at birth that may turn darker with age [ Some individuals exhibited additional features that should be monitored in other affected individuals. A female of northern European descent with Individuals with pathogenic variants in Bleeding is also mild, and pulmonary fibrosis has not been observed in individuals with BLOC-2 deficiency. Individuals with BLOC-2 deficiency can go undiagnosed for decades: a new diagnosis of Individuals with BLOC-3 deficiency exhibit a generally severe form of oculocutaneous albinism and bleeding diathesis [ BLOC-3 deficiency is associated with potentially lethal pulmonary fibrosis, a progressive restrictive lung disease. Individuals typically become symptomatic in their 30s and may die within a decade, unless transplanted [ Significant granulomatous colitis occurs primarily in individuals with ## Genotype-Phenotype Correlations Correlations between specific HPS-causing variants in any one gene and particular clinical presentations are not convincing. ## Nomenclature HPS may have been referred to as non-neuronal ceroid-lipofuscinosis to differentiate it from neuronal ceroid lipofuscinosis (Batten disease). In HPS, the nervous system appears to be spared. Individuals with HPS with mild hypopigmentation and a bleeding disorder could be referred to as having "delta storage pool deficiency"; however, individuals with isolated delta storage pool deficiency do not have vision defects. ## Prevalence HPS is a rare disorder with an estimated worldwide prevalence of one to nine in 1,000,000 individuals ( The prevalence per subtype can differ because of founder variants. The prevalence of Individuals with HPS have been identified in many other regions, including China, India, the Middle East, South America, and Western and Eastern Europe. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Differential Diagnosis of Hermansky-Pudlak Syndrome: Disorders with Albinism Characterized by ↓ or complete lack of melanin pigment in the skin, hair, & eyes. Often presents w/white/blond/light hair, white or light skin that does not tan & is very susceptible to damage from the sun incl skin cancer, & fully translucent irises that do not darken w/age. Ocular findings can include nystagmus, ↓ iris pigment w/iris translucency, ↓ retinal pigment, foveal hypoplasia w/significantly ↓ visual acuity, & misrouting of optic nerves resulting in alternating strabismus & ↓ stereoscopic vision. All persons w/OCA have severe visual changes, but amount of skin, hair, & iris pigment can vary depending on gene (or type of OCA) & pathogenic variant involved. Affected males have minor skin manifestations & congenital & persistent visual impairment. Characterized by congenital nystagmus, ↓ visual acuity, hypopigmentation of iris pigment epithelium & ocular fundus, & foveal hypoplasia. Significant refractive errors, ↓ or absent binocular functions, photophobia, & strabismus are common. AR = autosomal recessive; MOI = mode of inheritance; OCA = oculocutaneous albinism; XL = X-linked Differential Diagnosis of Hermansky-Pudlak Syndrome: Disorders of Platelet Delta Granules Significantly ↑ frequency of infection in childhood, partial OCA, & bleeding diathesis Characterized by huge, fused, dysfunctional lysosomes & macromelanosomes. Persons w/CHS always have giant intracellular granules in their neutrophils on peripheral blood smear (persons w/HPS never exhibit this finding). ~85% of affected persons develop hemophagocytic lymphohistiocytosis or the accelerated phase of CHS, a finding that also sporadically occurs in All affected persons – incl adolescents & adults w/atypical CHS & children w/classic CHS who have successfully undergone allogenic HSCT – develop neurologic findings. Mild hypopigmentation & immunodeficiency Can have the accelerated phase of lymphohistiocytosis A distinguishing finding is silver-gray hair. AR = autosomal recessive; HPS = Hermansky-Pudlak syndrome; HSCT = hematopoietic stem cell transplantation; MOI = mode of inheritance; OCA = oculocutaneous albinism Elejalde syndrome (OMIM • Characterized by ↓ or complete lack of melanin pigment in the skin, hair, & eyes. • Often presents w/white/blond/light hair, white or light skin that does not tan & is very susceptible to damage from the sun incl skin cancer, & fully translucent irises that do not darken w/age. • Ocular findings can include nystagmus, ↓ iris pigment w/iris translucency, ↓ retinal pigment, foveal hypoplasia w/significantly ↓ visual acuity, & misrouting of optic nerves resulting in alternating strabismus & ↓ stereoscopic vision. • All persons w/OCA have severe visual changes, but amount of skin, hair, & iris pigment can vary depending on gene (or type of OCA) & pathogenic variant involved. • Affected males have minor skin manifestations & congenital & persistent visual impairment. • Characterized by congenital nystagmus, ↓ visual acuity, hypopigmentation of iris pigment epithelium & ocular fundus, & foveal hypoplasia. • Significant refractive errors, ↓ or absent binocular functions, photophobia, & strabismus are common. • Significantly ↑ frequency of infection in childhood, partial OCA, & bleeding diathesis • Characterized by huge, fused, dysfunctional lysosomes & macromelanosomes. • Persons w/CHS always have giant intracellular granules in their neutrophils on peripheral blood smear (persons w/HPS never exhibit this finding). • ~85% of affected persons develop hemophagocytic lymphohistiocytosis or the accelerated phase of CHS, a finding that also sporadically occurs in • All affected persons – incl adolescents & adults w/atypical CHS & children w/classic CHS who have successfully undergone allogenic HSCT – develop neurologic findings. • Mild hypopigmentation & immunodeficiency • Can have the accelerated phase of lymphohistiocytosis • A distinguishing finding is silver-gray hair. ## Management Clinical practice guidelines for Hermansky-Pudlak syndrome (HPS) have not been published; however, clinicians with expertise in HPS care have published management recommendations [ To establish the extent of disease and needs in an individual diagnosed with HPS, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Hermansky-Pudlak Syndrome Assess frequency of infections. Laboratory assessment: WBC count & neutrophil function Community or Social work involvement for parental support; Home nursing referral as needed. HPS = Hermansky-Pudlak syndrome; MOI = mode of inheritance; WBC = white blood count Medical geneticist, certified genetic counselor, certified advanced genetic nurse There is no cure for HPS or its associated manifestations. Preventative and supportive care improves quality of life, maximizes function, and reduces complications. This ideally involves multidisciplinary care by specialists in relevant fields (see Treatment of Manifestations in Individuals with Hermansky-Pudlak Syndrome Correction of refractive errors to improve visual acuity Aids (e.g., handheld magnifying devices, bioptic lenses) as needed Preferential seating in school Low vision consultant as needed Protective clothing (hats w/brims, long sleeves, pants, socks) for prolonged exposure Sunscreen w/high SPF (45-50+) for sun-sensitive persons; SPF (15+) for less sun-sensitive persons Thrombin-soaked Gelfoam Recommend medical alert bracelet that explicitly describes the functional platelet defect, as the standard tests for bleeding dysfunction (e.g., platelet count, prothrombin time, partial thromboplastin time) are normal in those w/HPS. Oral contraceptives & IUDs can ↓ menorrhagia. Menorrhagia has been treated w/levonorgestrel-releasing intrauterine system [ For more invasive trauma, such as wisdom tooth extraction, DDAVP For extensive surgeries or protracted bleeding, platelet or RBC transfusions may be required. For elective surgical procedures w/estimated moderate or greater blood loss, HLA-matched single-donor platelets should be used. Recommend having platelets on standby for all surgical procedures w/risk of significant bleeding. Prompt treatment of asthma & pulmonary infections Influenza, pneumococcal, & COVID-19 vaccines Regular moderate exercise Optimized treatment for concomitant reactive airways disorders IUD = intrauterine device; RBC = red blood cell 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 Hermansky-Pudlak Syndrome PFT = pulmonary function testing The following should be avoided: All nonsteroidal anti-inflammatory medications and aspirin-containing products Therapeutic anticoagulants (should be used only if medically indicated) High-impact sports and activities that could increase the risk of bleeding Tobacco products (which decrease pulmonary function and may exacerbate pulmonary fibrosis) Other pulmonary toxicants (e.g., inorganic and organic fibers, volatile chemicals, polluted environments) Direct sun exposure without protection (e.g., protective clothing, sunscreen, and UV-blocking sunglasses) In individuals with In families with other types of HPS (caused by pathogenic variants in If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs. If the pathogenic variants in the family are not known, platelet whole mount electron microscopy studies can be used to clarify the status of at-risk sibs. See Pregnancies should proceed normally for an affected mother or an affected fetus. Delivery, however, carries risk for bleeding in a woman with HPS; surveillance and a hematology consultation for anticipation of bleeding complications during delivery should be initiated once pregnancy is confirmed. No medications are currently approved by the US Food and Drug Administration as treatment for HPS. Some medications for HPS-related pulmonary fibrosis have been investigated. Corticosteroid drugs were not effective and are not recommended for therapy [ Gene therapy and gene editing are potential future treatments for HPS [ Search In general, opaque contact lenses or darkly tinted lenses do not improve visual function. Dark glasses may be helpful for individuals with albinism, but many prefer to go without dark glasses because they reduce vision. No successful therapy for or prophylaxis against HPS-related pulmonary fibrosis exists. Steroids are often tried but have no apparent beneficial effect. • Assess frequency of infections. • Laboratory assessment: WBC count & neutrophil function • Community or • Social work involvement for parental support; • Home nursing referral as needed. • Correction of refractive errors to improve visual acuity • Aids (e.g., handheld magnifying devices, bioptic lenses) as needed • Preferential seating in school • Low vision consultant as needed • Protective clothing (hats w/brims, long sleeves, pants, socks) for prolonged exposure • Sunscreen w/high SPF (45-50+) for sun-sensitive persons; SPF (15+) for less sun-sensitive persons • Thrombin-soaked Gelfoam • Recommend medical alert bracelet that explicitly describes the functional platelet defect, as the standard tests for bleeding dysfunction (e.g., platelet count, prothrombin time, partial thromboplastin time) are normal in those w/HPS. • Oral contraceptives & IUDs can ↓ menorrhagia. • Menorrhagia has been treated w/levonorgestrel-releasing intrauterine system [ • For more invasive trauma, such as wisdom tooth extraction, DDAVP • For extensive surgeries or protracted bleeding, platelet or RBC transfusions may be required. • For elective surgical procedures w/estimated moderate or greater blood loss, HLA-matched single-donor platelets should be used. • Recommend having platelets on standby for all surgical procedures w/risk of significant bleeding. • Prompt treatment of asthma & pulmonary infections • Influenza, pneumococcal, & COVID-19 vaccines • Regular moderate exercise • Optimized treatment for concomitant reactive airways disorders • All nonsteroidal anti-inflammatory medications and aspirin-containing products • Therapeutic anticoagulants (should be used only if medically indicated) • High-impact sports and activities that could increase the risk of bleeding • Tobacco products (which decrease pulmonary function and may exacerbate pulmonary fibrosis) • Other pulmonary toxicants (e.g., inorganic and organic fibers, volatile chemicals, polluted environments) • Direct sun exposure without protection (e.g., protective clothing, sunscreen, and UV-blocking sunglasses) • If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs. • If the pathogenic variants in the family are not known, platelet whole mount electron microscopy studies can be used to clarify the status of at-risk sibs. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with HPS, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Hermansky-Pudlak Syndrome Assess frequency of infections. Laboratory assessment: WBC count & neutrophil function Community or Social work involvement for parental support; Home nursing referral as needed. HPS = Hermansky-Pudlak syndrome; MOI = mode of inheritance; WBC = white blood count Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Assess frequency of infections. • Laboratory assessment: WBC count & neutrophil function • Community or • Social work involvement for parental support; • Home nursing referral as needed. ## Treatment of Manifestations There is no cure for HPS or its associated manifestations. Preventative and supportive care improves quality of life, maximizes function, and reduces complications. This ideally involves multidisciplinary care by specialists in relevant fields (see Treatment of Manifestations in Individuals with Hermansky-Pudlak Syndrome Correction of refractive errors to improve visual acuity Aids (e.g., handheld magnifying devices, bioptic lenses) as needed Preferential seating in school Low vision consultant as needed Protective clothing (hats w/brims, long sleeves, pants, socks) for prolonged exposure Sunscreen w/high SPF (45-50+) for sun-sensitive persons; SPF (15+) for less sun-sensitive persons Thrombin-soaked Gelfoam Recommend medical alert bracelet that explicitly describes the functional platelet defect, as the standard tests for bleeding dysfunction (e.g., platelet count, prothrombin time, partial thromboplastin time) are normal in those w/HPS. Oral contraceptives & IUDs can ↓ menorrhagia. Menorrhagia has been treated w/levonorgestrel-releasing intrauterine system [ For more invasive trauma, such as wisdom tooth extraction, DDAVP For extensive surgeries or protracted bleeding, platelet or RBC transfusions may be required. For elective surgical procedures w/estimated moderate or greater blood loss, HLA-matched single-donor platelets should be used. Recommend having platelets on standby for all surgical procedures w/risk of significant bleeding. Prompt treatment of asthma & pulmonary infections Influenza, pneumococcal, & COVID-19 vaccines Regular moderate exercise Optimized treatment for concomitant reactive airways disorders IUD = intrauterine device; RBC = red blood cell • Correction of refractive errors to improve visual acuity • Aids (e.g., handheld magnifying devices, bioptic lenses) as needed • Preferential seating in school • Low vision consultant as needed • Protective clothing (hats w/brims, long sleeves, pants, socks) for prolonged exposure • Sunscreen w/high SPF (45-50+) for sun-sensitive persons; SPF (15+) for less sun-sensitive persons • Thrombin-soaked Gelfoam • Recommend medical alert bracelet that explicitly describes the functional platelet defect, as the standard tests for bleeding dysfunction (e.g., platelet count, prothrombin time, partial thromboplastin time) are normal in those w/HPS. • Oral contraceptives & IUDs can ↓ menorrhagia. • Menorrhagia has been treated w/levonorgestrel-releasing intrauterine system [ • For more invasive trauma, such as wisdom tooth extraction, DDAVP • For extensive surgeries or protracted bleeding, platelet or RBC transfusions may be required. • For elective surgical procedures w/estimated moderate or greater blood loss, HLA-matched single-donor platelets should be used. • Recommend having platelets on standby for all surgical procedures w/risk of significant bleeding. • Prompt treatment of asthma & pulmonary infections • Influenza, pneumococcal, & COVID-19 vaccines • Regular moderate exercise • Optimized treatment for concomitant reactive airways disorders ## 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 Hermansky-Pudlak Syndrome PFT = pulmonary function testing ## Agents/Circumstances to Avoid The following should be avoided: All nonsteroidal anti-inflammatory medications and aspirin-containing products Therapeutic anticoagulants (should be used only if medically indicated) High-impact sports and activities that could increase the risk of bleeding Tobacco products (which decrease pulmonary function and may exacerbate pulmonary fibrosis) Other pulmonary toxicants (e.g., inorganic and organic fibers, volatile chemicals, polluted environments) Direct sun exposure without protection (e.g., protective clothing, sunscreen, and UV-blocking sunglasses) • All nonsteroidal anti-inflammatory medications and aspirin-containing products • Therapeutic anticoagulants (should be used only if medically indicated) • High-impact sports and activities that could increase the risk of bleeding • Tobacco products (which decrease pulmonary function and may exacerbate pulmonary fibrosis) • Other pulmonary toxicants (e.g., inorganic and organic fibers, volatile chemicals, polluted environments) • Direct sun exposure without protection (e.g., protective clothing, sunscreen, and UV-blocking sunglasses) ## Evaluation of Relatives at Risk In individuals with In families with other types of HPS (caused by pathogenic variants in If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs. If the pathogenic variants in the family are not known, platelet whole mount electron microscopy studies can be used to clarify the status of at-risk sibs. See • If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs. • If the pathogenic variants in the family are not known, platelet whole mount electron microscopy studies can be used to clarify the status of at-risk sibs. ## Pregnancy Management Pregnancies should proceed normally for an affected mother or an affected fetus. Delivery, however, carries risk for bleeding in a woman with HPS; surveillance and a hematology consultation for anticipation of bleeding complications during delivery should be initiated once pregnancy is confirmed. ## Therapies Under Investigation No medications are currently approved by the US Food and Drug Administration as treatment for HPS. Some medications for HPS-related pulmonary fibrosis have been investigated. Corticosteroid drugs were not effective and are not recommended for therapy [ Gene therapy and gene editing are potential future treatments for HPS [ Search ## Other In general, opaque contact lenses or darkly tinted lenses do not improve visual function. Dark glasses may be helpful for individuals with albinism, but many prefer to go without dark glasses because they reduce vision. No successful therapy for or prophylaxis against HPS-related pulmonary fibrosis exists. Steroids are often tried but have no apparent beneficial effect. ## Genetic Counseling Hermansky-Pudlak syndrome (HPS) is inherited in an autosomal recessive manner. Rarely, families with two-generation pseudodominant inheritance have been identified. Pseudodominance (i.e., an autosomal recessive condition present in individuals in two or more generations) may occur when an affected individual has children with a reproductive partner who is heterozygous (i.e., a carrier) for a pathogenic variant in the same HPS-associated gene. The parents of an affected child are presumed to be heterozygous for an HPS-causing pathogenic variant. If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an HPS-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an HPS-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Carrier 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 for the reproductive partners of known carriers and for the reproductive partners of individuals affected with HPS should be considered, particularly if both partners are of the same ethnic background. Founder variants have been identified in individuals of Puerto Rican, Ashkenazi Jewish, European, Japanese, Swiss, and Israeli Bedouin ancestry (see Once the HPS-causing pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected child are presumed to be heterozygous for an HPS-causing pathogenic variant. • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an HPS-causing pathogenic variant and to allow reliable recurrence risk assessment. • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an HPS-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • Carrier testing for the reproductive partners of known carriers and for the reproductive partners of individuals affected with HPS should be considered, particularly if both partners are of the same ethnic background. Founder variants have been identified in individuals of Puerto Rican, Ashkenazi Jewish, European, Japanese, Swiss, and Israeli Bedouin ancestry (see ## Mode of Inheritance Hermansky-Pudlak syndrome (HPS) is inherited in an autosomal recessive manner. Rarely, families with two-generation pseudodominant inheritance have been identified. Pseudodominance (i.e., an autosomal recessive condition present in individuals in two or more generations) may occur when an affected individual has children with a reproductive partner who is heterozygous (i.e., a carrier) for a pathogenic variant in the same HPS-associated gene. ## Risk to Family Members The parents of an affected child are presumed to be heterozygous for an HPS-causing pathogenic variant. If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an HPS-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an HPS-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The parents of an affected child are presumed to be heterozygous for an HPS-causing pathogenic variant. • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an HPS-causing pathogenic variant and to allow reliable recurrence risk assessment. • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an HPS-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Carrier Detection Carrier testing for at-risk 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 for the reproductive partners of known carriers and for the reproductive partners of individuals affected with HPS should be considered, particularly if both partners are of the same ethnic background. Founder variants have been identified in individuals of Puerto Rican, Ashkenazi Jewish, European, Japanese, Swiss, and Israeli Bedouin 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 and for the reproductive partners of individuals affected with HPS should be considered, particularly if both partners are of the same ethnic background. Founder variants have been identified in individuals of Puerto Rican, Ashkenazi Jewish, European, Japanese, Swiss, and Israeli Bedouin ancestry (see ## Prenatal Testing and Preimplantation Genetic Testing Once the HPS-causing pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • • • ## Molecular Genetics Hermansky-Pudlak Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Hermansky-Pudlak Syndrome ( The proteins encoded by the eleven genes in which pathogenic variants are known to cause HPS associate into four HPS protein complexes, which are involved in cargo transport, cargo recycling, and cargo removal to maintain lysosome-related organelle (LRO) homeostasis [ AP-3, a heterotetrameric complex of which two subunits, encoded by BLOC-1 (biogenesis of lysosome-related organelles complex 1), consisting of eight subunits [ BLOC-2, including subunits encoded by BLOC-3, including subunits encoded by Genetic defects in HPS-related genes result in deficiency of the associated HPS protein complex, which leads to aberrant function of all LROs or only an individual LRO, resulting in a variety of clinical features. LROs affected in HPS include melanosomes in melanocytes (underlying pigmentation defects), platelet delta granules (underlying bleeding diathesis), lamellar bodies in alveolar type II cells (contributing to pulmonary fibrosis), and cytolytic granules in T cells and NK cells (contributing to immunodeficiency) [ Hermansky-Pudlak Syndrome: 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 • AP-3, a heterotetrameric complex of which two subunits, encoded by • BLOC-1 (biogenesis of lysosome-related organelles complex 1), consisting of eight subunits [ • BLOC-2, including subunits encoded by • BLOC-3, including subunits encoded by ## Molecular Pathogenesis The proteins encoded by the eleven genes in which pathogenic variants are known to cause HPS associate into four HPS protein complexes, which are involved in cargo transport, cargo recycling, and cargo removal to maintain lysosome-related organelle (LRO) homeostasis [ AP-3, a heterotetrameric complex of which two subunits, encoded by BLOC-1 (biogenesis of lysosome-related organelles complex 1), consisting of eight subunits [ BLOC-2, including subunits encoded by BLOC-3, including subunits encoded by Genetic defects in HPS-related genes result in deficiency of the associated HPS protein complex, which leads to aberrant function of all LROs or only an individual LRO, resulting in a variety of clinical features. LROs affected in HPS include melanosomes in melanocytes (underlying pigmentation defects), platelet delta granules (underlying bleeding diathesis), lamellar bodies in alveolar type II cells (contributing to pulmonary fibrosis), and cytolytic granules in T cells and NK cells (contributing to immunodeficiency) [ Hermansky-Pudlak Syndrome: 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 • AP-3, a heterotetrameric complex of which two subunits, encoded by • BLOC-1 (biogenesis of lysosome-related organelles complex 1), consisting of eight subunits [ • BLOC-2, including subunits encoded by • BLOC-3, including subunits encoded by ## Chapter Notes This work was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland. William A Gahl, MD, PhD (2000-present)Bernadette R Gochuico, MD; National Human Genome Research Institute (2017-2023)Marjan Huizing, PhD (2012-present)Wendy J Introne, MD (2023-present)May Christine V Malicdan, MD, PhD (2017-present)Kevin J O'Brien, RN, MS-CRNP (2023-present) 25 May 2023 (wi) Revision: clarification of preferred method of electron microscopy in 16 March 2023 (sw) Comprehensive update posted live 18 March 2021 (aa,mh) Revision: added 26 October 2017 (sw) Comprehensive update posted live 11 December 2014 (me) Comprehensive update posted live 28 February 2013 (cd) Revision: deletion/duplication analysis available for 11 October 2012 (me) Comprehensive update posted live 8 July 2010 (cd) Revision: sequence analysis available clinically for mutations in 4 May 2010 (me) Comprehensive update posted live 27 November 2007 (cd) Revision: sequence analysis available clinically for 21 March 2007 (me) Comprehensive update posted live 20 December 2004 (me) Comprehensive update posted live 2 January 2003 (tk) Comprehensive update posted live 24 July 2000 (me) Review posted live 27 January 2000 (wg) Original submission Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the • 25 May 2023 (wi) Revision: clarification of preferred method of electron microscopy in • 16 March 2023 (sw) Comprehensive update posted live • 18 March 2021 (aa,mh) Revision: added • 26 October 2017 (sw) Comprehensive update posted live • 11 December 2014 (me) Comprehensive update posted live • 28 February 2013 (cd) Revision: deletion/duplication analysis available for • 11 October 2012 (me) Comprehensive update posted live • 8 July 2010 (cd) Revision: sequence analysis available clinically for mutations in • 4 May 2010 (me) Comprehensive update posted live • 27 November 2007 (cd) Revision: sequence analysis available clinically for • 21 March 2007 (me) Comprehensive update posted live • 20 December 2004 (me) Comprehensive update posted live • 2 January 2003 (tk) Comprehensive update posted live • 24 July 2000 (me) Review posted live • 27 January 2000 (wg) Original submission ## Author Notes ## Acknowledgments This work was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland. ## Author History William A Gahl, MD, PhD (2000-present)Bernadette R Gochuico, MD; National Human Genome Research Institute (2017-2023)Marjan Huizing, PhD (2012-present)Wendy J Introne, MD (2023-present)May Christine V Malicdan, MD, PhD (2017-present)Kevin J O'Brien, RN, MS-CRNP (2023-present) ## Revision History 25 May 2023 (wi) Revision: clarification of preferred method of electron microscopy in 16 March 2023 (sw) Comprehensive update posted live 18 March 2021 (aa,mh) Revision: added 26 October 2017 (sw) Comprehensive update posted live 11 December 2014 (me) Comprehensive update posted live 28 February 2013 (cd) Revision: deletion/duplication analysis available for 11 October 2012 (me) Comprehensive update posted live 8 July 2010 (cd) Revision: sequence analysis available clinically for mutations in 4 May 2010 (me) Comprehensive update posted live 27 November 2007 (cd) Revision: sequence analysis available clinically for 21 March 2007 (me) Comprehensive update posted live 20 December 2004 (me) Comprehensive update posted live 2 January 2003 (tk) Comprehensive update posted live 24 July 2000 (me) Review posted live 27 January 2000 (wg) Original submission Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the • 25 May 2023 (wi) Revision: clarification of preferred method of electron microscopy in • 16 March 2023 (sw) Comprehensive update posted live • 18 March 2021 (aa,mh) Revision: added • 26 October 2017 (sw) Comprehensive update posted live • 11 December 2014 (me) Comprehensive update posted live • 28 February 2013 (cd) Revision: deletion/duplication analysis available for • 11 October 2012 (me) Comprehensive update posted live • 8 July 2010 (cd) Revision: sequence analysis available clinically for mutations in • 4 May 2010 (me) Comprehensive update posted live • 27 November 2007 (cd) Revision: sequence analysis available clinically for • 21 March 2007 (me) Comprehensive update posted live • 20 December 2004 (me) Comprehensive update posted live • 2 January 2003 (tk) Comprehensive update posted live • 24 July 2000 (me) Review posted live • 27 January 2000 (wg) Original submission ## References ## Literature Cited	[ "S Ammann, A Schulz, I Krageloh-Mann, NM Dieckmann, K Niethammer, S Fuchs, KM Eckl, R Plank, R Werner, J Altmuller, H Thiele, P Nurnberg, J Bank, A Strauss, H von Bernuth, U Zur Stadt, S Grieve, GM Griffiths, K Lehmberg, HC Hennies, S Ehl. Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome.. Blood 2016;127:997-1006", "PD Anderson, M Huizing, DA Claassen, J White, WA Gahl. Hermansky-Pudlak syndrome type 4 (HPS-4): clinical and molecular characteristics.. Hum Genet 2003;113:10-7", "Y Anikster, M Huizing, J White, YO Shevchenko, DL Fitzpatrick, JW Touchman, JG Compton, SJ Bale, RT Swank, WA Gahl, JR Toro. Mutation of a new gene causes a unique form of Hermansky-Pudlak syndrome in a genetic isolate of central Puerto Rico.. Nat Genet 2001;28:376-80", "R Badolato, A Prandini, S Caracciolo, F Colombo, G Tabellini, M Giacomelli, ME Cantarini, A Pession, CJ Bell, DL Dinwiddie, NA Miller, SL Hateley, CJ Saunders, L Zhang, GP Schroth, A Plebani, S Parolini, SF Kingsmore. Exome sequencing reveals a pallidin mutation in a Hermansky-Pudlak-like primary immunodeficiency syndrome.. Blood 2012;119:3185-7", "L Benvenuto, S Qayum, H Kim, H Robbins, L Shah, A Dimango, G Magda, H Grewal, P Lemaitre, BP Stanifer, J Sonett, F D'Ovidio, SM Arcasoy. Lung transplantation for pulmonary fibrosis associated with Hermansky-Pudlak syndrome. A single-center experience.. Transplant Direct 2022;8", "D Boeckelmann, M Wolter, K Neubauer, F Sobotta, A Lenz, H Glonnegger, B Käsmann-Kellner, J Mann, S Ehl, B Zieger. Hermansky-Pudlak syndrome: identification of novel variants in the genes HPS3, HPS5, and DTNBP1 (HPS-7).. Front Pharmacol 2022;12", "SL Bowman, J Bi-Karchin, L Le, MS Marks. The road to lysosome-related organelles: Insights from Hermansky-Pudlak syndrome and other rare diseases.. Traffic 2019;20:404-35", "KS Chan, BL Bohnsack, A Ing, A Drackley, V Castelluccio, KX Zhang, H Ralay-Ranaivo, JL Rossen. Diagnostic yield of genetic testing for ocular and oculocutaneous albinism in a diverse United States pediatric population.. Genes (Basel) 2023;14:135", "A Cordova, NJ Barrios, I Ortiz, E Rivera, C Cadilla, PJ Santiago-Borrero. Poor response to desmopressin acetate (DDAVP) in children with Hermansky-Pudlak syndrome.. Pediatr Blood Cancer 2005;44:51-4", "M de Boer, K van Leeuwen, J Geissler, F van Alphen, E de Vries, M van der Kuip, SWJ Terheggen, H Janssen, TK van den Berg, AB Meijer, D Roos, TW Kuijpers. Hermansky-Pudlak syndrome type 2: aberrant pre-mRNA splicing and mislocalization of granule proteins in neutrophils.. Hum Mutat 2017;38:1402-11", "EC Dell'Angelica, V Shotelersuk, RC Aguilar, WA Gahl, JS Bonifacino. Altered trafficking of lysosomal proteins in Hermansky-Pudlak syndrome due to mutations in the beta 3A subunit of the AP-3 adaptor.. Mol Cell 1999;3:11-21", "SM Di Pietro, JM Falcón-Pérez, EC Dell'Angelica. Characterization of BLOC-2, a complex containing the Hermansky-Pudlak syndrome proteins HPS3, HPS5 and HPS6.. Traffic 2004;5:276-83", "Y Erzin, S Cosgun, A Dobrucali, M Tasyurekli, S Erdamar, M Tuncer. Complicated granulomatous colitis in a patient with Hermansky-Pudlak syndrome, successfully treated with infliximab.. Acta Gastroenterol Belg. 2006;69:213-6", "JM Falcón-Pérez, M Starcevic, R Gautam, EC Dell'Angelica. BLOC-1, a novel complex containing the pallidin and muted proteins involved in the biogenesis of melanosomes and platelet-dense granules.. J Biol Chem 2002;277:28191-9", "LM Felipez, R Gokhale, S Guandalini. Hermansky-Pudlak syndrome: severe colitis and good response to infliximab.. J Pediatr Gastroenterol Nutr. 2010;51:665-7", "S Fontana, S Parolini, W Vermi, S Booth, F Gallo, M Donini, M Benassi, F Gentili, D Ferrari, LD Notarangelo, P Cavadini, E Marcenaro, S Dusi, M Cassatella, F Facchetti, GM Griffiths, A Moretta, LD Notarangelo, R Badolato. Innate immunity defects in Hermansky-Pudlak type 2 syndrome.. Blood 2006;107:4857-64", "A Frohne, M Koenighofer, H Cetin, M Nieratschker, DT Liu, F Laccone, J Neesen, SF Nemec, U Schwarz-Nemec, C Schoefer, KB Avraham, K Frei, K Grabmeier-Pfistershammer, B Kratzer, K Schmetterer, WF Pickl, T Parzefall. A homozygous AP3D1 missense variant in patients with sensorineural hearing loss as the leading manifestation.. Hum Genet. 2022", "WA Gahl, M Brantly, MI Kaiser-Kupfer, F Iwata, S Hazelwood, V Shotelersuk, LF Duffy, EM Kuehl, J Troendle, I Bernardini. Genetic defects and clinical characteristics of patients with a form of oculocutaneous albinism (Hermansky-Pudlak syndrome).. N Engl J Med 1998;338:1258-64", "WA Gahl, M Brantly, J Troendle, NA Avila, A Padua, C Montalvo, H Cardona, KA Calis, B Gochuico. Effect of pirfenidone on the pulmonary fibrosis of Hermansky-Pudlak syndrome.. Mol Genet Metab 2002;76:234-42", "BR Gochuico, M Huizing, GA Golas, CD Scher, M Tsokos, SD Denver, MJ Frei-Jones, WA Gahl. Interstitial lung disease and pulmonary fibrosis in Hermansky-Pudlak syndrome type 2, an adaptor protein-3 complex disease.. Mol Med. 2012;18:56-64", "M Gunay-Aygun, M Huizing, WA Gahl. Molecular defects that affect platelet dense granules.. Semin Thromb Hemost 2004;30:537-47", "T Hovnik, M Debeljak, M Tekavčič Pompe, S Bertok, T Battelino, B Stirn Kranjc, K Trebušak Podkrajšek. Genetic variability in Slovenian cohort of patients with oculocutaneous albinism.. Acta Chim Slov 2021;68:683-92", "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", "M Huizing, Y Anikster, DL Fitzpatrick, AB Jeong, M D'Souza, M Rausche, JR Toro, MI Kaiser-Kupfer, JG White, WA Gahl. Hermansky-Pudlak syndrome type 3 in Ashkenazi Jews and other non-Puerto Rican patients with hypopigmentation and platelet storage-pool deficiency.. Am J Hum Genet 2001;69:1022-32", "M Huizing, A Helip-Wooley, W Westbroek, M Gunay-Aygun, WA Gahl. Disorders of lysosome-related organelle biogenesis: clinical and molecular genetics.. Annu Rev Genomics Hum Genet 2008;9:359-86", "M Huizing, MCV Malicdan, JA Wang, H Pri-Chen, RA Hess, R Fischer, KJ O'Brien, MA Merideth, WA Gahl, BR Gochuico. Hermansky-Pudlak syndrome: mutation update.. Hum Mutat 2020;41:543-80", "N Hussain, M Quezado, M Huizing, D Geho, JG White, W Gahl, P Mannon. Intestinal disease in Hermansky-Pudlak syndrome: occurrence of colitis and relation to genotype.. Clin Gastroenterol Hepatol 2006;4:73-80", "Y Ikawa, R Hess, H Dorward, AR Cullinane, M Huizing, BR Gochuico, WA Gahl, F Candotti. In vitro functional correction of Hermansky–Pudlak syndrome type-1 by lentiviral-mediated gene transfer.. Mol Genet Metab 2015;114:62-5", "S Ito, T Suzuki, K Inagaki, N Suzuki, K Takamori, T Yamada, M Nakazawa, M Hatano, H Takiwaki, Y Kakuta, RA Spritz, Y Tomita. High frequency of Hermansky-Pudlak syndrome type 1 (HPS1) among Japanese albinism patients and functional analysis of HPS1 mutant protein.. J Invest Dermatol 2005;125:715-20", "S Iyer, S Suresh, D Guo, K Daman, JCJ Chen, P Liu, M Zieger, K Luk, BP Roscoe, C Mueller, OD King, CP Emerson, SA Wolfe. Precise therapeutic gene correction by a simple nuclease-induced double-stranded break.. Nature 2019;568:561-5", "ML Jones, SL Murden, C Brooks, V Maloney, RA Manning, KC Gilmour, V Bharadwaj, J de la Fuente, S Chakravorty, AD Mumford. Disruption of AP3B1 by a chromosome 5 inversion: a new disease mechanism in Hermansky-Pudlak syndrome type 2.. BMC Med Genet 2013;14:42", "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", "CE Kingman, RA Kadir, CA Lee, DL Economides. The use of levonorgestrel-releasing intrauterine system for treatment of menorrhagia in women with inherited bleeding disorders.. BJOG 2004;111:1425-8", "E Lasseaux, C Plaisant, V Michaud, P Pennamen, A Trimouille, L Gaston, S Monfermé, D Lacombe, C Rooryck, F Morice-Picard, B Arveiler. Molecular characterization of a series of 990 index patients with albinism.. Pigment Cell Melanoma Res 2018;31:466-74", "W Li, CJ Hao, ZH Hao, J Ma, QC Wang, YF Yuan, JJ Gong, YY Chen, JY Yu, AH Wei. New insights into the pathogenesis of Hermansky-Pudlak syndrome.. Pigment Cell Melanoma Res 2022;35:290-302", "T Liu, Y Yuan, D Bai, X Yao, T Zhang, Q Huang, Z Qi, L Yang, X Yang, W Li, A. Wei. The first Hermansky-Pudlak syndrome type 9 patient with two novel variants in Chinese population.. J Dermatol. 2021;48:676-80", "J Lohse, S Gehrisch, JT Tauer, R Knöfler. Therapy refractory menorrhagia as first manifestation of Hermansky-Pudlak syndrome.. Hamostaseologie. 2011;31:S61-3", "GC Lowe, I Sánchez Guiu, O Chapman, J Rivera, M Lordkipanidzé, N Dovlatova, J Wilde, SP Watson, NV Morgan. Microsatellite markers as a rapid approach for autozygosity mapping in Hermansky-Pudlak syndrome: identification of the second HPS7 mutation in a patient presenting late in life.. Thromb Haemost 2013;109:766-8", "JA Martina, K Moriyama, JS Bonifacino. BLOC-3, a protein complex containing the Hermansky-Pudlak syndrome gene products HPS1 and HPS4.. J Biol Chem 2003;278:29376-84", "V Michaud, M Fiore, V Coste, Y Huguenin, JC Bordet, C Plaisant, E Lasseaux, F Morice-Picard, B Arveiler. A new case with Hermansky-Pudlak syndrome type 9, a rare cause of syndromic albinism with severe defect of platelets dense bodies.. Platelets 2021;32:420-3", "M Mohammed, N Al-Hashmi, S Al-Rashdi, N Al-Sukaiti, K Al-Adawi, M Al-Riyami, A Al-Maawali. Biallelic mutations in AP3D1 cause Hermansky-Pudlak syndrome type 10 associated with immunodeficiency and seizure disorder.. Eur J Med Genet 2019;62", "AJ Mora, DM Wolfsohn. The management of gastrointestinal disease in Hermansky-Pudlak syndrome.. J Clin Gastroenterol. 2011;45:700-2", "G Nieto-Alamilla, M Behan, M Hossain, BR Gochuico, MCV Malicdan. Hermansky-Pudlak syndrome: gene therapy for pulmonary fibrosis.. Mol Genet Metab 2022;137:187-91", "KJ O'Brien, WJ Introne, O Akal, T Akal, A Barbu, MP McGowan, MA Merideth, SL Seward, WA Gahl, BR Gochuico. Prolonged treatment with open-label pirfenidone in Hermansky-Pudlak syndrome pulmonary fibrosis.. Mol Genet Metab 2018;125:168-73", "KJ O'Brien, X Parisi, NR Shelman, MA Merideth, WJ Introne, T Heller, WA Gahl, MCV Malicdan, BR Gochuico. Inflammatory bowel disease in Hermansky-Pudlak syndrome: a retrospective single-centre cohort study.. J Intern Med. 2021;290:129-40", "K O'Brien, J Troendle, BR Gochuico, TC Markello, J Salas, H Cardona, J Yao, I Bernardini, R Hess, WA Gahl. Pirfenidone for the treatment of Hermansky-Pudlak syndrome pulmonary fibrosis.. Mol Genet Metab 2011;103:128-34", "K Okamura, Y Abe, Y Araki, K Wakamatsu, M Seishima, T Umetsu, A Kato, M Kawaguchi, M Hayashi, Y Hozumi, T Suzuki. Characterization of melanosomes and melanin in patients with Hermansky-Pudlak syndrome Types 1,4,6 and 9.. Pigment Cell Melanoma Res 2018;31:267-76", "P Pennamen, L Le, A Tingaud-Sequeira, M Fiore, A Bauters, N Van Duong Béatrice, V Coste, JC Bordet, C Plaisant, M Diallo, V Michaud, A Trimouille, D Lacombe, E Lasseaux, C Delevoye, FM Picard, B Delobel, MS Marks, B Arveiler. BLOC1S5 pathogenic variants cause a new type of Hermansky-Pudlak syndrome.. Genet Med 2020;22:1613-22", "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", "AL Ringeisen, LA Schimmenti, JG White, C Schoonveld, CG Summers. Hermansky-Pudlak syndrome (HPS5) in a nonagenarian.. J AAPOS 2013;17:334-6", "PJ Santiago Borrero, Y Rodriguez-Perez, JY Renta, NJ Izquierdo, L Del Fierro, D Munoz, NL Molina, S Ramirez, G Pagan-Mercado, I Ortiz, E Rivera-Caragol, RA Spritz, CL Cadilla. Genetic testing for oculocutaneous albinism type 1 and 2 and Hermansky-Pudlak syndrome type 1 and 3 mutations in Puerto Rico.. J Invest Dermatol 2006;126:85-90", "KU Schallreuter, E Frenk, LS Wolfe, CJ Witkop, JM Wood. Hermansky-Pudlak syndrome in a Swiss population.. Dermatology 1993;187:248-56", "RA Schinella, M Greco, BL Cobert, LW Denmark, RP Cox. Hermansky-Pudlak syndrome with granulomatous colitis.. Ann Intern Med 1980;92:20-3", "N Schreyer-Shafir, M Huizing, Y Anikster, Z Nusinker, I Bejarano-Achache, G Maftzir, L Resnik, A Helip-Wooley, W Westbroek, L Gradstein, A Rosenmann, A Blumenfeld. A new genetic isolate with a unique phenotype of syndromic oculocutaneous albinism: clinical, molecular, and cellular characteristics.. Hum Mutat 2006;27:1158", "SL Seward, WA Gahl. Hermansky-Pudlak Syndrome: Health care throughout life.. Pediatrics 2013;132:153-60", "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 Torres-Serrant, SI Ramirez, CL Cadilla, G Ramos-Valencia, PJ Santiago-Borrero. Newborn screening for Hermansky-Pudlak syndrome type 3 in Puerto Rico.. J Pediatr Hematol Oncol 2010;32:448-53", "P Velázquez-Díaz, E Nakajima, P Sorkhdini, A Hernandez-Gutierrez, A Eberle, D Yang, Y Zhou. Hermansky-Pudlak syndrome and lung disease: pathogenesis and therapeutics.. Front Pharmacol 2021;12", "GW Vicary, Y Vergne, A Santiago-Cornier, LR Young, J Roman. Pulmonary fibrosis in Hermansky–Pudlak syndrome.. Ann Am Thorac Soc 2016;13:1839-46", "T Yokoyama, BR Gochuico. Eur Respir Rev 2021;30", "LR Young, PM Gulleman, JP Bridges, TE Weaver, GH Deutsch, TS Blackwell, FX McCormack. The alveolar epithelium determines susceptibility to lung fibrosis in Hermansky-Pudlak syndrome.. Am J Respir Crit Care Med 2012;186:1014-24" ]	24/7/2000	16/3/2023	25/5/2023	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
hrpt2	hrpt2	[ "Hyperparathyroidism-Jaw Tumor Syndrome", "Familial Isolated Hyperparathyroidism", "Parathyroid Carcinoma", "Parafibromin", "CDC73", "CDC73-Related Disorders" ]		Catherine M Skefos, Steven G Waguespack, Nancy D Perrier, Mimi I Hu	Summary The spectrum of The diagnosis is established in a proband with a germline heterozygous	Hyperparathyroidism-jaw tumor syndrome Parathyroid carcinoma Familial isolated hyperparathyroidism For synonyms and outdated names see For other genetic causes of these phenotypes, see • Hyperparathyroidism-jaw tumor syndrome • Parathyroid carcinoma • Familial isolated hyperparathyroidism ## Diagnosis Primary hyperparathyroidism and ossifying fibroma(s) of the jaw Primary hyperparathyroidism with age of onset <45 years and cystic, atypical, and/or malignant parathyroid histology Childhood- or adolescent-onset primary hyperparathyroidism Childhood-onset ossifying fibroma(s) of the maxilla or mandible. Note: The frequency of Elevated total calcium corrected for albumin (preferred) or ionized calcium Elevated or inappropriately normal intact parathyroid hormone (iPTH) Somatic Parathyroid carcinoma Atypical parathyroid adenoma Parathyroid adenoma with or without cystic features Absence of nuclear parafibromin staining as demonstrated by immunohistochemistry The diagnosis of a Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include Note: Targeted analysis for 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. • Primary hyperparathyroidism and ossifying fibroma(s) of the jaw • Primary hyperparathyroidism with age of onset <45 years and cystic, atypical, and/or malignant parathyroid histology • Childhood- or adolescent-onset primary hyperparathyroidism • Childhood-onset ossifying fibroma(s) of the maxilla or mandible. Note: The frequency of • Elevated total calcium corrected for albumin (preferred) or ionized calcium • Elevated or inappropriately normal intact parathyroid hormone (iPTH) • Somatic • Parathyroid carcinoma • Atypical parathyroid adenoma • Parathyroid adenoma with or without cystic features • Absence of nuclear parafibromin staining as demonstrated by immunohistochemistry • Note: Targeted analysis for • For an introduction to multigene panels click ## Suggestive Findings Primary hyperparathyroidism and ossifying fibroma(s) of the jaw Primary hyperparathyroidism with age of onset <45 years and cystic, atypical, and/or malignant parathyroid histology Childhood- or adolescent-onset primary hyperparathyroidism Childhood-onset ossifying fibroma(s) of the maxilla or mandible. Note: The frequency of Elevated total calcium corrected for albumin (preferred) or ionized calcium Elevated or inappropriately normal intact parathyroid hormone (iPTH) Somatic Parathyroid carcinoma Atypical parathyroid adenoma Parathyroid adenoma with or without cystic features Absence of nuclear parafibromin staining as demonstrated by immunohistochemistry • Primary hyperparathyroidism and ossifying fibroma(s) of the jaw • Primary hyperparathyroidism with age of onset <45 years and cystic, atypical, and/or malignant parathyroid histology • Childhood- or adolescent-onset primary hyperparathyroidism • Childhood-onset ossifying fibroma(s) of the maxilla or mandible. Note: The frequency of • Elevated total calcium corrected for albumin (preferred) or ionized calcium • Elevated or inappropriately normal intact parathyroid hormone (iPTH) • Somatic • Parathyroid carcinoma • Atypical parathyroid adenoma • Parathyroid adenoma with or without cystic features • Absence of nuclear parafibromin staining as demonstrated by immunohistochemistry ## Establishing the Diagnosis The diagnosis of a Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include Note: Targeted analysis for 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: Targeted analysis for • For an introduction to multigene panels click ## Clinical Characteristics The spectrum of Hyperparathyroidism-jaw tumor (HPT-JT) syndrome Parathyroid carcinoma Familial isolated hyperparathyroidism (FIHP) Primary hyperparathyroidism occurs in up to 95% of individuals with HPT-JT syndrome. The onset is typically in late adolescence or early adulthood and is often the first feature of HPT-JT syndrome [ Penetrance increases with age: in a Dutch population the penetrance of primary hyperparathyroidism in individuals with HPT-JT syndrome at ages 25, 50, and 70 years was reported to be 8%, 53%, and 75%, respectively [ In most individuals with HPT-JT syndrome, hyperparathyroidism is caused by a single benign parathyroid adenoma, which is often cystic or has atypical histologic features. Pathology of parafibromin-deficient parathyroid tumors may show distinct morphology, including microcystic features, sheet-like morphology, eosinophilic cytoplasm, nuclear enlargement with coarse chromatin, prominent vascularity, and a thickened capsule [ Many families segregating a In at least 10%-15% of individuals with HPT-JT syndrome, primary hyperparathyroidism is caused by parathyroid carcinoma. Two recent studies of individuals with HPT-JT syndrome and primary hyperparathyroidism identified that 31% (17/55) and 23.5% (4/17) had parathyroid carcinoma [ The frequency of The specific features of jaw tumors associated with HPT-JT syndrome have not been well defined; in fact, pathologists disagree on the nomenclature used to classify benign fibro-osseous lesions. Most jaw tumors in HPT-JT syndrome are reported as ossifying fibromas or cementifying fibromas that occur in molar or premolar areas [ Juvenile fibromas are histologic variants of ossifying fibromas that, when they occur sporadically, tend to occur at a younger mean age than ossifying fibromas. It is not clear if juvenile fibromas are part of HPT-JT syndrome. Of nine sporadic-appearing ossifying fibromas, parafibromin staining was negative in four of seven ossifying and cemento-ossifying fibromas and positive in three juvenile ossifying fibromas, indicating that loss of CDC73 expression may contribute to the development of ossifying fibromas but not juvenile fibromas [ Of note, the jaw tumors of HPT-JT syndrome are distinct from the "brown" tumors/osteoclastomas associated with severe hyperparathyroidism (osteitis fibrosa cystica) and do not resolve following curative parathyroidectomy. Kidney cystic disease is variable and ranges from a few minor cysts to bilateral polycystic disease presenting with end-stage kidney disease [ Renal malignancy is rare in individuals with HPT-JT syndrome. One individual with HPT-JT syndrome had both papillary renal carcinoma and multiple renal cell adenomas [ Individuals with HPT-JT syndrome may be at risk for multiple bilateral kidney lesions, and nephron-sparing surgery rather than radical kidney resection should be considered [ Clinical manifestations of parathyroid carcinoma can include palpable neck mass, renal calculi, hoarseness, difficulty speaking or swallowing, muscle weakness, nausea/vomiting, altered mental status, bone pain, and/or pathologic fractures. Parathyroid carcinomas are most often associated with extremely high serum calcium concentration (>12 mg/dL) and extremely high iPTH levels (>3x the upper limit of normal). However, nonfunctioning parathyroid carcinoma can rarely occur [ Familial isolated hyperparathyroidism (FIHP) is characterized by primary hyperparathyroidism without other associated syndromic features. Individuals with The vast majority of individuals with Although no genotype-phenotype correlations for A study of 419 individuals with a Despite emerging information regarding genotype-phenotype correlations, the phenotype (including age of onset and disease manifestations) may vary widely within the same family [ While the penetrance in HPT-JT syndrome is estimated at 80%-90%, lower penetrance in females has been reported in two families [ Hyperparathyroidism-jaw tumor (HPT-JT) syndrome is also known as familial primary hyperparathyroidism with multiple ossifying jaw fibromas and familial cystic parathyroid adenomatosis. The gene The prevalence of HPT-JT syndrome is not well established. • Hyperparathyroidism-jaw tumor (HPT-JT) syndrome • Parathyroid carcinoma • Familial isolated hyperparathyroidism (FIHP) ## Clinical Description The spectrum of Hyperparathyroidism-jaw tumor (HPT-JT) syndrome Parathyroid carcinoma Familial isolated hyperparathyroidism (FIHP) Primary hyperparathyroidism occurs in up to 95% of individuals with HPT-JT syndrome. The onset is typically in late adolescence or early adulthood and is often the first feature of HPT-JT syndrome [ Penetrance increases with age: in a Dutch population the penetrance of primary hyperparathyroidism in individuals with HPT-JT syndrome at ages 25, 50, and 70 years was reported to be 8%, 53%, and 75%, respectively [ In most individuals with HPT-JT syndrome, hyperparathyroidism is caused by a single benign parathyroid adenoma, which is often cystic or has atypical histologic features. Pathology of parafibromin-deficient parathyroid tumors may show distinct morphology, including microcystic features, sheet-like morphology, eosinophilic cytoplasm, nuclear enlargement with coarse chromatin, prominent vascularity, and a thickened capsule [ Many families segregating a In at least 10%-15% of individuals with HPT-JT syndrome, primary hyperparathyroidism is caused by parathyroid carcinoma. Two recent studies of individuals with HPT-JT syndrome and primary hyperparathyroidism identified that 31% (17/55) and 23.5% (4/17) had parathyroid carcinoma [ The frequency of The specific features of jaw tumors associated with HPT-JT syndrome have not been well defined; in fact, pathologists disagree on the nomenclature used to classify benign fibro-osseous lesions. Most jaw tumors in HPT-JT syndrome are reported as ossifying fibromas or cementifying fibromas that occur in molar or premolar areas [ Juvenile fibromas are histologic variants of ossifying fibromas that, when they occur sporadically, tend to occur at a younger mean age than ossifying fibromas. It is not clear if juvenile fibromas are part of HPT-JT syndrome. Of nine sporadic-appearing ossifying fibromas, parafibromin staining was negative in four of seven ossifying and cemento-ossifying fibromas and positive in three juvenile ossifying fibromas, indicating that loss of CDC73 expression may contribute to the development of ossifying fibromas but not juvenile fibromas [ Of note, the jaw tumors of HPT-JT syndrome are distinct from the "brown" tumors/osteoclastomas associated with severe hyperparathyroidism (osteitis fibrosa cystica) and do not resolve following curative parathyroidectomy. Kidney cystic disease is variable and ranges from a few minor cysts to bilateral polycystic disease presenting with end-stage kidney disease [ Renal malignancy is rare in individuals with HPT-JT syndrome. One individual with HPT-JT syndrome had both papillary renal carcinoma and multiple renal cell adenomas [ Individuals with HPT-JT syndrome may be at risk for multiple bilateral kidney lesions, and nephron-sparing surgery rather than radical kidney resection should be considered [ Clinical manifestations of parathyroid carcinoma can include palpable neck mass, renal calculi, hoarseness, difficulty speaking or swallowing, muscle weakness, nausea/vomiting, altered mental status, bone pain, and/or pathologic fractures. Parathyroid carcinomas are most often associated with extremely high serum calcium concentration (>12 mg/dL) and extremely high iPTH levels (>3x the upper limit of normal). However, nonfunctioning parathyroid carcinoma can rarely occur [ Familial isolated hyperparathyroidism (FIHP) is characterized by primary hyperparathyroidism without other associated syndromic features. Individuals with The vast majority of individuals with • Hyperparathyroidism-jaw tumor (HPT-JT) syndrome • Parathyroid carcinoma • Familial isolated hyperparathyroidism (FIHP) ## HPT-JT Syndrome Primary hyperparathyroidism occurs in up to 95% of individuals with HPT-JT syndrome. The onset is typically in late adolescence or early adulthood and is often the first feature of HPT-JT syndrome [ Penetrance increases with age: in a Dutch population the penetrance of primary hyperparathyroidism in individuals with HPT-JT syndrome at ages 25, 50, and 70 years was reported to be 8%, 53%, and 75%, respectively [ In most individuals with HPT-JT syndrome, hyperparathyroidism is caused by a single benign parathyroid adenoma, which is often cystic or has atypical histologic features. Pathology of parafibromin-deficient parathyroid tumors may show distinct morphology, including microcystic features, sheet-like morphology, eosinophilic cytoplasm, nuclear enlargement with coarse chromatin, prominent vascularity, and a thickened capsule [ Many families segregating a In at least 10%-15% of individuals with HPT-JT syndrome, primary hyperparathyroidism is caused by parathyroid carcinoma. Two recent studies of individuals with HPT-JT syndrome and primary hyperparathyroidism identified that 31% (17/55) and 23.5% (4/17) had parathyroid carcinoma [ The frequency of The specific features of jaw tumors associated with HPT-JT syndrome have not been well defined; in fact, pathologists disagree on the nomenclature used to classify benign fibro-osseous lesions. Most jaw tumors in HPT-JT syndrome are reported as ossifying fibromas or cementifying fibromas that occur in molar or premolar areas [ Juvenile fibromas are histologic variants of ossifying fibromas that, when they occur sporadically, tend to occur at a younger mean age than ossifying fibromas. It is not clear if juvenile fibromas are part of HPT-JT syndrome. Of nine sporadic-appearing ossifying fibromas, parafibromin staining was negative in four of seven ossifying and cemento-ossifying fibromas and positive in three juvenile ossifying fibromas, indicating that loss of CDC73 expression may contribute to the development of ossifying fibromas but not juvenile fibromas [ Of note, the jaw tumors of HPT-JT syndrome are distinct from the "brown" tumors/osteoclastomas associated with severe hyperparathyroidism (osteitis fibrosa cystica) and do not resolve following curative parathyroidectomy. Kidney cystic disease is variable and ranges from a few minor cysts to bilateral polycystic disease presenting with end-stage kidney disease [ Renal malignancy is rare in individuals with HPT-JT syndrome. One individual with HPT-JT syndrome had both papillary renal carcinoma and multiple renal cell adenomas [ Individuals with HPT-JT syndrome may be at risk for multiple bilateral kidney lesions, and nephron-sparing surgery rather than radical kidney resection should be considered [ ## Parathyroid Carcinoma Clinical manifestations of parathyroid carcinoma can include palpable neck mass, renal calculi, hoarseness, difficulty speaking or swallowing, muscle weakness, nausea/vomiting, altered mental status, bone pain, and/or pathologic fractures. Parathyroid carcinomas are most often associated with extremely high serum calcium concentration (>12 mg/dL) and extremely high iPTH levels (>3x the upper limit of normal). However, nonfunctioning parathyroid carcinoma can rarely occur [ ## Familial Isolated Hyperparathyroidism Familial isolated hyperparathyroidism (FIHP) is characterized by primary hyperparathyroidism without other associated syndromic features. Individuals with The vast majority of individuals with ## Genotype-Phenotype Correlations Although no genotype-phenotype correlations for A study of 419 individuals with a Despite emerging information regarding genotype-phenotype correlations, the phenotype (including age of onset and disease manifestations) may vary widely within the same family [ ## Penetrance While the penetrance in HPT-JT syndrome is estimated at 80%-90%, lower penetrance in females has been reported in two families [ ## Nomenclature Hyperparathyroidism-jaw tumor (HPT-JT) syndrome is also known as familial primary hyperparathyroidism with multiple ossifying jaw fibromas and familial cystic parathyroid adenomatosis. The gene ## Prevalence The prevalence of HPT-JT syndrome is not well established. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this Sporadic tumors (including parathyroid carcinoma, benign parathyroid tumors, and renal tumors [clear cell, papillary, chromophobe renal cell carcinomas, oncocytomas, and Wilms tumors]) occurring as single tumors in the absence of any other findings of ## Cancer and Benign Tumors Sporadic tumors (including parathyroid carcinoma, benign parathyroid tumors, and renal tumors [clear cell, papillary, chromophobe renal cell carcinomas, oncocytomas, and Wilms tumors]) occurring as single tumors in the absence of any other findings of ## Differential Diagnosis The following disorders should be considered in the differential diagnosis of Genes of Interest in the Differential Diagnosis of Primary Hyperparathyroidism / Familial Isolated Hyperparathyroidism In a small proportion of persons w/FHH, germline pathogenic variants in Phenotype overlaps w/MEN1; however, less is known about penetrance of MEN4 & assoc lifetime risk for endocrine tumors. Primary hyperparathyroidism tends to occur at a later age in MEN4 than in MEN1. The proportion of simplex or familial primary hyperparathyroidism explained by MEN4 remains unknown. Additional endocrine tumors seen in persons w/MEN4 incl pituitary adenomas & foregut neuroendocrine tumors, which also appear to exhibit a less aggressive course than those seen in MEN1. Early data suggest that persons w/ Persons in these kindreds do not appear to be at ↑ risk for other endocrine tumors. Most common hereditary cause of primary hyperparathyroidism, accounting for 2%-4% of primary hyperparathyroidism MEN1 is also assoc w/pituitary adenomas & foregut neuroendocrine tumors, primarily gastrinomas & insulinomas. Primary hyperparathyroidism occurs in up to 20%-30% of persons w/MEN2A but is rarely the presenting feature. Additional manifestations of MEN2A incl medullary thyroid carcinoma & pheochromocytoma. AD = autosomal dominant; AR = autosomal recessive; FHH = familial hypocalciuric hypercalcemia; FIHP = familial isolated hyperparathyroidism; MOI = mode of inheritance; PTH = parathyroid hormone The differential diagnosis for ossifying fibromas of the jaw seen as part of hyperparathyroidism-jaw tumor (HPT-JT) syndrome is dependent on the radiologic characteristics of the lesions, specifically whether they are radiolucent, have mixed radiographic features, or are completely radiopaque [ Benign lesions that can be confused with HPT-JT on panoramic x-rays include but are not limited to periapical cementoplasia, giant cell lesions of the jaw (including central and peripheral giant cell granulomas), and idiopathic bone cyst. Benign anatomic variations such as exostosis, mandibular tori, maxillary torus palatinus, and the lingual concavity of the body of the mandible can also be misinterpreted as jaw tumors. See Age 20-29 years: 14% of men and 7% of women Age 30-39 years: 20% of men and 11% of women Age 40-49 years: 26% of men and 15% of women Age 50-59 years: 36% of men and 19% of women Age 60-69 years: 49% of men and 34% of women Age 70+ years: 55% of men and 43% of women Note: Of individuals with kidney cysts, 31.7% of men and 19.7% of women had bilateral cysts. Genes of Interest in the Differential Diagnosis of Renal Cysts Multiple bilateral kidney cysts; cysts in other organs (primarily liver, seminal vesicles, pancreas, & arachnoid membrane); vascular abnormalities; & abdominal wall hernias Onset typically in adulthood • In a small proportion of persons w/FHH, germline pathogenic variants in • Phenotype overlaps w/MEN1; however, less is known about penetrance of MEN4 & assoc lifetime risk for endocrine tumors. • Primary hyperparathyroidism tends to occur at a later age in MEN4 than in MEN1. • The proportion of simplex or familial primary hyperparathyroidism explained by MEN4 remains unknown. • Additional endocrine tumors seen in persons w/MEN4 incl pituitary adenomas & foregut neuroendocrine tumors, which also appear to exhibit a less aggressive course than those seen in MEN1. • Early data suggest that persons w/ • Persons in these kindreds do not appear to be at ↑ risk for other endocrine tumors. • Most common hereditary cause of primary hyperparathyroidism, accounting for 2%-4% of primary hyperparathyroidism • MEN1 is also assoc w/pituitary adenomas & foregut neuroendocrine tumors, primarily gastrinomas & insulinomas. • Primary hyperparathyroidism occurs in up to 20%-30% of persons w/MEN2A but is rarely the presenting feature. • Additional manifestations of MEN2A incl medullary thyroid carcinoma & pheochromocytoma. • Age 20-29 years: 14% of men and 7% of women • Age 30-39 years: 20% of men and 11% of women • Age 40-49 years: 26% of men and 15% of women • Age 50-59 years: 36% of men and 19% of women • Age 60-69 years: 49% of men and 34% of women • Age 70+ years: 55% of men and 43% of women • Note: Of individuals with kidney cysts, 31.7% of men and 19.7% of women had bilateral cysts. • Multiple bilateral kidney cysts; cysts in other organs (primarily liver, seminal vesicles, pancreas, & arachnoid membrane); vascular abnormalities; & abdominal wall hernias • Onset typically in adulthood ## Primary Hyperparathyroidism / Familial Isolated Hyperparathyroidism Genes of Interest in the Differential Diagnosis of Primary Hyperparathyroidism / Familial Isolated Hyperparathyroidism In a small proportion of persons w/FHH, germline pathogenic variants in Phenotype overlaps w/MEN1; however, less is known about penetrance of MEN4 & assoc lifetime risk for endocrine tumors. Primary hyperparathyroidism tends to occur at a later age in MEN4 than in MEN1. The proportion of simplex or familial primary hyperparathyroidism explained by MEN4 remains unknown. Additional endocrine tumors seen in persons w/MEN4 incl pituitary adenomas & foregut neuroendocrine tumors, which also appear to exhibit a less aggressive course than those seen in MEN1. Early data suggest that persons w/ Persons in these kindreds do not appear to be at ↑ risk for other endocrine tumors. Most common hereditary cause of primary hyperparathyroidism, accounting for 2%-4% of primary hyperparathyroidism MEN1 is also assoc w/pituitary adenomas & foregut neuroendocrine tumors, primarily gastrinomas & insulinomas. Primary hyperparathyroidism occurs in up to 20%-30% of persons w/MEN2A but is rarely the presenting feature. Additional manifestations of MEN2A incl medullary thyroid carcinoma & pheochromocytoma. AD = autosomal dominant; AR = autosomal recessive; FHH = familial hypocalciuric hypercalcemia; FIHP = familial isolated hyperparathyroidism; MOI = mode of inheritance; PTH = parathyroid hormone • In a small proportion of persons w/FHH, germline pathogenic variants in • Phenotype overlaps w/MEN1; however, less is known about penetrance of MEN4 & assoc lifetime risk for endocrine tumors. • Primary hyperparathyroidism tends to occur at a later age in MEN4 than in MEN1. • The proportion of simplex or familial primary hyperparathyroidism explained by MEN4 remains unknown. • Additional endocrine tumors seen in persons w/MEN4 incl pituitary adenomas & foregut neuroendocrine tumors, which also appear to exhibit a less aggressive course than those seen in MEN1. • Early data suggest that persons w/ • Persons in these kindreds do not appear to be at ↑ risk for other endocrine tumors. • Most common hereditary cause of primary hyperparathyroidism, accounting for 2%-4% of primary hyperparathyroidism • MEN1 is also assoc w/pituitary adenomas & foregut neuroendocrine tumors, primarily gastrinomas & insulinomas. • Primary hyperparathyroidism occurs in up to 20%-30% of persons w/MEN2A but is rarely the presenting feature. • Additional manifestations of MEN2A incl medullary thyroid carcinoma & pheochromocytoma. ## Jaw Tumors The differential diagnosis for ossifying fibromas of the jaw seen as part of hyperparathyroidism-jaw tumor (HPT-JT) syndrome is dependent on the radiologic characteristics of the lesions, specifically whether they are radiolucent, have mixed radiographic features, or are completely radiopaque [ Benign lesions that can be confused with HPT-JT on panoramic x-rays include but are not limited to periapical cementoplasia, giant cell lesions of the jaw (including central and peripheral giant cell granulomas), and idiopathic bone cyst. Benign anatomic variations such as exostosis, mandibular tori, maxillary torus palatinus, and the lingual concavity of the body of the mandible can also be misinterpreted as jaw tumors. See ## Kidney Cysts Age 20-29 years: 14% of men and 7% of women Age 30-39 years: 20% of men and 11% of women Age 40-49 years: 26% of men and 15% of women Age 50-59 years: 36% of men and 19% of women Age 60-69 years: 49% of men and 34% of women Age 70+ years: 55% of men and 43% of women Note: Of individuals with kidney cysts, 31.7% of men and 19.7% of women had bilateral cysts. Genes of Interest in the Differential Diagnosis of Renal Cysts Multiple bilateral kidney cysts; cysts in other organs (primarily liver, seminal vesicles, pancreas, & arachnoid membrane); vascular abnormalities; & abdominal wall hernias Onset typically in adulthood • Age 20-29 years: 14% of men and 7% of women • Age 30-39 years: 20% of men and 11% of women • Age 40-49 years: 26% of men and 15% of women • Age 50-59 years: 36% of men and 19% of women • Age 60-69 years: 49% of men and 34% of women • Age 70+ years: 55% of men and 43% of women • Note: Of individuals with kidney cysts, 31.7% of men and 19.7% of women had bilateral cysts. • Multiple bilateral kidney cysts; cysts in other organs (primarily liver, seminal vesicles, pancreas, & arachnoid membrane); vascular abnormalities; & abdominal wall hernias • Onset typically in adulthood ## Management To establish the extent of disease and needs in an individual identified to have a pathogenic variant in Measurement of concomitant serum calcium & iPTH Serum 25-hydroxyvitamin D to evaluate for coexisting vitamin D deficiency as a cause of ↑ iPTH or unexpectedly "normal" calcium concentrations Pelvic exam as part of routine gynecologic care Pelvic US is preferred; CT &/or MRI as clinically indicated DXA = dual-energy x-ray absorptiometry; iPTH = intact parathyroid hormone; MOI = mode of inheritance; US = ultrasound Medical geneticist, certified genetic counselor, certified advanced genetic nurse There are currently no well-established, evidence-based surveillance guidelines for individuals with a Measurement of concomitant serum calcium & iPTH Serum 25-hydroxyvitamin D to evaluate for coexisting vitamin D deficiency as a cause of ↑ iPTH or unexpectedly "normal" calcium concentrations Regular dental visits Note: Dental providers should be notified of presence of a Renal US exam to assess for kidney lesions CT or MRI as clinically indicated Gynecologic eval (incl pelvic exam) Note: Gynecologist should be notified of risk of uterine tumors. Pelvic US Further imaging studies (CT/MRI) as clinically indicated iPTH = intact parathyroid hormone; US = ultrasound Localization studies may include thyroid/parathyroid ultrasound, sestamibi, and 4D neck CT with contrast. The following should be avoided: Dehydration Radiation exposure to the neck Biopsy of extrathyroidal tissue in the neck, which increases the risk of seeding of parathyroid tissue Molecular genetic testing for the See Primary hyperparathyroidism during pregnancy may pose increased risks to the mother (symptomatic hypercalcemia) and to the fetus (intrauterine growth deficiency, preterm delivery, intrauterine fetal demise, and/or postpartum neonatal hypocalcemia) [ See Search • Measurement of concomitant serum calcium & iPTH • Serum 25-hydroxyvitamin D to evaluate for coexisting vitamin D deficiency as a cause of ↑ iPTH or unexpectedly "normal" calcium concentrations • Pelvic exam as part of routine gynecologic care • Pelvic US is preferred; CT &/or MRI as clinically indicated • Measurement of concomitant serum calcium & iPTH • Serum 25-hydroxyvitamin D to evaluate for coexisting vitamin D deficiency as a cause of ↑ iPTH or unexpectedly "normal" calcium concentrations • Regular dental visits • Note: Dental providers should be notified of presence of a • Renal US exam to assess for kidney lesions • CT or MRI as clinically indicated • Gynecologic eval (incl pelvic exam) • Note: Gynecologist should be notified of risk of uterine tumors. • Pelvic US • Further imaging studies (CT/MRI) as clinically indicated • Dehydration • Radiation exposure to the neck • Biopsy of extrathyroidal tissue in the neck, which increases the risk of seeding of parathyroid tissue ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual identified to have a pathogenic variant in Measurement of concomitant serum calcium & iPTH Serum 25-hydroxyvitamin D to evaluate for coexisting vitamin D deficiency as a cause of ↑ iPTH or unexpectedly "normal" calcium concentrations Pelvic exam as part of routine gynecologic care Pelvic US is preferred; CT &/or MRI as clinically indicated DXA = dual-energy x-ray absorptiometry; iPTH = intact parathyroid hormone; MOI = mode of inheritance; US = ultrasound Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Measurement of concomitant serum calcium & iPTH • Serum 25-hydroxyvitamin D to evaluate for coexisting vitamin D deficiency as a cause of ↑ iPTH or unexpectedly "normal" calcium concentrations • Pelvic exam as part of routine gynecologic care • Pelvic US is preferred; CT &/or MRI as clinically indicated ## Treatment of Manifestations ## Surveillance There are currently no well-established, evidence-based surveillance guidelines for individuals with a Measurement of concomitant serum calcium & iPTH Serum 25-hydroxyvitamin D to evaluate for coexisting vitamin D deficiency as a cause of ↑ iPTH or unexpectedly "normal" calcium concentrations Regular dental visits Note: Dental providers should be notified of presence of a Renal US exam to assess for kidney lesions CT or MRI as clinically indicated Gynecologic eval (incl pelvic exam) Note: Gynecologist should be notified of risk of uterine tumors. Pelvic US Further imaging studies (CT/MRI) as clinically indicated iPTH = intact parathyroid hormone; US = ultrasound Localization studies may include thyroid/parathyroid ultrasound, sestamibi, and 4D neck CT with contrast. • Measurement of concomitant serum calcium & iPTH • Serum 25-hydroxyvitamin D to evaluate for coexisting vitamin D deficiency as a cause of ↑ iPTH or unexpectedly "normal" calcium concentrations • Regular dental visits • Note: Dental providers should be notified of presence of a • Renal US exam to assess for kidney lesions • CT or MRI as clinically indicated • Gynecologic eval (incl pelvic exam) • Note: Gynecologist should be notified of risk of uterine tumors. • Pelvic US • Further imaging studies (CT/MRI) as clinically indicated ## Agents/Circumstances to Avoid The following should be avoided: Dehydration Radiation exposure to the neck Biopsy of extrathyroidal tissue in the neck, which increases the risk of seeding of parathyroid tissue • Dehydration • Radiation exposure to the neck • Biopsy of extrathyroidal tissue in the neck, which increases the risk of seeding of parathyroid tissue ## Evaluation of Relatives at Risk Molecular genetic testing for the See ## Pregnancy Management Primary hyperparathyroidism during pregnancy may pose increased risks to the mother (symptomatic hypercalcemia) and to the fetus (intrauterine growth deficiency, preterm delivery, intrauterine fetal demise, and/or postpartum neonatal hypocalcemia) [ See ## Therapies Under Investigation Search ## Genetic Counseling Some individuals with a Some individuals diagnosed with a If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status, determine their need for appropriate clinical surveillance (see If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. * A parent with somatic and germline mosaicism for a The family history of some individuals diagnosed with a If a parent of the proband is affected and/or is known to be heterozygous for the Age of onset, severity, type of symptoms, and rate of progression cannot be predicted in sibs who inherit a If the The absence of clinical symptoms in parents whose genetic status is unknown cannot be used to predict risk to sibs of a proband because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism. See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • Some individuals with a • Some individuals diagnosed with a • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status, determine their need for appropriate clinical surveillance (see • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • * A parent with somatic and germline mosaicism for a • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • * A parent with somatic and germline mosaicism for a • The family history of some individuals diagnosed with a • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • * A parent with somatic and germline mosaicism for a • If a parent of the proband is affected and/or is known to be heterozygous for the • Age of onset, severity, type of symptoms, and rate of progression cannot be predicted in sibs who inherit a • If the • The absence of clinical symptoms in parents whose genetic status is unknown cannot be used to predict risk to sibs of a proband because of the possibility of reduced penetrance in a heterozygous parent or 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 ## Risk to Family Members Some individuals with a Some individuals diagnosed with a If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status, determine their need for appropriate clinical surveillance (see If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. * A parent with somatic and germline mosaicism for a The family history of some individuals diagnosed with a If a parent of the proband is affected and/or is known to be heterozygous for the Age of onset, severity, type of symptoms, and rate of progression cannot be predicted in sibs who inherit a If the The absence of clinical symptoms in parents whose genetic status is unknown cannot be used to predict risk to sibs of a proband because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism. • Some individuals with a • Some individuals diagnosed with a • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status, determine their need for appropriate clinical surveillance (see • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • * A parent with somatic and germline mosaicism for a • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • * A parent with somatic and germline mosaicism for a • The family history of some individuals diagnosed with a • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • * A parent with somatic and germline mosaicism for a • If a parent of the proband is affected and/or is known to be heterozygous for the • Age of onset, severity, type of symptoms, and rate of progression cannot be predicted in sibs who inherit a • If the • The absence of clinical symptoms in parents whose genetic status is unknown cannot be used to predict risk to sibs of a proband because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism. ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources National Institutes of Health National Institutes of Health • • • • • • • • National Institutes of Health • • • National Institutes of Health • ## Molecular Genetics CDC73-Related Disorders: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for CDC73-Related Disorders ( Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions ## Molecular Pathogenesis Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions ## Chapter Notes All four authors are actively working with individuals with Maria E Cabanillas, MD; University of Texas, Houston (2008-2012) Mimi I Hu, MD (2012-present) Samuel M Hyde, MMSc, CGC; University of Texas MD Anderson Cancer Center (2018-2023) Michelle A Jackson, MS, CGC; University of Texas MD Anderson Cancer Center (2015-2018) Jack W Martin, MD; University of Texas MD Anderson Cancer Center (2008-2015) Nancy D Perrier, MD, FACS (2008-present) Thereasa A Rich, MS, CGC, University of Texas MD Anderson Cancer Center (2008-2023) Catherine M Skefos, MA, MS (2023-present) Steven G Waguespack, MD (2008-present) 21 September 2023 (sw) Comprehensive update posted live 26 April 2018 (sw) Comprehensive update posted live 15 January 2015 (me) Comprehensive update posted live 24 May 2012 (me) Comprehensive update posted live 31 December 2008 (me) Review posted live 12 August 2008 (tar) Original submission • 21 September 2023 (sw) Comprehensive update posted live • 26 April 2018 (sw) Comprehensive update posted live • 15 January 2015 (me) Comprehensive update posted live • 24 May 2012 (me) Comprehensive update posted live • 31 December 2008 (me) Review posted live • 12 August 2008 (tar) Original submission ## Author Notes All four authors are actively working with individuals with ## Author History Maria E Cabanillas, MD; University of Texas, Houston (2008-2012) Mimi I Hu, MD (2012-present) Samuel M Hyde, MMSc, CGC; University of Texas MD Anderson Cancer Center (2018-2023) Michelle A Jackson, MS, CGC; University of Texas MD Anderson Cancer Center (2015-2018) Jack W Martin, MD; University of Texas MD Anderson Cancer Center (2008-2015) Nancy D Perrier, MD, FACS (2008-present) Thereasa A Rich, MS, CGC, University of Texas MD Anderson Cancer Center (2008-2023) Catherine M Skefos, MA, MS (2023-present) Steven G Waguespack, MD (2008-present) ## Revision History 21 September 2023 (sw) Comprehensive update posted live 26 April 2018 (sw) Comprehensive update posted live 15 January 2015 (me) Comprehensive update posted live 24 May 2012 (me) Comprehensive update posted live 31 December 2008 (me) Review posted live 12 August 2008 (tar) Original submission • 21 September 2023 (sw) Comprehensive update posted live • 26 April 2018 (sw) Comprehensive update posted live • 15 January 2015 (me) Comprehensive update posted live • 24 May 2012 (me) Comprehensive update posted live • 31 December 2008 (me) Review posted live • 12 August 2008 (tar) Original submission ## References Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available National Cancer Institute Statement: Cancer Genetics Risk Assessment and Counseling – for health professionals (part of PDQ National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available Hampel H, Bennett RL, Buchanan A, Pearlman R, Wiesner GL; Guideline Development Group, American College of Medical Genetics and Genomics Professional Practice and Guidelines Committee and National Society of Genetic Counselors Practice Guidelines Committee. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015;17:70-87. [ • 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 Cancer Institute Statement: Cancer Genetics Risk Assessment and Counseling – for health professionals (part of PDQ • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available • Hampel H, Bennett RL, Buchanan A, Pearlman R, Wiesner GL; Guideline Development Group, American College of Medical Genetics and Genomics Professional Practice and Guidelines Committee and National Society of Genetic Counselors Practice Guidelines Committee. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015;17:70-87. [ ## 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 Cancer Institute Statement: Cancer Genetics Risk Assessment and Counseling – for health professionals (part of PDQ National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available Hampel H, Bennett RL, Buchanan A, Pearlman R, Wiesner GL; Guideline Development Group, American College of Medical Genetics and Genomics Professional Practice and Guidelines Committee and National Society of Genetic Counselors Practice Guidelines Committee. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015;17:70-87. [ • 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 Cancer Institute Statement: Cancer Genetics Risk Assessment and Counseling – for health professionals (part of PDQ • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available • Hampel H, Bennett RL, Buchanan A, Pearlman R, Wiesner GL; Guideline Development Group, American College of Medical Genetics and Genomics Professional Practice and Guidelines Committee and National Society of Genetic Counselors Practice Guidelines Committee. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015;17:70-87. [ ## Literature Cited	[]	31/12/2008	21/9/2023		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
hsan2	hsan2	[ "Hereditary Sensory and Autonomic Neuropathy Type 2 (HSAN2)", "HSANII", "HSANII", "Hereditary Sensory and Autonomic Neuropathy Type 2 (HSAN2)", "WNK1-Related HSAN2 (HSAN2A)", "RETREG1-Related HSAN2 (HSAN2B)", "KIF1A-Related HSAN2 (HSAN2C)", "SCN9A-Related HSAN2 (HSAN2D)", "Kinesin-like protein KIF1A", "Reticulophagy regulator 1", "Serine/threonine-protein kinase WNK1", "Sodium channel protein type 9 subunit alpha", "KIF1A", "RETREG1", "SCN9A", "WNK1", "Hereditary Sensory and Autonomic Neuropathy Type II" ]	Hereditary Sensory and Autonomic Neuropathy Type II	Ingo Kurth	Summary Hereditary sensory and autonomic neuropathy type II (HSAN2) is characterized by progressively reduced sensation to pain, temperature, and touch. Onset can be at birth and is often before puberty. The sensory deficit is predominantly distal with the lower limbs more severely affected than the upper limbs. Over time sensory function becomes severely reduced. Unnoticed injuries and neuropathic skin promote ulcerations and infections that result in spontaneous amputation of digits or the need for surgical amputation. Osteomyelitis is common. Painless fractures can complicate the disease. Autonomic disturbances are variable and can include hyperhidrosis, tonic pupils, and urinary incontinence in those with more advanced disease. The diagnosis of HSAN2 is established in a proband with suggestive clinical and electrophysiologic findings and biallelic pathogenic variants in one of four genes: HSAN2 is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an HSAN2-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the HSAN2-causing pathogenic variants in the family are known, carrier testing of at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible.	For synonyms and outdated names see For other genetic causes of these phenotypes, see ## Diagnosis No consensus clinical diagnostic criteria for hereditary sensory and autonomic neuropathy type II (HSAN2) have been published. Hereditary sensory and autonomic neuropathy type II (HSAN2) Congenital or early-onset (1st to 2nd decade) sensory deficit Sensory loss affecting all modalities Ulcerations of hands/feet often requiring amputation Acral mutilations Painless fractures and neuropathic arthropathy in some Varying degree of autonomic involvement: hyperhidrosis, urinary incontinence, and slow pupillary reaction to light Reduced/absent sensory nerve action potentials Preserved or reduced motor nerve conduction velocities (NCV) Variably reduced compound muscle action potentials (CMAP) The diagnosis of HSAN2 is established in a proband with suggestive clinical and electrophysiologic findings and biallelic pathogenic variants in one of four genes: Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in When the phenotypic and electrophysiologic findings suggest the diagnosis of HSAN2, the molecular genetic testing approach is use of a For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Hereditary Sensory and Autonomic Neuropathy Type II (HSAN2) 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. Data derived from the subscription-based professional view of Human Gene Mutation Database [ And Author, unpublished data Author, unpublished data • Congenital or early-onset (1st to 2nd decade) sensory deficit • Sensory loss affecting all modalities • Ulcerations of hands/feet often requiring amputation • Acral mutilations • Painless fractures and neuropathic arthropathy in some • Varying degree of autonomic involvement: hyperhidrosis, urinary incontinence, and slow pupillary reaction to light • Reduced/absent sensory nerve action potentials • Preserved or reduced motor nerve conduction velocities (NCV) • Variably reduced compound muscle action potentials (CMAP) ## Suggestive Findings Hereditary sensory and autonomic neuropathy type II (HSAN2) Congenital or early-onset (1st to 2nd decade) sensory deficit Sensory loss affecting all modalities Ulcerations of hands/feet often requiring amputation Acral mutilations Painless fractures and neuropathic arthropathy in some Varying degree of autonomic involvement: hyperhidrosis, urinary incontinence, and slow pupillary reaction to light Reduced/absent sensory nerve action potentials Preserved or reduced motor nerve conduction velocities (NCV) Variably reduced compound muscle action potentials (CMAP) • Congenital or early-onset (1st to 2nd decade) sensory deficit • Sensory loss affecting all modalities • Ulcerations of hands/feet often requiring amputation • Acral mutilations • Painless fractures and neuropathic arthropathy in some • Varying degree of autonomic involvement: hyperhidrosis, urinary incontinence, and slow pupillary reaction to light • Reduced/absent sensory nerve action potentials • Preserved or reduced motor nerve conduction velocities (NCV) • Variably reduced compound muscle action potentials (CMAP) ## Establishing the Diagnosis The diagnosis of HSAN2 is established in a proband with suggestive clinical and electrophysiologic findings and biallelic pathogenic variants in one of four genes: Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in When the phenotypic and electrophysiologic findings suggest the diagnosis of HSAN2, the molecular genetic testing approach is use of a For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Hereditary Sensory and Autonomic Neuropathy Type II (HSAN2) 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. Data derived from the subscription-based professional view of Human Gene Mutation Database [ And Author, unpublished data Author, unpublished data ## Option 1 When the phenotypic and electrophysiologic findings suggest the diagnosis of HSAN2, the molecular genetic testing approach is use of a For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Hereditary Sensory and Autonomic Neuropathy Type II (HSAN2) 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. Data derived from the subscription-based professional view of Human Gene Mutation Database [ And Author, unpublished data Author, unpublished data ## Clinical Characteristics The published clinical descriptions of hereditary sensory and autonomic neuropathy type II (HSAN2) are inconsistent, possibly in part as a result of reports that lack molecular genetic confirmation of the diagnosis. Clinically, Autonomic dysfunction may be more pronounced in Hereditary Sensory and Autonomic Neuropathy Type II (HSAN2): Gene-Phenotype Correlations ++= most common; ++= less common; += rare; -= not observed In molecularly confirmed HSAN2, onset is typically in the first two decades (often before puberty). It is characterized by progressive numbness of the hands and feet, together with reduced sensation to pain, temperature, and touch. The sensory deficit is predominantly distal with the lower limbs more severely affected than the upper limbs. Over time, sensory function becomes severely reduced. Neuropathic skin tends to produce excessive keratin and hyperkeratosis that may be forced down into the deeper layers of soft tissue and/or may crack, promoting ulcerations and infections that result in spontaneous amputation of digits or the need for surgical amputation. Osteomyelitis is common. Secondary muscle atrophy and Charcot joints may occur. Painless fractures can complicate the disease. Intellectual development is usually normal but can be impaired, especially in Sweating and tearing are usually normal but hyperhidrosis is present in some cases. Tonic pupils are observed. With progression of the disease urinary incontinence is reported. No genotype-phenotype correlations are known. Inter- and intrafamilial phenotypic variability is reported. HSAN2 has also been reported as the following: Morvan's disease Congenital sensory neuropathy Neurogenic acroosteolysis Hereditary sensory radicular neuropathy Dyck originally proposed five different HSAN types on the basis of clinical manifestations and nerve biopsy specimens [ The worldwide prevalence of HSAN2 is unknown. Several hundred affected individuals have been reported. For comparison, the overall prevalence of the closely related hereditary motor and sensory neuropathies (HMSN or Charcot-Marie-Tooth neuropathy) is about 30:100,000, and hereditary sensory and autonomic neuropathies (HSAN) occur with markedly lower frequency. See • Morvan's disease • Congenital sensory neuropathy • Neurogenic acroosteolysis • Hereditary sensory radicular neuropathy ## Clinical Description The published clinical descriptions of hereditary sensory and autonomic neuropathy type II (HSAN2) are inconsistent, possibly in part as a result of reports that lack molecular genetic confirmation of the diagnosis. Clinically, Autonomic dysfunction may be more pronounced in Hereditary Sensory and Autonomic Neuropathy Type II (HSAN2): Gene-Phenotype Correlations ++= most common; ++= less common; += rare; -= not observed In molecularly confirmed HSAN2, onset is typically in the first two decades (often before puberty). It is characterized by progressive numbness of the hands and feet, together with reduced sensation to pain, temperature, and touch. The sensory deficit is predominantly distal with the lower limbs more severely affected than the upper limbs. Over time, sensory function becomes severely reduced. Neuropathic skin tends to produce excessive keratin and hyperkeratosis that may be forced down into the deeper layers of soft tissue and/or may crack, promoting ulcerations and infections that result in spontaneous amputation of digits or the need for surgical amputation. Osteomyelitis is common. Secondary muscle atrophy and Charcot joints may occur. Painless fractures can complicate the disease. Intellectual development is usually normal but can be impaired, especially in Sweating and tearing are usually normal but hyperhidrosis is present in some cases. Tonic pupils are observed. With progression of the disease urinary incontinence is reported. ## Genotype-Phenotype Correlations No genotype-phenotype correlations are known. Inter- and intrafamilial phenotypic variability is reported. ## Nomenclature HSAN2 has also been reported as the following: Morvan's disease Congenital sensory neuropathy Neurogenic acroosteolysis Hereditary sensory radicular neuropathy Dyck originally proposed five different HSAN types on the basis of clinical manifestations and nerve biopsy specimens [ • Morvan's disease • Congenital sensory neuropathy • Neurogenic acroosteolysis • Hereditary sensory radicular neuropathy ## Prevalence The worldwide prevalence of HSAN2 is unknown. Several hundred affected individuals have been reported. For comparison, the overall prevalence of the closely related hereditary motor and sensory neuropathies (HMSN or Charcot-Marie-Tooth neuropathy) is about 30:100,000, and hereditary sensory and autonomic neuropathies (HSAN) occur with markedly lower frequency. See ## Genetically Related (Allelic) Disorders Other phenotypes associated with germline pathogenic variants in Allelic Disorders to Consider in the Differential Diagnosis of Hereditary Sensory and Autonomic Neuropathy Type II (HSAN2) AD = autosomal dominant; AR = autosomal recessive; LOF = loss of function; MOI = mode of inheritance ## Differential Diagnosis HSAN is a heterogeneous group of disorders in which pathogenic variants in other genes lead to overlapping clinical phenotypes. The distinction between HSAN and clinically similar congenital insensitivity to pain (CIP) is inconsistent. A list of genes implicated in other types of HSAN and/or CIP is provided in Disorders of Interest in the Differential Diagnosis of Hereditary Sensory and Autonomic Neuropathy Type II (HSAN2) Adapted from AD = autosomal dominant; AR = autosomal recessive; CIP = congenital insensitivity to pain; CMT = Charcot-Marie-Tooth hereditary neuropathy; DD = developmental delay; HSAN = hereditary sensory and autonomic neuropathy; HSN = hereditary sensory neuropathy; ID = intellectual disability; MOI = mode of inheritance ## Management No clinical practice guidelines for hereditary sensory and autonomic neuropathy type II (HSAN2) have been published. To establish the extent of disease and needs in an individual diagnosed with hereditary sensory and autonomic neuropathy type II (HSAN2), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended: Neurologic examination to determine extent of sensory loss and involvement of autonomic and motor nervous system 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 HSAN2 in order to facilitate medical and personal decision making Treatment is symptomatic and often involves a multidisciplinary team including neurologists, orthopedic surgeons, and physiotherapists. Training in the care of the sensory-impaired limb is important and includes self-examination – especially of the feet – for any signs of trauma. A diabetic clinic is a good source of advice. Appropriate shoes and socks are recommended. It is best to prevent callous formation in neuropathic skin; once present, calluses should be treated with hydration and lipid-based unguents to prevent cracking and may require medical consultation. Cleaning and protection of wounds on neuropathic limbs in combination with antiseptic treatment to eradicate infections helps prevent osteomyelitis and the possible future need to amputate a limb. The feet should be inspected daily for injuries and sources of wear. Affected individuals should be followed annually by centers with comprehensive care, such as those for diabetic foot care and/or Charcot-Marie-Tooth neuropathy, also known as hereditary motor and sensory neuropathy. Avoid ill-fitting shoes or other sources of trauma to the feet or hands (e.g., use protective gloves when handling hot items when cooking). It is appropriate to clarify the genetic status of at-risk sibs in order to identify those who will develop sensory loss and would benefit from measures to prevent injury to limbs and/or self-mutilation. See Search • Neurologic examination to determine extent of sensory loss and involvement of autonomic and motor nervous system • 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 HSAN2 in order to facilitate medical and personal decision making ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with hereditary sensory and autonomic neuropathy type II (HSAN2), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended: Neurologic examination to determine extent of sensory loss and involvement of autonomic and motor nervous system 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 HSAN2 in order to facilitate medical and personal decision making • Neurologic examination to determine extent of sensory loss and involvement of autonomic and motor nervous system • 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 HSAN2 in order to facilitate medical and personal decision making ## Treatment of Manifestations Treatment is symptomatic and often involves a multidisciplinary team including neurologists, orthopedic surgeons, and physiotherapists. Training in the care of the sensory-impaired limb is important and includes self-examination – especially of the feet – for any signs of trauma. A diabetic clinic is a good source of advice. Appropriate shoes and socks are recommended. It is best to prevent callous formation in neuropathic skin; once present, calluses should be treated with hydration and lipid-based unguents to prevent cracking and may require medical consultation. Cleaning and protection of wounds on neuropathic limbs in combination with antiseptic treatment to eradicate infections helps prevent osteomyelitis and the possible future need to amputate a limb. ## Surveillance The feet should be inspected daily for injuries and sources of wear. Affected individuals should be followed annually by centers with comprehensive care, such as those for diabetic foot care and/or Charcot-Marie-Tooth neuropathy, also known as hereditary motor and sensory neuropathy. ## Agents/Circumstances to Avoid Avoid ill-fitting shoes or other sources of trauma to the feet or hands (e.g., use protective gloves when handling hot items when cooking). ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of at-risk sibs in order to identify those who will develop sensory loss and would benefit from measures to prevent injury to limbs and/or self-mutilation. See ## Therapies Under Investigation Search ## Genetic Counseling Hereditary sensory and autonomic neuropathy type II (HSAN2) is an autosomal recessive disorder caused by biallelic In most families, both parents of an affected child are carriers (i.e., heterozygotes) for a In rare families, only one parent is heterozygous for a pathogenic variant and the child has HSAN2 as the result of uniparental isodisomy and consequent homozygosity for the HSAN2-causing pathogenic variant from the carrier parent. (Uniparental isodisomy has been reported in a child with Accurate recurrence risk counseling relies on carrier testing of both parents to determine if both are heterozygous for an HSAN2-causing pathogenic variant. If carrier testing detects the pathogenic variant in only one parent: And the child appears to have homozygous HSAN2-causing pathogenic variants, possible explanations include a large deletion on one allele (if not previously tested for) and uniparental isodisomy [ And the child has compound heterozygous HSAN2-causing pathogenic variants, the child may theoretically have one inherited pathogenic variant and one Heterozygotes (carriers) are asymptomatic except for the report of increased sensitivity to thermal stimuli in individuals who are heterozygous for an HSAN2-related If both parents are known to be heterozygous for an HSAN2-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Significant clinical variability between affected sibs can be observed. If the proband has HSAN2 as the result of uniparental isodisomy, if only one parent is heterozygous for an HSAN2-causing pathogenic variant, and if neither parent has a chromosome rearrangement, each sib of an affected individual has at conception a 50% chance of being a carrier and an approximately 50% chance of being unaffected and not a carrier. (The risk to sibs of a proband of being affected is unknown but is presumed to be <1%.) Heterozygotes (carriers) are typically asymptomatic (see exception in Carrier testing for at-risk relatives requires prior identification of the HSAN2-causing pathogenic variants in the family. See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once the HSAN2-causing pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • In most families, both parents of an affected child are carriers (i.e., heterozygotes) for a • In rare families, only one parent is heterozygous for a pathogenic variant and the child has HSAN2 as the result of uniparental isodisomy and consequent homozygosity for the HSAN2-causing pathogenic variant from the carrier parent. (Uniparental isodisomy has been reported in a child with • Accurate recurrence risk counseling relies on carrier testing of both parents to determine if both are heterozygous for an HSAN2-causing pathogenic variant. If carrier testing detects the pathogenic variant in only one parent: • And the child appears to have homozygous HSAN2-causing pathogenic variants, possible explanations include a large deletion on one allele (if not previously tested for) and uniparental isodisomy [ • And the child has compound heterozygous HSAN2-causing pathogenic variants, the child may theoretically have one inherited pathogenic variant and one • And the child appears to have homozygous HSAN2-causing pathogenic variants, possible explanations include a large deletion on one allele (if not previously tested for) and uniparental isodisomy [ • And the child has compound heterozygous HSAN2-causing pathogenic variants, the child may theoretically have one inherited pathogenic variant and one • Heterozygotes (carriers) are asymptomatic except for the report of increased sensitivity to thermal stimuli in individuals who are heterozygous for an HSAN2-related • And the child appears to have homozygous HSAN2-causing pathogenic variants, possible explanations include a large deletion on one allele (if not previously tested for) and uniparental isodisomy [ • And the child has compound heterozygous HSAN2-causing pathogenic variants, the child may theoretically have one inherited pathogenic variant and one • If both parents are known to be heterozygous for an HSAN2-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. • Significant clinical variability between affected sibs can be observed. • If the proband has HSAN2 as the result of uniparental isodisomy, if only one parent is heterozygous for an HSAN2-causing pathogenic variant, and if neither parent has a chromosome rearrangement, each sib of an affected individual has at conception a 50% chance of being a carrier and an approximately 50% chance of being unaffected and not a carrier. (The risk to sibs of a proband of being affected is unknown but is presumed to be <1%.) • Heterozygotes (carriers) are typically asymptomatic (see exception in • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance Hereditary sensory and autonomic neuropathy type II (HSAN2) is an autosomal recessive disorder caused by biallelic ## Risk to Family Members In most families, both parents of an affected child are carriers (i.e., heterozygotes) for a In rare families, only one parent is heterozygous for a pathogenic variant and the child has HSAN2 as the result of uniparental isodisomy and consequent homozygosity for the HSAN2-causing pathogenic variant from the carrier parent. (Uniparental isodisomy has been reported in a child with Accurate recurrence risk counseling relies on carrier testing of both parents to determine if both are heterozygous for an HSAN2-causing pathogenic variant. If carrier testing detects the pathogenic variant in only one parent: And the child appears to have homozygous HSAN2-causing pathogenic variants, possible explanations include a large deletion on one allele (if not previously tested for) and uniparental isodisomy [ And the child has compound heterozygous HSAN2-causing pathogenic variants, the child may theoretically have one inherited pathogenic variant and one Heterozygotes (carriers) are asymptomatic except for the report of increased sensitivity to thermal stimuli in individuals who are heterozygous for an HSAN2-related If both parents are known to be heterozygous for an HSAN2-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Significant clinical variability between affected sibs can be observed. If the proband has HSAN2 as the result of uniparental isodisomy, if only one parent is heterozygous for an HSAN2-causing pathogenic variant, and if neither parent has a chromosome rearrangement, each sib of an affected individual has at conception a 50% chance of being a carrier and an approximately 50% chance of being unaffected and not a carrier. (The risk to sibs of a proband of being affected is unknown but is presumed to be <1%.) Heterozygotes (carriers) are typically asymptomatic (see exception in • In most families, both parents of an affected child are carriers (i.e., heterozygotes) for a • In rare families, only one parent is heterozygous for a pathogenic variant and the child has HSAN2 as the result of uniparental isodisomy and consequent homozygosity for the HSAN2-causing pathogenic variant from the carrier parent. (Uniparental isodisomy has been reported in a child with • Accurate recurrence risk counseling relies on carrier testing of both parents to determine if both are heterozygous for an HSAN2-causing pathogenic variant. If carrier testing detects the pathogenic variant in only one parent: • And the child appears to have homozygous HSAN2-causing pathogenic variants, possible explanations include a large deletion on one allele (if not previously tested for) and uniparental isodisomy [ • And the child has compound heterozygous HSAN2-causing pathogenic variants, the child may theoretically have one inherited pathogenic variant and one • And the child appears to have homozygous HSAN2-causing pathogenic variants, possible explanations include a large deletion on one allele (if not previously tested for) and uniparental isodisomy [ • And the child has compound heterozygous HSAN2-causing pathogenic variants, the child may theoretically have one inherited pathogenic variant and one • Heterozygotes (carriers) are asymptomatic except for the report of increased sensitivity to thermal stimuli in individuals who are heterozygous for an HSAN2-related • And the child appears to have homozygous HSAN2-causing pathogenic variants, possible explanations include a large deletion on one allele (if not previously tested for) and uniparental isodisomy [ • And the child has compound heterozygous HSAN2-causing pathogenic variants, the child may theoretically have one inherited pathogenic variant and one • If both parents are known to be heterozygous for an HSAN2-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. • Significant clinical variability between affected sibs can be observed. • If the proband has HSAN2 as the result of uniparental isodisomy, if only one parent is heterozygous for an HSAN2-causing pathogenic variant, and if neither parent has a chromosome rearrangement, each sib of an affected individual has at conception a 50% chance of being a carrier and an approximately 50% chance of being unaffected and not a carrier. (The risk to sibs of a proband of being affected is unknown but is presumed to be <1%.) • Heterozygotes (carriers) are typically asymptomatic (see exception in ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the HSAN2-causing pathogenic variants in the family. ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including 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 HSAN2-causing pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • ## Molecular Genetics Hereditary Sensory and Autonomic Neuropathy Type II: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Hereditary Sensory and Autonomic Neuropathy Type II ( Notable Variants listed in the table have been provided by the author. Nucleotide and amino acid nomenclature is based on the reference sequences for The alias nucleotide and amino acid changes are derived from ## Molecular Pathogenesis Notable Variants listed in the table have been provided by the author. Nucleotide and amino acid nomenclature is based on the reference sequences for The alias nucleotide and amino acid changes are derived from ## Chapter Notes Website: The Institute of Human Genetics offers HSAN testing on a research basis via the ENISNIP consortium. For further information regarding massive parallel sequencing of HSAN-relevant genes, please contact [email protected]. 1 April 2021 (bp) Comprehensive update posted live 19 February 2015 (me) Comprehensive update posted live 3 November 2011 (ik) Revision: added HSAN2C, caused by 23 November 2010 (me) Review posted live 14 July 2010 (ik) Original submission • 1 April 2021 (bp) Comprehensive update posted live • 19 February 2015 (me) Comprehensive update posted live • 3 November 2011 (ik) Revision: added HSAN2C, caused by • 23 November 2010 (me) Review posted live • 14 July 2010 (ik) Original submission ## Author Notes Website: The Institute of Human Genetics offers HSAN testing on a research basis via the ENISNIP consortium. For further information regarding massive parallel sequencing of HSAN-relevant genes, please contact [email protected]. ## Revision History 1 April 2021 (bp) Comprehensive update posted live 19 February 2015 (me) Comprehensive update posted live 3 November 2011 (ik) Revision: added HSAN2C, caused by 23 November 2010 (me) Review posted live 14 July 2010 (ik) Original submission • 1 April 2021 (bp) Comprehensive update posted live • 19 February 2015 (me) Comprehensive update posted live • 3 November 2011 (ik) Revision: added HSAN2C, caused by • 23 November 2010 (me) Review posted live • 14 July 2010 (ik) Original submission ## References ## Literature Cited	[ "D Chiabrando, M Castori, M di Rocco, M Ungelenk, S Gießelmann, M Di Capua, A Madeo, P Grammatico, S Bartsch, CA Hübner, F Altruda, L Silengo, E Tolosano, I Kurth. Mutations in the heme exporter FLVCR1 cause sensory neurodegeneration with loss of pain perception.. PLoS Genet. 2016;12", "JJ Cox, CG Woods, I Kurth. Peripheral sensory neuropathies – pain loss vs. pain gain.. Med Genet. 2020;32:233-41", "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", "RG Lafreniere, ML MacDonald, MP Dube, J MacFarlane, M O'Driscoll, B Brais, S Meilleur, RR Brinkman, O Dadivas, T Pape, C Platon, C Radomski, J Risler, J Thompson, AM Guerra-Escobio, G Davar, XO Breakefield, SN Pimstone, R Green, W Pryse-Phillips, YP Goldberg, HB Younghusband, MR Hayden, R Sherrington, GA Rouleau, ME Samuels. Identification of a novel gene (HSN2) causing hereditary sensory and autonomic neuropathy type II through the Study of Canadian Genetic Isolates.. Am J Hum Genet. 2004;74:1064-73", "ML Loggia, MC Bushnell, M Tétreault, I Thiffault, C Bhérer, NK Mohammed, AA Kuchinad, A Laferrière, MJ Dicaire, L Loisel, JS Mogil, B Brais. Carriers of recessive WNK1/HSN2 mutations for hereditary sensory and autonomic neuropathy type 2 (HSAN2) are more sensitive to thermal stimuli.. J Neurosci. 2009;29:2162-6", "F Nicita, M Ginevrino, L Travaglini, S D'Arrigo, G Zorzi, R Borgatti, G Terrone, M Catteruccia, G Vasco, V Brankovic, S Siliquini, S Romano, C Veredice, M Pedemonte, M Armando, D Lettori, F Stregapede, L Bosco, A Sferra, V Tessarollo, R Romaniello, G Ristori, E Bertini, EM Valente, G Zanni. Heterozygous KIF1A variants underlie a wide spectrum of neurodevelopmental and neurodegenerative disorders.. J Med Genet. 2020", "GY Park, DH Jang, DW Lee, JH Jang, J Joo. Hereditary Sensory and Autonomic Neuropathy 2B Caused by a Novel RETREG1 Mutation (c.765dupT) and Paternal Uniparental Isodisomy of Chromosome 5.. Front Genet. 2019;10:1085", "M Pennings, MI Schouten, J van Gaalen, RPP Meijer, ST de Bot, M Kriek, CGJ Saris, LH van den Berg, MA van Es, DMH Zuidgeest, MW Elting, JM van de Kamp, KY van Spaendonck-Zwarts, C Die-Smulders, EH Brilstra, CC Verschuuren, BBA de Vries, J Bruijn, K Sofou, FA Duijkers, B Jaeger, JH Schieving, BP van de Warrenburg, EJ Kamsteeg. KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia.. Eur J Hum Genet. 2020;28:40-9", "K Roddier, T Thomas, G Marleau, AM Gagnon, MJ Dicaire, A St-Denis, I Gosselin, AM Sarrazin, A Larbrisseau, M Lambert, M Vanasse, D Gaudet, GA Rouleau, B Brais. Two mutations in the HSN2 gene explain the high prevalence of HSAN2 in French Canadians.. Neurology. 2005;64:1762-7", "A Rotthier, J Baets, V Timmerman, K Janssens. Mechanisms of disease in hereditary sensory and autonomic neuropathies.. Nat Rev Neurol. 2012;8:73-85", "M Shekarabi, N Girard, JB Rivière, P Dion, M Houle, A Toulouse, RG Lafrenière, F Vercauteren, P Hince, J Laganiere, D Rochefort, L Faivre, M Samuels, GA Rouleau. Mutations in the nervous system--specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II.. J Clin Invest. 2008;118:2496-505", "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", "C Schwartzlow, M Kazamel. Hereditary sensory and autonomic neuropathies: adding more to the classification.. Curr Neurol Neurosci Rep. 2019;19:52", "K Verhoeven, V Timmerman, B Mauko, TR Pieber, P De Jonghe, M Auer-Grumbach. Recent advances in hereditary sensory and autonomic neuropathies.. Curr Opin Neurol. 2006;19:474-80", "JJ Wang, B Yu, Z Li. The coexistence of a novel WNK1 variant and a copy number variation causes hereditary sensory and autonomic neuropathy type IIA.. BMC Med Genet. 2019;20:91", "J Yuan, E Matsuura, Y Higuchi, A Hashiguchi, T Nakamura, S Nozuma, Y Sakiyama, A Yoshimura, S Izumo, H Takashima. Hereditary sensory and autonomic neuropathy type IID cause by an SCN9A mutation.. Neurology. 2013;80:1641-9", "JH Yuan, A Hashiguchi, A Yoshimura, N Sakai, MP Takahashi, T Ueda, A Taniguchi, S Okamoto, N Kanazawa, Y Yamamoto, K Saigoh, S Kusunoki, M Ando, Y Hiramatsu, Y Okamoto, H Takashima. WNK1/HSN2 founder mutation in patients with hereditary sensory and autonomic neuropathy: a Japanese cohort study.. Clin Genet. 2017;92:659-63" ]	23/11/2010	1/4/2021	3/11/2011	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
hsan4	hsan4	[ "Hereditary Sensory and Autonomic Neuropathy Type IV (HSAN IV)", "Hereditary Sensory and Autonomic Neuropathy Type IV (HSAN IV)", "High affinity nerve growth factor receptor", "NTRK1", "NTRK1 Congenital Insensitivity to Pain with Anhidrosis" ]		Yasuhiro Indo	Summary The diagnosis of For AR inheritance, once the For uniparental isodisomy, once the	## Diagnosis Impaired perception of pain: In infants. Biting of the tongue, lips, or fingers after the first teeth erupt In older individuals. Repeated traumatic injuries including bruising, bone fractures, and painless joint dislocations often associated with neurogenic arthropathy (Charcot joint) of the knees and ankles. A history of failure to recognize burns and other injuries Failure of painful stimuli fail to evoke either withdrawal or emotional change. For example, no tenderness or pain sensation is elicited even when apparently injured joints or broken bones are moved passively or actively. Impaired visceral pain perception Impaired temperature perception, confirmed when: Consistent errors are made in distinguishing between hot and cold moist substances; Extreme cold or heat fails to elicit the usual withdrawal response. Anhidrosis (absence of sweating), manifesting as recurrent febrile episodes beginning in early infancy Impairment of the autonomic nervous system, which may be evident by the presence of Horner syndrome and the cold pressor test Intellectual disability The diagnosis of Note: Identification of biallelic Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Note: Targeted analysis for pathogenic variants can be performed first in individuals of the following ancestry (see Note: Homozygosity for an For an introduction to multigene panels click If exome sequencing is not diagnostic, For 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 While two variants common in Asian populations, 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. Detection rate varies by population. An intragenic deletion was observed in multiple Chinese families [ • Impaired perception of pain: • In infants. Biting of the tongue, lips, or fingers after the first teeth erupt • In older individuals. Repeated traumatic injuries including bruising, bone fractures, and painless joint dislocations often associated with neurogenic arthropathy (Charcot joint) of the knees and ankles. • A history of failure to recognize burns and other injuries • Failure of painful stimuli fail to evoke either withdrawal or emotional change. For example, no tenderness or pain sensation is elicited even when apparently injured joints or broken bones are moved passively or actively. • Impaired visceral pain perception • In infants. Biting of the tongue, lips, or fingers after the first teeth erupt • In older individuals. Repeated traumatic injuries including bruising, bone fractures, and painless joint dislocations often associated with neurogenic arthropathy (Charcot joint) of the knees and ankles. • A history of failure to recognize burns and other injuries • Failure of painful stimuli fail to evoke either withdrawal or emotional change. For example, no tenderness or pain sensation is elicited even when apparently injured joints or broken bones are moved passively or actively. • Impaired visceral pain perception • Impaired temperature perception, confirmed when: • Consistent errors are made in distinguishing between hot and cold moist substances; • Extreme cold or heat fails to elicit the usual withdrawal response. • Consistent errors are made in distinguishing between hot and cold moist substances; • Extreme cold or heat fails to elicit the usual withdrawal response. • Anhidrosis (absence of sweating), manifesting as recurrent febrile episodes beginning in early infancy • Impairment of the autonomic nervous system, which may be evident by the presence of Horner syndrome and the cold pressor test • Intellectual disability • In infants. Biting of the tongue, lips, or fingers after the first teeth erupt • In older individuals. Repeated traumatic injuries including bruising, bone fractures, and painless joint dislocations often associated with neurogenic arthropathy (Charcot joint) of the knees and ankles. • A history of failure to recognize burns and other injuries • Failure of painful stimuli fail to evoke either withdrawal or emotional change. For example, no tenderness or pain sensation is elicited even when apparently injured joints or broken bones are moved passively or actively. • Impaired visceral pain perception • Consistent errors are made in distinguishing between hot and cold moist substances; • Extreme cold or heat fails to elicit the usual withdrawal response. ## Suggestive Findings Impaired perception of pain: In infants. Biting of the tongue, lips, or fingers after the first teeth erupt In older individuals. Repeated traumatic injuries including bruising, bone fractures, and painless joint dislocations often associated with neurogenic arthropathy (Charcot joint) of the knees and ankles. A history of failure to recognize burns and other injuries Failure of painful stimuli fail to evoke either withdrawal or emotional change. For example, no tenderness or pain sensation is elicited even when apparently injured joints or broken bones are moved passively or actively. Impaired visceral pain perception Impaired temperature perception, confirmed when: Consistent errors are made in distinguishing between hot and cold moist substances; Extreme cold or heat fails to elicit the usual withdrawal response. Anhidrosis (absence of sweating), manifesting as recurrent febrile episodes beginning in early infancy Impairment of the autonomic nervous system, which may be evident by the presence of Horner syndrome and the cold pressor test Intellectual disability • Impaired perception of pain: • In infants. Biting of the tongue, lips, or fingers after the first teeth erupt • In older individuals. Repeated traumatic injuries including bruising, bone fractures, and painless joint dislocations often associated with neurogenic arthropathy (Charcot joint) of the knees and ankles. • A history of failure to recognize burns and other injuries • Failure of painful stimuli fail to evoke either withdrawal or emotional change. For example, no tenderness or pain sensation is elicited even when apparently injured joints or broken bones are moved passively or actively. • Impaired visceral pain perception • In infants. Biting of the tongue, lips, or fingers after the first teeth erupt • In older individuals. Repeated traumatic injuries including bruising, bone fractures, and painless joint dislocations often associated with neurogenic arthropathy (Charcot joint) of the knees and ankles. • A history of failure to recognize burns and other injuries • Failure of painful stimuli fail to evoke either withdrawal or emotional change. For example, no tenderness or pain sensation is elicited even when apparently injured joints or broken bones are moved passively or actively. • Impaired visceral pain perception • Impaired temperature perception, confirmed when: • Consistent errors are made in distinguishing between hot and cold moist substances; • Extreme cold or heat fails to elicit the usual withdrawal response. • Consistent errors are made in distinguishing between hot and cold moist substances; • Extreme cold or heat fails to elicit the usual withdrawal response. • Anhidrosis (absence of sweating), manifesting as recurrent febrile episodes beginning in early infancy • Impairment of the autonomic nervous system, which may be evident by the presence of Horner syndrome and the cold pressor test • Intellectual disability • In infants. Biting of the tongue, lips, or fingers after the first teeth erupt • In older individuals. Repeated traumatic injuries including bruising, bone fractures, and painless joint dislocations often associated with neurogenic arthropathy (Charcot joint) of the knees and ankles. • A history of failure to recognize burns and other injuries • Failure of painful stimuli fail to evoke either withdrawal or emotional change. For example, no tenderness or pain sensation is elicited even when apparently injured joints or broken bones are moved passively or actively. • Impaired visceral pain perception • Consistent errors are made in distinguishing between hot and cold moist substances; • Extreme cold or heat fails to elicit the usual withdrawal response. ## Establishing the Diagnosis The diagnosis of Note: Identification of biallelic Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Note: Targeted analysis for pathogenic variants can be performed first in individuals of the following ancestry (see Note: Homozygosity for an For an introduction to multigene panels click If exome sequencing is not diagnostic, For 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 While two variants common in Asian populations, 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. Detection rate varies by population. An intragenic deletion was observed in multiple Chinese families [ ## Option 1 Note: Targeted analysis for pathogenic variants can be performed first in individuals of the following ancestry (see Note: Homozygosity for an For an introduction to multigene panels click ## Option 2 If exome sequencing is not diagnostic, For 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 While two variants common in Asian populations, 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. Detection rate varies by population. An intragenic deletion was observed in multiple Chinese families [ ## Clinical Characteristics Recurrent episodic fevers, usually the first clinical sign of Occasionally, hypothermia is observed in cold environments. Anhidrosis is present on the trunk and upper extremities in 100% of cases and more variable in other areas of the body [ Tongue ulcers and fingertip biting, the characteristic self-mutilation signs observed in infants with Biting of the fingers and ulcerated fingertips is common. Bruises, cuts, and burns do not elicit normal reactions and are often unrecognized at the time that they occur. Accidental injuries such as falls or burns lead to multiple scars and can lead to cellulitis in the skin. Orthopedic problems are one of the most characteristic and serious complications of Frequent orthopedic complications: Multiple fractures often with hyperplastic new bone formation, avascular necrosis, and osteomyelitis Auto-amputation, self-mutilation (including self-inflicted soft tissue injuries) Leg length discrepancy Joint subluxation and dislocation resulting in Charcot neuroarthropathy of the feet, ankles, knees, and hips Septic arthritis Progressive scoliosis Amputations of fingers or limbs are common as a result of these complications. Decreased pain perception does not spare any area, affecting even cranial nerves and visceral sensation [ Neurotrophic keratitis (degenerative disease of the corneal epithelium resulting from impaired corneal sensation) manifests initially as superficial punctate keratopathy which later can result in corneal ulceration and even perforation [ Irritability, hyperactivity, impulsivity, and acting-out behaviors typically improve with age. The prognosis for independent functioning varies. Often the skin is dry with lichenification; the nails are dystrophic. Palmoplantar hyperkeratosis (thickening of the soles and the palms) appears in late infancy, often with scars and abrasions [ Hypotonia is seen frequently in the early years, but strength and tone normalize as the individual gets older; tendon reflexes are normal [ Gastrointestinal dysmotility is mild or absent. Vomiting is not a feature, but can be observed in some affected individuals. Speech is usually clear. Touch, vibration, and position senses Motor functions (unless repeated trauma has caused secondary dysfunction of motor neurons or limbs) Deep tendon reflexes and superficial abdominal and cremasteric reflexes See Clinical phenotype varies widely even among individuals with the same two Terms previously used to describe Familial dysautonomia type II Congenital sensory neuropathy with anhidrosis While Relatively common founder pathogenic variants have been reported in the Japanese and Israeli Bedouin populations [ Three variants – One variant – Half of reported affected individuals are offspring of consanguineous parents [ Specific carrier frequencies are not available. • Multiple fractures often with hyperplastic new bone formation, avascular necrosis, and osteomyelitis • Auto-amputation, self-mutilation (including self-inflicted soft tissue injuries) • Leg length discrepancy • Joint subluxation and dislocation resulting in Charcot neuroarthropathy of the feet, ankles, knees, and hips • Septic arthritis • Progressive scoliosis • Often the skin is dry with lichenification; the nails are dystrophic. Palmoplantar hyperkeratosis (thickening of the soles and the palms) appears in late infancy, often with scars and abrasions [ • Hypotonia is seen frequently in the early years, but strength and tone normalize as the individual gets older; tendon reflexes are normal [ • Gastrointestinal dysmotility is mild or absent. • Vomiting is not a feature, but can be observed in some affected individuals. • Speech is usually clear. • Touch, vibration, and position senses • Motor functions (unless repeated trauma has caused secondary dysfunction of motor neurons or limbs) • Deep tendon reflexes and superficial abdominal and cremasteric reflexes • Familial dysautonomia type II • Congenital sensory neuropathy with anhidrosis • Three variants – • One variant – ## Clinical Description Recurrent episodic fevers, usually the first clinical sign of Occasionally, hypothermia is observed in cold environments. Anhidrosis is present on the trunk and upper extremities in 100% of cases and more variable in other areas of the body [ Tongue ulcers and fingertip biting, the characteristic self-mutilation signs observed in infants with Biting of the fingers and ulcerated fingertips is common. Bruises, cuts, and burns do not elicit normal reactions and are often unrecognized at the time that they occur. Accidental injuries such as falls or burns lead to multiple scars and can lead to cellulitis in the skin. Orthopedic problems are one of the most characteristic and serious complications of Frequent orthopedic complications: Multiple fractures often with hyperplastic new bone formation, avascular necrosis, and osteomyelitis Auto-amputation, self-mutilation (including self-inflicted soft tissue injuries) Leg length discrepancy Joint subluxation and dislocation resulting in Charcot neuroarthropathy of the feet, ankles, knees, and hips Septic arthritis Progressive scoliosis Amputations of fingers or limbs are common as a result of these complications. Decreased pain perception does not spare any area, affecting even cranial nerves and visceral sensation [ Neurotrophic keratitis (degenerative disease of the corneal epithelium resulting from impaired corneal sensation) manifests initially as superficial punctate keratopathy which later can result in corneal ulceration and even perforation [ Irritability, hyperactivity, impulsivity, and acting-out behaviors typically improve with age. The prognosis for independent functioning varies. Often the skin is dry with lichenification; the nails are dystrophic. Palmoplantar hyperkeratosis (thickening of the soles and the palms) appears in late infancy, often with scars and abrasions [ Hypotonia is seen frequently in the early years, but strength and tone normalize as the individual gets older; tendon reflexes are normal [ Gastrointestinal dysmotility is mild or absent. Vomiting is not a feature, but can be observed in some affected individuals. Speech is usually clear. Touch, vibration, and position senses Motor functions (unless repeated trauma has caused secondary dysfunction of motor neurons or limbs) Deep tendon reflexes and superficial abdominal and cremasteric reflexes See • Multiple fractures often with hyperplastic new bone formation, avascular necrosis, and osteomyelitis • Auto-amputation, self-mutilation (including self-inflicted soft tissue injuries) • Leg length discrepancy • Joint subluxation and dislocation resulting in Charcot neuroarthropathy of the feet, ankles, knees, and hips • Septic arthritis • Progressive scoliosis • Often the skin is dry with lichenification; the nails are dystrophic. Palmoplantar hyperkeratosis (thickening of the soles and the palms) appears in late infancy, often with scars and abrasions [ • Hypotonia is seen frequently in the early years, but strength and tone normalize as the individual gets older; tendon reflexes are normal [ • Gastrointestinal dysmotility is mild or absent. • Vomiting is not a feature, but can be observed in some affected individuals. • Speech is usually clear. • Touch, vibration, and position senses • Motor functions (unless repeated trauma has caused secondary dysfunction of motor neurons or limbs) • Deep tendon reflexes and superficial abdominal and cremasteric reflexes ## Genotype-Phenotype Correlations Clinical phenotype varies widely even among individuals with the same two ## Nomenclature Terms previously used to describe Familial dysautonomia type II Congenital sensory neuropathy with anhidrosis • Familial dysautonomia type II • Congenital sensory neuropathy with anhidrosis ## Prevalence While Relatively common founder pathogenic variants have been reported in the Japanese and Israeli Bedouin populations [ Three variants – One variant – Half of reported affected individuals are offspring of consanguineous parents [ Specific carrier frequencies are not available. • Three variants – • One variant – ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The differential diagnosis of Hereditary Disorders in the Differential Diagnosis of Fractures cause pain & occur w/minimal or no trauma. Assoc w/other features incl blue sclera, short stature, joint hypermobility, deafness Hypohidrosis Risk of hyperthermia Hyperuricemia Progressive, severe DD/ID Abnormal involuntary movements Absent pain responses from birth DD Infantile-onset liver dysfunction typically → liver failure; failure to thrive, lactic acidosis, & hypoglycemia More severe neurologic involvement; may incl white matter abnormalities on MRI & seizures AD = autosomal dominant; AR = autosomal recessive; CIPA = congenital insensitivity to pain with anhidrosis; DD = developmental delay; GI = gastrointestinal; HSAN = hereditary sensory and autonomic neuropathy; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked Acquired Conditions in the Differential Diagnosis of Insensitivity to pain Painless injuries Skin lesions (hypopigmented macules, nodules, plaques, or diffuse skin infiltration) Enlargement of peripheral nerves Localized (not universal) insensitivity to pain Absence of anhidrosis Normal response to pain (although caregivers may deny this) Different pattern of injuries (proportionate to size & development) Absence of anhidrosis • Fractures cause pain & occur w/minimal or no trauma. • Assoc w/other features incl blue sclera, short stature, joint hypermobility, deafness • Hypohidrosis • Risk of hyperthermia • Hyperuricemia • Progressive, severe DD/ID • Abnormal involuntary movements • Absent pain responses from birth • DD • Infantile-onset liver dysfunction typically → liver failure; failure to thrive, lactic acidosis, & hypoglycemia • More severe neurologic involvement; may incl white matter abnormalities on MRI & seizures • Insensitivity to pain • Painless injuries • Skin lesions (hypopigmented macules, nodules, plaques, or diffuse skin infiltration) • Enlargement of peripheral nerves • Localized (not universal) insensitivity to pain • Absence of anhidrosis • Normal response to pain (although caregivers may deny this) • Different pattern of injuries (proportionate to size & development) • Absence of anhidrosis ## Management To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with Use of community or Need for social work involvement for parental support. ADHD = attention-deficit/hyperactivity disorder; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance Medical geneticist, certified genetic counselor, or certified advanced genetic nurse Treatment is supportive and is best provided by specialists in pediatrics, orthopedics, dentistry, ophthalmology, and dermatology at a center that provides comprehensive care and communication between the various subspecialties that are needed for optimal care. It is important to provide assistance and encourage therapies for behavioral, developmental, and motor delays that are appreciated during infancy and early childhood as well as to provide educational and social support for school-age children and adolescents. For details see For details see For details see In addition to daily evaluation by parents and caregivers for early signs of otherwise unrecognized injury, regular examinations by a pediatrician, orthopedist, dentist, dermatologist, and ophthalmologist are recommended to assess and advise on various physical, mental, and behavioral problems. For details, see Avoid the following: Hot or cold environments; hot or cold foods; hot showers or baths Jumping or high-impact activities and sports If the Hyperpyrexia and its potential complications, including febrile seizures; Injuries to the tongue, lips, and teeth when the primary teeth erupt. See Women with CIP are able to become pregnant and bear children normally; however, reports regarding pregnancy in women with Search • Use of community or • Need for social work involvement for parental support. • Hot or cold environments; hot or cold foods; hot showers or baths • Jumping or high-impact activities and sports • Hyperpyrexia and its potential complications, including febrile seizures; • Injuries to the tongue, lips, and teeth when the primary teeth erupt. ## 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 Use of community or Need for social work involvement for parental support. ADHD = attention-deficit/hyperactivity disorder; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance Medical geneticist, certified genetic counselor, or certified advanced genetic nurse • Use of community or • Need for social work involvement for parental support. ## Treatment of Manifestations Treatment is supportive and is best provided by specialists in pediatrics, orthopedics, dentistry, ophthalmology, and dermatology at a center that provides comprehensive care and communication between the various subspecialties that are needed for optimal care. It is important to provide assistance and encourage therapies for behavioral, developmental, and motor delays that are appreciated during infancy and early childhood as well as to provide educational and social support for school-age children and adolescents. For details see ## Prevention of Primary Manifestations For details see ## Prevention of Secondary Complications For details see ## Surveillance In addition to daily evaluation by parents and caregivers for early signs of otherwise unrecognized injury, regular examinations by a pediatrician, orthopedist, dentist, dermatologist, and ophthalmologist are recommended to assess and advise on various physical, mental, and behavioral problems. For details, see ## Agents/Circumstances to Avoid Avoid the following: Hot or cold environments; hot or cold foods; hot showers or baths Jumping or high-impact activities and sports • Hot or cold environments; hot or cold foods; hot showers or baths • Jumping or high-impact activities and sports ## Evaluation of Relatives at Risk If the Hyperpyrexia and its potential complications, including febrile seizures; Injuries to the tongue, lips, and teeth when the primary teeth erupt. See • Hyperpyrexia and its potential complications, including febrile seizures; • Injuries to the tongue, lips, and teeth when the primary teeth erupt. ## Pregnancy Management Women with CIP are able to become pregnant and bear children normally; however, reports regarding pregnancy in women with ## Therapies Under Investigation Search ## Genetic Counseling In most families, both parents of an affected child are carriers (i.e., heterozygotes) for an Less commonly, only one parent is heterozygous for an Accurate recurrence risk counseling relies on carrier testing of both parents to determine if both are heterozygous for an And the child appears to have homozygous And the child has compound heterozygous Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If each parent is known to be heterozygous for an If the proband has Carrier testing for parents, sibs, and other 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. • In most families, both parents of an affected child are carriers (i.e., heterozygotes) for an • Less commonly, only one parent is heterozygous for an • Accurate recurrence risk counseling relies on carrier testing of both parents to determine if both are heterozygous for an • And the child appears to have homozygous • And the child has compound heterozygous • And the child appears to have homozygous • And the child has compound heterozygous • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • And the child appears to have homozygous • And the child has compound heterozygous • If each parent is known to be heterozygous for an • If the proband has • 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 In most families, both parents of an affected child are carriers (i.e., heterozygotes) for an Less commonly, only one parent is heterozygous for an Accurate recurrence risk counseling relies on carrier testing of both parents to determine if both are heterozygous for an And the child appears to have homozygous And the child has compound heterozygous Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If each parent is known to be heterozygous for an If the proband has • In most families, both parents of an affected child are carriers (i.e., heterozygotes) for an • Less commonly, only one parent is heterozygous for an • Accurate recurrence risk counseling relies on carrier testing of both parents to determine if both are heterozygous for an • And the child appears to have homozygous • And the child has compound heterozygous • And the child appears to have homozygous • And the child has compound heterozygous • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • And the child appears to have homozygous • And the child has compound heterozygous • If each parent is known to be heterozygous for an • If the proband has ## Carrier Detection Carrier testing for parents, sibs, and other 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 Kitami 8-15-35-307 Tokyo 157-0067 Japan • • • • • Kitami 8-15-35-307 • Tokyo 157-0067 • Japan • ## Molecular Genetics NTRK1 Congenital Insensitivity to Pain with Anhidrosis: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for NTRK1 Congenital Insensitivity to Pain with Anhidrosis ( NGF-dependent neurons in the peripheral nervous system (PNS) include sympathetic postganglionic neurons and NGF-dependent primary afferents that depend on the NGF-TrkA system during development [ NGF-dependent neurons in the PNS also contribute to inflammatory processes; therefore, control of various neuronal or inflammatory processes via these neurons in pain, itch, and inflammation response is likely abnormal in the absence of TrkA [ These NGF-dependent neurons play pivotal roles in interoception to represent the physiologic status of all tissues of the body, as well as in stress response [ Lack of all NGF-dependent neurons in the PNS causes: Absence of pain due to absence of primary afferents (sensory neurons) in the dorsal root ganglion, which carry nerve impulses from painful and temperature stimuli; Anhidrosis due to absence of sympathetic postganglionic neurons, which innervate sweat glands. Intellectual disability and characteristic behaviors are probably neuron-deficient within the CNS (brain). Notable Variants listed in the table have been provided by the author. Variant designation that does not conform to current naming conventions Named according to • Absence of pain due to absence of primary afferents (sensory neurons) in the dorsal root ganglion, which carry nerve impulses from painful and temperature stimuli; • Anhidrosis due to absence of sympathetic postganglionic neurons, which innervate sweat glands. ## Molecular Pathogenesis NGF-dependent neurons in the peripheral nervous system (PNS) include sympathetic postganglionic neurons and NGF-dependent primary afferents that depend on the NGF-TrkA system during development [ NGF-dependent neurons in the PNS also contribute to inflammatory processes; therefore, control of various neuronal or inflammatory processes via these neurons in pain, itch, and inflammation response is likely abnormal in the absence of TrkA [ These NGF-dependent neurons play pivotal roles in interoception to represent the physiologic status of all tissues of the body, as well as in stress response [ Lack of all NGF-dependent neurons in the PNS causes: Absence of pain due to absence of primary afferents (sensory neurons) in the dorsal root ganglion, which carry nerve impulses from painful and temperature stimuli; Anhidrosis due to absence of sympathetic postganglionic neurons, which innervate sweat glands. Intellectual disability and characteristic behaviors are probably neuron-deficient within the CNS (brain). Notable Variants listed in the table have been provided by the author. Variant designation that does not conform to current naming conventions Named according to • Absence of pain due to absence of primary afferents (sensory neurons) in the dorsal root ganglion, which carry nerve impulses from painful and temperature stimuli; • Anhidrosis due to absence of sympathetic postganglionic neurons, which innervate sweat glands. ## References ## Literature Cited ## Chapter Notes Dr Indo’s work is in the fields of Pediatrics, Clinical and Molecular Genetics, and Clinical Neuroscience. Kumamoto University Repository – This work was supported in part by the Japan Society for the Promotion of Science (JSPS) (KAKENHI) Grant-in-Aid for Scientific Research and by the Ministry of Health, Labor and Welfare: Health and Labor Science Research Grants (Research on Intractable Diseases). Felicia B Axelrod, MD; New York University Medical Center (2008-2014)Gabrielle Gold-von Simson, MD, MSc; New York University Medical Center (2008-2014)Yasuhiro Indo, MD, PhD (2014-present)Carole Oddoux, PhD; New York University Medical Center (2008-2014) 30 April 2020 (bp) Comprehensive update posted live 17 April 2014 (me) Comprehensive update posted live 24 November 2009 (cd) Revision: deletion/duplication analysis available clinically 5 August 2008 (me) Review posted live 5 May 2008 (fba) Original submission • 30 April 2020 (bp) Comprehensive update posted live • 17 April 2014 (me) Comprehensive update posted live • 24 November 2009 (cd) Revision: deletion/duplication analysis available clinically • 5 August 2008 (me) Review posted live • 5 May 2008 (fba) Original submission ## Author Notes Dr Indo’s work is in the fields of Pediatrics, Clinical and Molecular Genetics, and Clinical Neuroscience. Kumamoto University Repository – ## Acknowledgments This work was supported in part by the Japan Society for the Promotion of Science (JSPS) (KAKENHI) Grant-in-Aid for Scientific Research and by the Ministry of Health, Labor and Welfare: Health and Labor Science Research Grants (Research on Intractable Diseases). ## Author History Felicia B Axelrod, MD; New York University Medical Center (2008-2014)Gabrielle Gold-von Simson, MD, MSc; New York University Medical Center (2008-2014)Yasuhiro Indo, MD, PhD (2014-present)Carole Oddoux, PhD; New York University Medical Center (2008-2014) ## Revision History 30 April 2020 (bp) Comprehensive update posted live 17 April 2014 (me) Comprehensive update posted live 24 November 2009 (cd) Revision: deletion/duplication analysis available clinically 5 August 2008 (me) Review posted live 5 May 2008 (fba) Original submission • 30 April 2020 (bp) Comprehensive update posted live • 17 April 2014 (me) Comprehensive update posted live • 24 November 2009 (cd) Revision: deletion/duplication analysis available clinically • 5 August 2008 (me) Review posted live • 5 May 2008 (fba) Original submission	[ "A Amano, S Akiyama, M Ikeda, I Morisaki. Oral manifestations of hereditary sensory and autonomic neuropathy type IV. Congenital insensitivity to pain with anhidrosis.. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1998;86:425-31", "S Amano, S Fukuoda, T Usui, N Honda, R Ideta, M Ochiai, S Yamagami, M Araie, Y Awaya. Ocular manifestations of congenital insensitivity to pain with anhidrosis.. Am J Ophthalmol. 2006;141:472-7", "FB Axelrod. Hereditary sensory and autonomic neuropathies. Familial dysautonomia and other HSANs.. Clin Auton Res. 2002;12:I2-14", "E Bar-On, D Weigl, R Parvari, K Katz, R Weitz, T Steinberg. Congenital insensitivity to pain. Orthopedic manifestations.. J Bone Joint Surg Br. 2002;84:252-7", "JL Bonkowsky, J Johnson, JC Carey, AG Smith, KJ Swoboda. An infant with primary tooth loss and palmar hyperkeratosis: a novel mutation in the NTRK1 gene causing congenital insensitivity to pain with anhidrosis.. Pediatrics. 2003;112:e237-41", "OP Carvalho, GK Thornton, J Hertecant, H Houlden, AK Nicholas, JJ Cox, M Rielly, L Al-Gazali, CG Woods. A novel NGF mutation clarifies the molecular mechanism and extends the phenotypic spectrum of the HSAN5 neuropathy.. J Med Genet. 2011;48:131-5", "K Daneshjou, H Jafarieh, SR Raaeskarami. Congenital insensitivity to pain and anhydrosis (CIPA) syndrome; a report of 4 cases.. Iran J Pediatr. 2012;22:412-6", "X Geng, Y Liu, X Ren, Y Guan, Y Wang, B Mao, X Zhao, X. Zhang. Novel NTRK1 mutations in Chinese patients with congenital insensitivity to pain with anhidrosis.. Mol Pain. 2018;14", "N. Haga, M Kubota, Z Miwa. Hereditary sensory and autonomic neuropathy types IV and V in Japan.. Pediatr Int. 2015;57:30-6", "K Huehne, C Zweier, K Raab, S Odent, M Bonnaure-Mallet, JL Sixou, P Landrieu, C Goizet, J Sarlangue, M Baumann, T Eggermann, A Rauch, S Ruppert, GM Stettner, B Rautenstrauss. Novel missense, insertion and deletion mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) associated with congenital insensitivity to pain with anhidrosis.. Neuromuscul Disord. 2008;18:159-66", "S Iftikhar, MA Javed. Seeing is not always believing: congenital insensitivity to pain with anhidrosis mimicking leprosy.. Mayo Clin Proc. 2013;88:e153-4", "Y. Indo. Genetics of congenital insensitivity to pain with anhidrosis (CIPA) or hereditary sensory and autonomic neuropathy type IV. Clinical, biologicial and molecular aspects of mutations in TRKA (NTRK1) gene encoding the receptor tyrosine kinase for nerve growth factor.. Clin Auton Res. 2002;12:I20-32", "Y. Indo. Molecular basis of congenial insensitivity to pain with anhidrosis (CIPA): mutations and polymorphisms in TRKA (NTRK1) gene encoding the receptor tyrosine kinase for nerve growth factor.. Hum Mutat. 2001;18:462-71", "Y. Indo. Nerve growth factor, pain, itch and inflammation: lessons from congenital insensitivity to pain with anhidrosis.. Expert Rev Neurother. 2010;10:1707-24", "Y. Indo. Nerve growth factor and the physiology of pain: lessons from congenital insensitivity to pain with anhidrosis.. Clin Genet. 2012;82:341-50", "Y. Indo. Neurobiology of pain, interoception and emotional response: lessons from nerve growth factor-dependent neurons.. Eur J Neurosci. 2014;39:375-91", "Y. Indo. NGF-dependent neurons and neurobiology of emotions and feelings: Lessons from congenital insensitivity to pain with anhidrosis.. Neurosci Biobehav Rev. 2018;87:1-16", "Y Indo, S Mardy, Y Miura, A Moosa, EA Ismail, E Toscano, G Andria, V Pavone, DL Brown, A Brooks, F Endo, I Matsuda. Congenital insensitivity to pain with anhidrosis (CIPA): novel mutations of the TRKA (NTRK1) gene, a putative uniparental disomy, and a linkage of the mutant TRKA and PKLR genes in a family with CIPA and pyruvate kinase deficiency.. Hum Mutat. 2001;18:308-18", "Y Indo, M Tsuruta, Y Hayashida, MA Karim, K Ohta, T Kawano, H Mitsubuchi, H Tonoki, Y Awaya, I Matsuda. Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis.. Nat Genet. 1996;13:485-8", "EA Ismail, N Al-Shammari, JT Anim, A Moosa. Congenital insensitivity to pain with anhidrosis: lack of eccrine sweat gland innervation confirmed.. J Child Neurol. 1998;13:243-6", "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", "W Kim, A Guinot, S Marleix, M Chapuis, B Fraisse, P Violas. Hereditary sensory and autonomic neuropathy type IV and orthopaedic complications.. Orthop Traumatol Surg Res. 2013;99:881-5", "I Kurth, M Baumgartner, M Schabhuttl, C Tomni, R Windhager, TM Strom, T Wieland, K Gremel, M Auer-Grumbach. Whole exome sequencing in congenital pain insensitivity identifies a novel causative intronic NTRK1-mutation due to uniparental disomy.. Am J Med Genet B Neuropsychiatr Genet. 2016;171:875-8", "ST Lee, J Lee, M Lee, JW Kim, CS Ki. Clinical and genetic analysis of Korean patients with congenital insensitivity to pain with anhidrosis.. Muscle Nerve. 2009;40:855-9", "D Levy Erez, J Levy, M Friger, Y Aharoni-Mayer, M Cohen-Iluz, E. Goldstein. Assessment of cognitive and adaptive behaviour among individuals with congenital insensitivity to pain and anhidrosis.. Dev Med Child Neurol. 2010;52:559-62", "N Li, S Guo, Q Wang, G Duan, J Sun, Y Liu, J Zhang, C Wang, C Zhu, J Liu, X Zhang. Heterogeneity of clinical features and mutation analysis of NTRK1 in Han Chinese patients with congenital insensitivity to pain with anhidrosis.. J Pain Res. 2019;12:453-65", "S Mardy, Y Miura, F Endo, I Matsuda, Y Indo. Congenital insensitivity to pain with anhidrosis (CIPA): effect of TRKA (NTRK1) missense mutations on autophosphorylation of the receptor tyrosine kinase for nerve growth factor.. Hum Mol Genet. 2001;10:179-88", "S Mardy, Y Miura, F Endo, I Matsuda, L Sztriha, P Frossard, A Moosa, EA Ismail, A Macaya, G Andria, E Toscano, W Gibson, GE Graham, Y Indo. Congenital insensitivity to pain with anhidrosis: novel mutations in the TRKA (NTRK1) gene encoding a high-affinity receptor for nerve growth factor.. Am J Hum Genet. 1999;64:1570-9", "T Mimura, S Amano, S Fukuoka, N Honda, R Arita, M Ochiai, M Yanagisawa, T Usui, K Ono, F Araki, S Yamagami, M Araie, Y. Awaya. In vivo confocal microscopy of hereditary sensory and autonomic neuropathy.. Curr Eye Res. 2008;33:940-5", "Y Miura, M Hiura, K Torigoe, O Numata, A Kuwahara, M Matsunaga, S Hasegawa, N Boku, H Ino, S Mardy, F Endo, I Matsuda, Y Indo. Complete paternal uniparental isodisomy for chromosome 1 revealed by mutation analyses of the TRKA (NTRK1) gene encoding a receptor tyrosine kinase for nerve growth factor in a patient with congenital insensitivity to pain with anhidrosis.. Hum Genet. 2000a;107:205-9", "Y Miura, S Mardy, Y Awaya, K Nihei, F Endo, I Matsuda, Y Indo. Mutation and polymorphism analysis of the TRKA (NTRK1) gene encoding a high-affinity receptor for nerve growth factor in congenital insensitivity to pain with anhidrosis (CIPA) families.. Hum Genet. 2000b;106:116-24", "S Shatzky, S Moses, J Levy, V Pinsk, E Hershkovitz, L Herzog, Z Shorer, A Luder, R Parvari. Congenital insensitivity to pain with anhidrosis (CIPA) in Israeli-Bedouins: genetic heterogeneity, novel mutations in the TRKA/NGF receptor gene, clinical findings, and results of nerve conduction studies.. Am J Med Genet. 2000;92:353-60", "Z Shorer, SW Moses, E Hershkovitz, V Pinsk, J Levy. Neurophysioloic studies in congenital insensitivity to pain with anhidrosis.. Pediatr Neurol. 2001;25:397-400", "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", "B Tüysüz, F Bayrakli, ML DiLuna, K Bilguvar, Y Bayri, C Yalcinkaya, A Bursali, E Ozdamar, B Korkmaz, CE Mason, AK Ozturk, RP Lifton, MW State, M Gunel. Novel NTRK1 mutations cause hereditary sensory and autonomic neuropathy type IV: demonstration of a founder mutation in the Turkish population.. Neurogenetics. 2008;9:119-25", "XM Xue, YQ Liu, P Pang, CF Sun. Congenital loss of permanent teeth in a patient with congenital insensitivity to pain with anhidrosis due to 2 novel mutations in the NTRK1 gene.. J Oral Maxillofac Surg. 2018;76:2582.e1-2582.e9", "R Yagev, J Levy, Z Shorer, T Lifshitz. Congenital insensitivity to pain with anhidrosis: ocular and systemic manifestations.. Am J Ophthalmol. 1999;127:322-6" ]	5/8/2008	30/4/2020	24/11/2009	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
hsn1	hsn1	[ "Hereditary Sensory and Autonomic Neuropathy Type IA", "Hereditary Sensory Neuropathy Type IA", "HSAN1A", "HSN1A", "Hereditary Sensory and Autonomic Neuropathy Type IA", "Hereditary Sensory Neuropathy Type IA", "HSAN1A", "HSN1A", "Serine palmitoyltransferase 1", "SPTLC1", "SPTLC1-Related Hereditary Sensory Neuropathy" ]		Garth A Nicholson	Summary The diagnosis of	## Diagnosis Initial sensory neuropathy that then becomes a motor and sensory axonal neuropathy Painless injuries in the feet and hands with skin ulceration, Charcot joints, sometimes amputations Distal muscle weakness that spreads proximally producing limb girdle weakness in advanced stages At some stage, occurrence of typical sharp shooting "lightning" pains lasting seconds to minutes Sensorineural hearing loss (variably present) Family history consistent with autosomal dominant inheritance 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 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, 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 Includes pathogenic variants in exon 5 and exon 6 [ 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 duplications or deletions have been found or are expected as the disease mechanism involves a gain-of-function pathogenic variant of the active site of the enzyme (see • Initial sensory neuropathy that then becomes a motor and sensory axonal neuropathy • Painless injuries in the feet and hands with skin ulceration, Charcot joints, sometimes amputations • Distal muscle weakness that spreads proximally producing limb girdle weakness in advanced stages • At some stage, occurrence of typical sharp shooting "lightning" pains lasting seconds to minutes • Sensorineural hearing loss (variably present) • Family history consistent with autosomal dominant inheritance • For an introduction to multigene panels click ## Suggestive Findings Initial sensory neuropathy that then becomes a motor and sensory axonal neuropathy Painless injuries in the feet and hands with skin ulceration, Charcot joints, sometimes amputations Distal muscle weakness that spreads proximally producing limb girdle weakness in advanced stages At some stage, occurrence of typical sharp shooting "lightning" pains lasting seconds to minutes Sensorineural hearing loss (variably present) Family history consistent with autosomal dominant inheritance • Initial sensory neuropathy that then becomes a motor and sensory axonal neuropathy • Painless injuries in the feet and hands with skin ulceration, Charcot joints, sometimes amputations • Distal muscle weakness that spreads proximally producing limb girdle weakness in advanced stages • At some stage, occurrence of typical sharp shooting "lightning" pains lasting seconds to minutes • Sensorineural hearing loss (variably present) • Family history consistent with autosomal dominant inheritance ## 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 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, 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 Includes pathogenic variants in exon 5 and exon 6 [ 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 duplications or deletions have been found or are expected as the disease mechanism involves a gain-of-function pathogenic variant of the active site of the enzyme (see • 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, 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 Includes pathogenic variants in exon 5 and exon 6 [ 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 duplications or deletions have been found or are expected as the disease mechanism involves a gain-of-function pathogenic variant of the active site of the enzyme (see ## Clinical Characteristics If the sensory loss is unheeded, chronic ulcerations of the extremities may lead to osteomyelitis and require amputations. Neuropathic joints are common. Weakness commences in the distal lower limbs, followed by the distal upper limbs and in severe cases, proximal upper- and lower-limb girdle muscles. Distal muscle weakness and wasting are present in all advanced cases. The weakness of ankle flexors produces a floppy, flipper-like foot rather than A few instances of early severe motor involvement have been reported [ Older affected individuals may require a wheelchair for mobility. Retained and even brisk proximal reflexes in some affected individuals may indicate some upper motor neuron involvement. Corticospinal degeneration was not observed on an autopsy of an individual with Sensorineural hearing loss is variable. When present, its onset is in middle to late adulthood. Rarely, pupillary abnormalities termed "tonic pupils" or pseudo-Argyll-Robertson pupils (i.e., those not associated with syphilis) are present. Visceral autonomic features are rare [Nicholson, unpublished data], with abdominal pain, diarrhea, and weight loss reported in some individuals in one family only [ Sensory nerve action potentials are reduced only late in the disease. Motor nerve conduction velocities are normal until motor action potential amplitudes become reduced. Motor nerve conduction velocities are mildly slowed and motor action potentials are reduced in advanced cases. An individual with pathogenic variant p.Ser331Tyr was included in a description of Variable penetrance has been observed [ The term "hereditary sensory neuropathy" (HSN) was first used by Motor involvement was also noted in other families in southern England and described by Ellison in his University of Edinburgh MD thesis, and later by Even so, the terms "HSN" and "HSAN" are not ideal, as the disorder is both a sensory and a The term "HSN1" designates HSN affects 25 of 600 families (4.2%) with CMT studied by the author. Of these families with HSN, 25% have If the overall incidence of motor and sensory neuropathies is 30:100,000, the prevalence of HSN is on the order of 2:1,000,000. HSN1A may be underestimated because diagnosis previously depended erroneously on finding pure sensory involvement, shooting pains, and/or skin damage or ulcers. • Sensory nerve action potentials are reduced only late in the disease. • Motor nerve conduction velocities are normal until motor action potential amplitudes become reduced. • Motor nerve conduction velocities are mildly slowed and motor action potentials are reduced in advanced cases. ## Clinical Description If the sensory loss is unheeded, chronic ulcerations of the extremities may lead to osteomyelitis and require amputations. Neuropathic joints are common. Weakness commences in the distal lower limbs, followed by the distal upper limbs and in severe cases, proximal upper- and lower-limb girdle muscles. Distal muscle weakness and wasting are present in all advanced cases. The weakness of ankle flexors produces a floppy, flipper-like foot rather than A few instances of early severe motor involvement have been reported [ Older affected individuals may require a wheelchair for mobility. Retained and even brisk proximal reflexes in some affected individuals may indicate some upper motor neuron involvement. Corticospinal degeneration was not observed on an autopsy of an individual with Sensorineural hearing loss is variable. When present, its onset is in middle to late adulthood. Rarely, pupillary abnormalities termed "tonic pupils" or pseudo-Argyll-Robertson pupils (i.e., those not associated with syphilis) are present. Visceral autonomic features are rare [Nicholson, unpublished data], with abdominal pain, diarrhea, and weight loss reported in some individuals in one family only [ Sensory nerve action potentials are reduced only late in the disease. Motor nerve conduction velocities are normal until motor action potential amplitudes become reduced. Motor nerve conduction velocities are mildly slowed and motor action potentials are reduced in advanced cases. • Sensory nerve action potentials are reduced only late in the disease. • Motor nerve conduction velocities are normal until motor action potential amplitudes become reduced. • Motor nerve conduction velocities are mildly slowed and motor action potentials are reduced in advanced cases. ## Genotype-Phenotype Correlations An individual with pathogenic variant p.Ser331Tyr was included in a description of ## Penetrance Variable penetrance has been observed [ ## Nomenclature The term "hereditary sensory neuropathy" (HSN) was first used by Motor involvement was also noted in other families in southern England and described by Ellison in his University of Edinburgh MD thesis, and later by Even so, the terms "HSN" and "HSAN" are not ideal, as the disorder is both a sensory and a The term "HSN1" designates ## Prevalence HSN affects 25 of 600 families (4.2%) with CMT studied by the author. Of these families with HSN, 25% have If the overall incidence of motor and sensory neuropathies is 30:100,000, the prevalence of HSN is on the order of 2:1,000,000. HSN1A may be underestimated because diagnosis previously depended erroneously on finding pure sensory involvement, shooting pains, and/or skin damage or ulcers. ## Genetically Related (Allelic) Disorders ## Differential Diagnosis Dominant forms of hereditary sensory neuropathy (HSN) are genetically heterogeneous: HSAN1B (OMIM HSAN1C (OMIM HSN1D (OMIM HSN1E ( Disorders with similar phenotypes are two forms of CMT2B, a motor and sensory neuropathy with severe sensory loss and foot ulcers but no shooting pains. CMT2B is caused by pathogenic variants in CMT2I/J. The Painful diabetic neuropathy may have a similar phenotype but usually lacks a family history of neuropathy. See • HSAN1B (OMIM • HSAN1C (OMIM • HSN1D (OMIM • HSN1E ( • CMT2B, a motor and sensory neuropathy with severe sensory loss and foot ulcers but no shooting pains. CMT2B is caused by pathogenic variants in • CMT2I/J. The ## Management To establish the extent of disease and needs in an individual diagnosed with Examination of the skin of the feet, ankles, and hands Examination of joints for evidence of Charcot joints Strength assessment Examination for loss of sweating and compensatory patchy hyperhidrosis Consultation with a clinical geneticist and/or genetic counselor Wounds on neuropathic limbs heal if they are clean and protected and the limb is rested. Principles of treatment are the same as for leprosy surgery; see Foot drop can be treated with ankle/foot orthotics, but these need sleeving with stockings or some form of second skin to prevent skin abrasion. Charcot joints may require arthrodesis. Shooting pains are difficult to treat and only partial relief can be obtained with carbamazepine, gabapentin, or amitriptyline, or a combination of anti-seizure and antidepressant medication. Opiates are contraindicated as Foot ulcers are frequently caused by breakdown of callus. Therefore, it is important to prevent callus formation by removing sources of pressure and to treat existing callus by softening the skin. Routine foot care by a diabetic clinic or by a podiatrist instructed to treat as for a diabetic foot is recommended. Burns can be prevented by using gloves as needed (e.g., during cooking). A diabetic education clinic is an excellent source of advice regarding skin care. Feet should be inspected at least daily for injuries or sources of wear. Opiates are contraindicated as this is a chronic disorder. See Search • Examination of the skin of the feet, ankles, and hands • Examination of joints for evidence of Charcot joints • Strength assessment • Examination for loss of sweating and compensatory patchy hyperhidrosis • 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 Examination of the skin of the feet, ankles, and hands Examination of joints for evidence of Charcot joints Strength assessment Examination for loss of sweating and compensatory patchy hyperhidrosis Consultation with a clinical geneticist and/or genetic counselor • Examination of the skin of the feet, ankles, and hands • Examination of joints for evidence of Charcot joints • Strength assessment • Examination for loss of sweating and compensatory patchy hyperhidrosis • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations Wounds on neuropathic limbs heal if they are clean and protected and the limb is rested. Principles of treatment are the same as for leprosy surgery; see Foot drop can be treated with ankle/foot orthotics, but these need sleeving with stockings or some form of second skin to prevent skin abrasion. Charcot joints may require arthrodesis. Shooting pains are difficult to treat and only partial relief can be obtained with carbamazepine, gabapentin, or amitriptyline, or a combination of anti-seizure and antidepressant medication. Opiates are contraindicated as ## Prevention of Secondary Complications Foot ulcers are frequently caused by breakdown of callus. Therefore, it is important to prevent callus formation by removing sources of pressure and to treat existing callus by softening the skin. Routine foot care by a diabetic clinic or by a podiatrist instructed to treat as for a diabetic foot is recommended. Burns can be prevented by using gloves as needed (e.g., during cooking). A diabetic education clinic is an excellent source of advice regarding skin care. ## Surveillance Feet should be inspected at least daily for injuries or sources of wear. ## Agents/Circumstances to Avoid Opiates are contraindicated as this is a chronic disorder. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Most individuals diagnosed with Some individuals diagnosed with If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a Molecular genetic testing is recommended for the parents of a proband with an apparent The family history of some individuals diagnosed with If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to each sib of inheriting the pathogenic variant is 50%; sibs who inherit the pathogenic variant may or may not be affected as reduced penetrance has been observed. If the If the parents have not been tested for the Note: Because diagnostic clinical and electrophysiologic findings have not been reported to emerge after age 30 years, sibs who are asymptomatic at age 30 years are no longer considered to be at increased risk for Predictive testing for at-risk relatives is possible once the Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. 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 HSN1A it is appropriate to consider testing of symptomatic individuals regardless of age. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, 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 • Some individuals diagnosed with • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a • Molecular genetic testing is recommended for the parents of a proband with an apparent • The family history of some individuals diagnosed with • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to each sib of inheriting the pathogenic variant is 50%; sibs who inherit the pathogenic variant may or may not be affected as reduced penetrance has been observed. • If the • If the parents have not been tested for the • Note: Because diagnostic clinical and electrophysiologic findings have not been reported to emerge after age 30 years, sibs who are asymptomatic at age 30 years are no longer considered to be at increased risk for • Predictive testing for at-risk relatives is possible once the • Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. • 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 Some individuals diagnosed with If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a Molecular genetic testing is recommended for the parents of a proband with an apparent The family history of some individuals diagnosed with If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to each sib of inheriting the pathogenic variant is 50%; sibs who inherit the pathogenic variant may or may not be affected as reduced penetrance has been observed. If the If the parents have not been tested for the Note: Because diagnostic clinical and electrophysiologic findings have not been reported to emerge after age 30 years, sibs who are asymptomatic at age 30 years are no longer considered to be at increased risk for • Most individuals diagnosed with • Some individuals diagnosed with • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a • Molecular genetic testing is recommended for the parents of a proband with an apparent • The family history of some individuals diagnosed with • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to each sib of inheriting the pathogenic variant is 50%; sibs who inherit the pathogenic variant may or may not be affected as reduced penetrance has been observed. • If the • If the parents have not been tested for the • Note: Because diagnostic clinical and electrophysiologic findings have not been reported to emerge after age 30 years, sibs who are asymptomatic at age 30 years are no longer considered to be at increased risk for ## Related Genetic Counseling Issues Predictive testing for at-risk relatives is possible once the Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. 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 HSN1A it is appropriate to consider testing of symptomatic individuals regardless of age. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • Predictive testing for at-risk relatives is possible once the • Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. • 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 SPTLC1-Related Hereditary Sensory Neuropathy: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for SPTLC1-Related Hereditary Sensory Neuropathy ( The most common pathogenic variant, p.Cys133Trp in exon 5, was found in English and Canadian families and in US and Australian families of English origin [ A pathogenic variant affecting the same codon, p.Cys133Tyr, was described in two families of Austrian and German origin [ The pathogenic variant p.Val144Asp in exon 6 was found in two Australian families of English and Scottish origins [ Variants listed in the table have been provided by the author. See Expression of the mutated gene product has not been investigated. Overexpression of the wild type allele in a mouse model of HSN1A has reversed the phenotype [ • The most common pathogenic variant, p.Cys133Trp in exon 5, was found in English and Canadian families and in US and Australian families of English origin [ • A pathogenic variant affecting the same codon, p.Cys133Tyr, was described in two families of Austrian and German origin [ • The pathogenic variant p.Val144Asp in exon 6 was found in two Australian families of English and Scottish origins [ ## Chapter Notes 2 December 2021 (aa) Revision: additions to Genetically Related Disorders and Genotype-Phenotype Correlations [ 21 November 2018 (sw) Comprehensive update posted live 10 September 2015 (me) Comprehensive update posted live 7 March 2013 (me) Comprehensive update posted live 3 May 2012 (gn) Revision: edits to Therapies Under Investigation 15 March 2012 (cd) Revision: targeted mutation analysis no longer listed as available clinically in the GeneTests™ Laboratory Directory 22 September 2011 (cd) Revision: addition to Differential Diagnosis; change in disease nomenclature (HSN1 → HSN1A) 20 July 2010 (me) Comprehensive update posted live 2 October 2007 (me) Comprehensive update posted live 11 March 2005 (me) Comprehensive update posted live 28 September 2004 (me) Comprehensive update posted live 21 May 2004 (gn) Revision: prenatal testing available 23 September 2002 (me) Review posted live 21 March 2002 (gn) Original submission • 2 December 2021 (aa) Revision: additions to Genetically Related Disorders and Genotype-Phenotype Correlations [ • 21 November 2018 (sw) Comprehensive update posted live • 10 September 2015 (me) Comprehensive update posted live • 7 March 2013 (me) Comprehensive update posted live • 3 May 2012 (gn) Revision: edits to Therapies Under Investigation • 15 March 2012 (cd) Revision: targeted mutation analysis no longer listed as available clinically in the GeneTests™ Laboratory Directory • 22 September 2011 (cd) Revision: addition to Differential Diagnosis; change in disease nomenclature (HSN1 → HSN1A) • 20 July 2010 (me) Comprehensive update posted live • 2 October 2007 (me) Comprehensive update posted live • 11 March 2005 (me) Comprehensive update posted live • 28 September 2004 (me) Comprehensive update posted live • 21 May 2004 (gn) Revision: prenatal testing available • 23 September 2002 (me) Review posted live • 21 March 2002 (gn) Original submission ## Revision History 2 December 2021 (aa) Revision: additions to Genetically Related Disorders and Genotype-Phenotype Correlations [ 21 November 2018 (sw) Comprehensive update posted live 10 September 2015 (me) Comprehensive update posted live 7 March 2013 (me) Comprehensive update posted live 3 May 2012 (gn) Revision: edits to Therapies Under Investigation 15 March 2012 (cd) Revision: targeted mutation analysis no longer listed as available clinically in the GeneTests™ Laboratory Directory 22 September 2011 (cd) Revision: addition to Differential Diagnosis; change in disease nomenclature (HSN1 → HSN1A) 20 July 2010 (me) Comprehensive update posted live 2 October 2007 (me) Comprehensive update posted live 11 March 2005 (me) Comprehensive update posted live 28 September 2004 (me) Comprehensive update posted live 21 May 2004 (gn) Revision: prenatal testing available 23 September 2002 (me) Review posted live 21 March 2002 (gn) Original submission • 2 December 2021 (aa) Revision: additions to Genetically Related Disorders and Genotype-Phenotype Correlations [ • 21 November 2018 (sw) Comprehensive update posted live • 10 September 2015 (me) Comprehensive update posted live • 7 March 2013 (me) Comprehensive update posted live • 3 May 2012 (gn) Revision: edits to Therapies Under Investigation • 15 March 2012 (cd) Revision: targeted mutation analysis no longer listed as available clinically in the GeneTests™ Laboratory Directory • 22 September 2011 (cd) Revision: addition to Differential Diagnosis; change in disease nomenclature (HSN1 → HSN1A) • 20 July 2010 (me) Comprehensive update posted live • 2 October 2007 (me) Comprehensive update posted live • 11 March 2005 (me) Comprehensive update posted live • 28 September 2004 (me) Comprehensive update posted live • 21 May 2004 (gn) Revision: prenatal testing available • 23 September 2002 (me) Review posted live • 21 March 2002 (gn) Original submission ## References ## Published Guidelines / Consensus Statements ## Literature Cited	[]	23/9/2002	21/11/2018	2/12/2021	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
hsp	hsp	[ "Strumpell-Lorrain Syndrome", "Uncomplicated Hereditary Spastic Paraparesis", "Strumpell-Lorrain Syndrome", "Uncomplicated Hereditary Spastic Paraparesis", "ENTPD1-Related Neurodevelopmental Disorder", "60 kDa heat shock protein, mitochondrial", "Acetyl-coenzyme A transporter 1", "AP-5 complex subunit zeta-1", "Atlastin-1", "Cytochrome P450 7B1", "Delta-1-pyrroline-5-carboxylate synthase", "Double-stranded RNA-specific adenosine deaminase", "Dynamin-2", "Erlin-2", "Kinesin heavy chain isoform 5A", "Kinesin-like protein KIF1A", "Magnesium transporter NIPA1", "Mitochondrial inner membrane m-AAA protease component paraplegin", "Palmitoyl thioesterase CPT1C", "Phospholipase DDHD1", "Plasma membrane calcium-transporting ATPase 4", "Receptor expression-enhancing protein 1", "Receptor expression-enhancing protein 2", "Reticulon-2", "Seipin", "Spastin", "Ubiquitin carboxyl-terminal hydrolase 8", "WASH complex subunit 5", "ADAR", "ALDH18A1", "AP5Z1", "ATL1", "ATP2B4", "BSCL2", "CPT1C", "CYP7B1", "DDHD1", "DNM2", "ERLIN2", "HSPD1", "KIF1A", "KIF5A", "NIPA1", "REEP1", "REEP2", "RTN2", "SLC33A1", "SPAST", "SPG7", "USP8", "WASHC5", "Uncomplicated (Pure) Hereditary Spastic Paraplegia Overview", "Overview" ]	Uncomplicated (Pure) Hereditary Spastic Paraplegia Overview	Peter Hedera	Summary The purpose of this overview is to: Briefly describe the Review the Review the Provide an Review Inform	## Clinical Characteristics of Uncomplicated Hereditary Spastic Paraplegia The predominant manifestations of uncomplicated (pure) hereditary spastic paraplegia (HSP) are progressive bilateral lower-extremity spasticity (maximal in hamstrings, quadriceps, adductors, and gastrocnemius-soleus muscles) and weakness (maximal in the iliopsoas, hamstring, and tibialis anterior muscles). Spasticity and weakness are variable; while some individuals have spasticity and no demonstrable weakness, others have spasticity and weakness in approximately the same proportions. Onset may occur in very early childhood with (typically) non-progressive manifestations that resemble spastic diplegic cerebral palsy, or later in childhood or older with (typically) slowly progressive manifestations. Though manifestations may be disabling, life span is not shortened. Difficulty walking that may be non-progressive or may worsen insidiously (affected individuals often present with stumbling due to difficulties with foot dorsiflexion). After several years, individuals with progressively worsening gait may experience a "functional plateau" (i.e., the rate of further worsening of gait impairment is like that attributable to age). Often, the need for canes, walkers, or wheelchairs Possible urinary urgency (hypertonic urinary bladder disturbance) and lower-extremity paresthesias (mild diminution of distal lower-extremity vibration sensation) Typically, normal strength and dexterity of the upper extremities No involvement of speech, chewing, or swallowing Lower-extremity hyperreflexia and extensor plantar responses may be demonstrated on neurologic examination. The combination of progressive gait abnormality and frank, symmetrical corticospinal tract deficit is a clinical hallmark of uncomplicated HSP. • Difficulty walking that may be non-progressive or may worsen insidiously (affected individuals often present with stumbling due to difficulties with foot dorsiflexion). After several years, individuals with progressively worsening gait may experience a "functional plateau" (i.e., the rate of further worsening of gait impairment is like that attributable to age). • Often, the need for canes, walkers, or wheelchairs • Possible urinary urgency (hypertonic urinary bladder disturbance) and lower-extremity paresthesias (mild diminution of distal lower-extremity vibration sensation) • Typically, normal strength and dexterity of the upper extremities • No involvement of speech, chewing, or swallowing ## Causes of Uncomplicated Hereditary Spastic Paraplegia To date, more than 20 genes associated with uncomplicated (pure) hereditary spastic paraplegia (HSP) have been identified. Inheritance can be autosomal dominant or autosomal recessive. It has been emphasized that because the phenotypic spectrum within a given genetic disorder can be broad and intrafamilial variability and interfamilial variability are typical, knowledge of the causative gene does not inform the phenotype in an individual or a family [ SPG4 (caused by a pathogenic variant in SPG3A (caused by a pathogenic variant in SPG30 (caused by a pathogenic variant in Other types of autosomal dominant uncomplicated HSP with a predominantly adult onset are relatively rare, accounting for 1% or less. Note: Many of the genes included in Autosomal Dominant Uncomplicated Hereditary Spastic Paraplegia: Genes and Selected Clinical Features Uncomplicated HSP Cataracts Gastroesophageal reflux Motor neuronopathy Variably present: dysarthria, ataxia, cognitive impairment Rare Also assoc w/AR complicated HSP (SPG9B) Uncomplicated HSP characterized by minimal progression w/status course; may present as spastic diplegic cerebral palsy Complicated HSP w/axonal motor neuropathy &/or distal amyotrophy w/lower motor neuron involvement (Silver syndrome phenotype) 80% of early-onset AD HSP 10%-15% of all AD HSP AR inheritance reported in 2 families. Uncomplicated HSP (foot deformity may be present) Complicated HSP w/amyotrophy of leg muscles &/or pathologic nerve conduction velocities; can be indistinguishable from ALS Uncomplicated HSP Amyotrophy w/ALS-like phenotype can develop in later stages of disease Uncomplicated HSP Complicated HSP ± mild ID, optic nerve atrophy, & rarely epilepsy 5%-6% of all AD HSP Also assoc w/AR hereditary sensory & motor neuropathy type 2 Uncomplicated HSP or predominantly uncomplicated HSP Complicated HSP w/polyneuropathy, pes cavus, &/or ataxia 1%-2% of all AD HSP 5%-8% of all complicated AD HSP Uncomplicated HSP characterized by severe weakness & spasticity; rapidly progressive Complicated HSP w/epilepsy or variable peripheral neuropathy Rare Inheritance can be AD or AR. Uncomplicated HSP w/mild pes cavus; slowly progressive Complicated HSP Uncomplicated HSP. Subtle cognitive impairment has been documented but its relation to the disease remains undetermined (deficits appear late in disease course & are not present in all affected members of a given family). Complicated HSP w/variable distal amyotrophy &/or ataxia Uncomplicated HSP Complicated HSP w/dysarthria, ataxia, optic atrophy, &/or supranuclear palsy AD = autosomal dominant; AR = autosomal recessive; ALS = amyotrophic lateral sclerosis; HSP = hereditary spastic paraplegia; ID = intellectual disability; Genes are listed alphabetically. The most common types of autosomal recessive HSP in the general population are: SPG5 (caused by pathogenic variants in SPG7 (caused by pathogenic variants in SPG11 (caused by pathogenic variants in Note: Most of the genes included in Autosomal Recessive Uncomplicated Hereditary Spastic Paraplegia: Genes and Selected Clinical Features Uncomplicated HSP w/urinary incontinence Complicated HSP w/parkinsonism, dystonia, thin corpus callosum, & leukodystrophy; severe DD in infantile onset Uncomplicated HSP w/minimal progression & static course; may present as spastic diplegic cerebral palsy Complicated HSP w/peripheral neuropathy; autonomic failure reported Uncomplicated HSP Complicated HSP w/ataxia, polyneuropathy, extrapyramidal signs, & MRI signs of leukodystrophy Uncomplicated HSP Complicated HSP w/scoliosis, axonal neuropathy, & cerebellar ataxia Uncomplicated HSP Complicated HSP w/DD, seizures, & contractures; juvenile primary lateral sclerosis phenotype reported Rare Typically assoc w/complicated HSP (uncomplicated AR HSP reported rarely) Also assoc w/AD uncomplicated HSP Rare Inheritance can be AD or AR. Uncomplicated HSP Complicated HSP incl optic neuropathy, progressive external ophthalmoplegia/ptosis, slowed speech, swallowing difficulties, palatal tremor, & subtle cognitive impairment 5%-12% of AR HSP AD inheritance suggested for some pathogenic variants; this remains controversial Uncomplicated HSP Complicated HSP w/ID, polyneuropathy, & ataxia; can also present as juvenile ALS. AD = autosomal dominant; AR = autosomal recessive; ALS = amyotrophic lateral sclerosis; DD = developmental delay; HSP = hereditary spastic paraplegia; ID = intellectual disability Genes are listed alphabetically. • SPG4 (caused by a pathogenic variant in • SPG3A (caused by a pathogenic variant in • SPG30 (caused by a pathogenic variant in • Other types of autosomal dominant uncomplicated HSP with a predominantly adult onset are relatively rare, accounting for 1% or less. • Uncomplicated HSP • Cataracts • Gastroesophageal reflux • Motor neuronopathy • Variably present: dysarthria, ataxia, cognitive impairment • Rare • Also assoc w/AR complicated HSP (SPG9B) • Uncomplicated HSP characterized by minimal progression w/status course; may present as spastic diplegic cerebral palsy • Complicated HSP w/axonal motor neuropathy &/or distal amyotrophy w/lower motor neuron involvement (Silver syndrome phenotype) • 80% of early-onset AD HSP • 10%-15% of all AD HSP • AR inheritance reported in 2 families. • Uncomplicated HSP (foot deformity may be present) • Complicated HSP w/amyotrophy of leg muscles &/or pathologic nerve conduction velocities; can be indistinguishable from ALS • Uncomplicated HSP • Amyotrophy w/ALS-like phenotype can develop in later stages of disease • Uncomplicated HSP • Complicated HSP ± mild ID, optic nerve atrophy, & rarely epilepsy • 5%-6% of all AD HSP • Also assoc w/AR hereditary sensory & motor neuropathy type 2 • Uncomplicated HSP or predominantly uncomplicated HSP • Complicated HSP w/polyneuropathy, pes cavus, &/or ataxia • 1%-2% of all AD HSP • 5%-8% of all complicated AD HSP • Uncomplicated HSP characterized by severe weakness & spasticity; rapidly progressive • Complicated HSP w/epilepsy or variable peripheral neuropathy • Rare • Inheritance can be AD or AR. • Uncomplicated HSP w/mild pes cavus; slowly progressive • Complicated HSP • Uncomplicated HSP. Subtle cognitive impairment has been documented but its relation to the disease remains undetermined (deficits appear late in disease course & are not present in all affected members of a given family). • Complicated HSP w/variable distal amyotrophy &/or ataxia • Uncomplicated HSP • Complicated HSP w/dysarthria, ataxia, optic atrophy, &/or supranuclear palsy • SPG5 (caused by pathogenic variants in • SPG7 (caused by pathogenic variants in • SPG11 (caused by pathogenic variants in • Uncomplicated HSP w/urinary incontinence • Complicated HSP w/parkinsonism, dystonia, thin corpus callosum, & leukodystrophy; severe DD in infantile onset • Uncomplicated HSP w/minimal progression & static course; may present as spastic diplegic cerebral palsy • Complicated HSP w/peripheral neuropathy; autonomic failure reported • Uncomplicated HSP • Complicated HSP w/ataxia, polyneuropathy, extrapyramidal signs, & MRI signs of leukodystrophy • Uncomplicated HSP • Complicated HSP w/scoliosis, axonal neuropathy, & cerebellar ataxia • Uncomplicated HSP • Complicated HSP w/DD, seizures, & contractures; juvenile primary lateral sclerosis phenotype reported • Rare • Typically assoc w/complicated HSP (uncomplicated AR HSP reported rarely) • Also assoc w/AD uncomplicated HSP • Rare • Inheritance can be AD or AR. • Uncomplicated HSP • Complicated HSP incl optic neuropathy, progressive external ophthalmoplegia/ptosis, slowed speech, swallowing difficulties, palatal tremor, & subtle cognitive impairment • 5%-12% of AR HSP • AD inheritance suggested for some pathogenic variants; this remains controversial • Uncomplicated HSP • Complicated HSP w/ID, polyneuropathy, & ataxia; can also present as juvenile ALS. ## Differential Diagnosis of Uncomplicated Hereditary Spastic Paraplegia The differential diagnosis of uncomplicated (pure) hereditary spastic paraplegia (HSP) includes complicated HSP (characterized by the impairments present in uncomplicated HSP plus other system involvement or other neurologic findings such as ataxia, seizures, intellectual disability, dementia, muscle atrophy, extrapyramidal disturbance, and/or peripheral neuropathy), other genetic disorders, and acquired conditions. Cobalamin C disease (See Glycine encephalopathy (See Purine nucleoside phosphorylase deficiency (OMIM Steadily progressive Note: A complete list of non-genetic disorders in the differential diagnosis of uncomplicated HSP is out the scope of this chapter; see • • Cobalamin C disease (See • • • Glycine encephalopathy (See • • • Purine nucleoside phosphorylase deficiency (OMIM • • Cobalamin C disease (See • • • Glycine encephalopathy (See • • • Purine nucleoside phosphorylase deficiency (OMIM • • Cobalamin C disease (See • • • Glycine encephalopathy (See • • • Purine nucleoside phosphorylase deficiency (OMIM • Steadily progressive ## Evaluation Strategies to Identify the Genetic Cause of Uncomplicated Hereditary Spastic Paraplegia in a Proband Establishing a specific genetic cause of uncomplicated (pure) hereditary spastic paraplegia (HSP): Can aid in discussions of prognosis (which are beyond the scope of this Usually involves a medical history, physical examination, laboratory testing, family history, and genomic/genetic testing. Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires the clinician to hypothesize which gene(s) are likely involved, whereas genomic testing does not. For an introduction to multigene panels click For an introduction to comprehensive genomic testing click • Can aid in discussions of prognosis (which are beyond the scope of this • Usually involves a medical history, physical examination, laboratory testing, family history, and genomic/genetic testing. • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Genomic/Genetic Testing Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires the clinician to hypothesize which gene(s) are likely involved, whereas genomic testing does not. For an introduction to multigene panels click For an introduction to comprehensive genomic testing click • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Management No clinical practice guidelines for uncomplicated (pure) hereditary spastic paraplegia (HSP) have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder and information provided by To establish the extent of disease and needs in an individual diagnosed with uncomplicated HSP, the evaluations summarized in Uncomplicated Hereditary Spastic Paraplegia: Recommended Evaluations Following Initial Diagnosis Muscle tone; joint range of motion; posture; mobility; strength, coordination, & endurance; pain; bedsores Need for adaptive devices Footwear needs PT needs To assess small motor function, e.g., hands, feet, face, fingers, & toes To assess ADL Referral to urologist Consider urodynamic eval. Community or online resources such as Social work involvement for parental support ADL = activities of daily living; EMG = electromyography; HSP = hereditary spastic paraplegia; MOI = mode of inheritance; NCV = nerve conduction velocity; OT = occupational therapy; PT = physical therapy; SLP = speech-language pathologist Spastic Paraplegia Rating Scale (SPRS) [ Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) At present, no specific treatments can prevent or reverse nerve degeneration in uncomplicated HSP. 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 Uncomplicated Hereditary Spastic Paraplegia: Treatment of Manifestations Stretching exercises to improve flexibility, ↓ spasticity, & maintain or improve joint range of motion & prevent joint contractures Aerobic exercise to improve cardiovascular fitness to maintain & improve muscle strength, coordination, & balance Strengthening exercises to improve posture, walking, arm strength to improve use of mobility aids, ADL Massage, ultrasound, electrical stimulation, whirlpool Anodal spinal direct current stimulation Determine exact cause of swallowing malfunction. Modify food types & consistency, head positioning during swallowing, & exercises to improve swallowing. Appropriate footwear; orthotics (shoe inserts, splints, braces) to address gait problems, improve balance, relieve &/or improve pressure sores Gait training; use of assistive walking devices (e.g., canes, walker, walker w/wheels, walker w/seat, wheelchairs) Transfers (e.g., from bed to wheelchair, wheelchair to car) Training how to fall to minimize risk of injury To accomplish tasks such as mobility, washing, dressing, eating, cooking, grooming To assist w/household modifications to meet special needs ADL = activities of daily living; OT = occupational therapy/therapist; PT = physical therapy/therapist; SLP = speech-language pathologist The role of surgical hamstring and heel cord lengthening and release of the adductor longus remains unknown but should be considered if contractures appear. Demonstrated by Baclofen can be tried first and can be used with an intrathecal pump in some individuals. The entire therapeutic range of doses in all four drugs is used. The drugs are administered before sleep if nocturnal cramps are problematic; otherwise, three to four times per day. It usually takes a few days for their effects to become evident. No significant toxicity limits their use. There is no consensus regarding the frequency of clinical follow up visits; however, routine reevaluations for individuals with uncomplicated HSP are warranted (see Uncomplicated Hereditary Spastic Paraplegia: Recommended Surveillance ADL = activities of daily living; OT = occupational therapist; PT = physical therapist Dantrolene should be avoided in persons who are ambulatory as it may induce irreversible weakness that can adversely affect overall mobility. • Muscle tone; joint range of motion; posture; mobility; strength, coordination, & endurance; pain; bedsores • Need for adaptive devices • Footwear needs • PT needs • To assess small motor function, e.g., hands, feet, face, fingers, & toes • To assess ADL • Referral to urologist • Consider urodynamic eval. • Community or online resources such as • Social work involvement for parental support • Stretching exercises to improve flexibility, ↓ spasticity, & maintain or improve joint range of motion & prevent joint contractures • Aerobic exercise to improve cardiovascular fitness to maintain & improve muscle strength, coordination, & balance • Strengthening exercises to improve posture, walking, arm strength to improve use of mobility aids, ADL • Massage, ultrasound, electrical stimulation, whirlpool • Anodal spinal direct current stimulation • Determine exact cause of swallowing malfunction. • Modify food types & consistency, head positioning during swallowing, & exercises to improve swallowing. • Appropriate footwear; orthotics (shoe inserts, splints, braces) to address gait problems, improve balance, relieve &/or improve pressure sores • Gait training; use of assistive walking devices (e.g., canes, walker, walker w/wheels, walker w/seat, wheelchairs) • Transfers (e.g., from bed to wheelchair, wheelchair to car) • Training how to fall to minimize risk of injury • To accomplish tasks such as mobility, washing, dressing, eating, cooking, grooming • To assist w/household modifications to meet special needs ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with uncomplicated HSP, the evaluations summarized in Uncomplicated Hereditary Spastic Paraplegia: Recommended Evaluations Following Initial Diagnosis Muscle tone; joint range of motion; posture; mobility; strength, coordination, & endurance; pain; bedsores Need for adaptive devices Footwear needs PT needs To assess small motor function, e.g., hands, feet, face, fingers, & toes To assess ADL Referral to urologist Consider urodynamic eval. Community or online resources such as Social work involvement for parental support ADL = activities of daily living; EMG = electromyography; HSP = hereditary spastic paraplegia; MOI = mode of inheritance; NCV = nerve conduction velocity; OT = occupational therapy; PT = physical therapy; SLP = speech-language pathologist Spastic Paraplegia Rating Scale (SPRS) [ Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Muscle tone; joint range of motion; posture; mobility; strength, coordination, & endurance; pain; bedsores • Need for adaptive devices • Footwear needs • PT needs • To assess small motor function, e.g., hands, feet, face, fingers, & toes • To assess ADL • Referral to urologist • Consider urodynamic eval. • Community or online resources such as • Social work involvement for parental support ## Treatment of Manifestations At present, no specific treatments can prevent or reverse nerve degeneration in uncomplicated HSP. 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 Uncomplicated Hereditary Spastic Paraplegia: Treatment of Manifestations Stretching exercises to improve flexibility, ↓ spasticity, & maintain or improve joint range of motion & prevent joint contractures Aerobic exercise to improve cardiovascular fitness to maintain & improve muscle strength, coordination, & balance Strengthening exercises to improve posture, walking, arm strength to improve use of mobility aids, ADL Massage, ultrasound, electrical stimulation, whirlpool Anodal spinal direct current stimulation Determine exact cause of swallowing malfunction. Modify food types & consistency, head positioning during swallowing, & exercises to improve swallowing. Appropriate footwear; orthotics (shoe inserts, splints, braces) to address gait problems, improve balance, relieve &/or improve pressure sores Gait training; use of assistive walking devices (e.g., canes, walker, walker w/wheels, walker w/seat, wheelchairs) Transfers (e.g., from bed to wheelchair, wheelchair to car) Training how to fall to minimize risk of injury To accomplish tasks such as mobility, washing, dressing, eating, cooking, grooming To assist w/household modifications to meet special needs ADL = activities of daily living; OT = occupational therapy/therapist; PT = physical therapy/therapist; SLP = speech-language pathologist The role of surgical hamstring and heel cord lengthening and release of the adductor longus remains unknown but should be considered if contractures appear. Demonstrated by Baclofen can be tried first and can be used with an intrathecal pump in some individuals. The entire therapeutic range of doses in all four drugs is used. The drugs are administered before sleep if nocturnal cramps are problematic; otherwise, three to four times per day. It usually takes a few days for their effects to become evident. No significant toxicity limits their use. • Stretching exercises to improve flexibility, ↓ spasticity, & maintain or improve joint range of motion & prevent joint contractures • Aerobic exercise to improve cardiovascular fitness to maintain & improve muscle strength, coordination, & balance • Strengthening exercises to improve posture, walking, arm strength to improve use of mobility aids, ADL • Massage, ultrasound, electrical stimulation, whirlpool • Anodal spinal direct current stimulation • Determine exact cause of swallowing malfunction. • Modify food types & consistency, head positioning during swallowing, & exercises to improve swallowing. • Appropriate footwear; orthotics (shoe inserts, splints, braces) to address gait problems, improve balance, relieve &/or improve pressure sores • Gait training; use of assistive walking devices (e.g., canes, walker, walker w/wheels, walker w/seat, wheelchairs) • Transfers (e.g., from bed to wheelchair, wheelchair to car) • Training how to fall to minimize risk of injury • To accomplish tasks such as mobility, washing, dressing, eating, cooking, grooming • To assist w/household modifications to meet special needs ## Surveillance There is no consensus regarding the frequency of clinical follow up visits; however, routine reevaluations for individuals with uncomplicated HSP are warranted (see Uncomplicated Hereditary Spastic Paraplegia: Recommended Surveillance ADL = activities of daily living; OT = occupational therapist; PT = physical therapist ## Agents/Circumstances to Avoid Dantrolene should be avoided in persons who are ambulatory as it may induce irreversible weakness that can adversely affect overall mobility. ## Genetic Counseling Uncomplicated (pure) hereditary spastic paraplegia (HSP) can be inherited in an autosomal dominant or autosomal recessive manner. Genetic counseling and risk assessment depend on determination of the specific genetic cause of uncomplicated HSP in an individual. Several genes involved in uncomplicated HSP are associated with both autosomal dominant and autosomal recessive HSP (see Most individuals diagnosed with autosomal dominant uncomplicated HSP have an affected parent. Some individuals diagnosed with autosomal dominant uncomplicated HSP 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. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of a parent before the onset of symptoms, or late onset of the disease in an affected parent. Therefore, If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Parental gonadal mosaicism has been reported in If a parent of the proband is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. The age of onset and degree of disability are highly variable among heterozygous members of the same family. If the HSP-related pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [ If the parents 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 an affected individual are presumed to be heterozygous for an autosomal recessive uncomplicated HSP-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 HSP-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. Heterozygous parents of an individual with autosomal recessive uncomplicated HSP are typically asymptomatic. The only exception reported to date was a family in which the proband had compound heterozygosity for biallelic If both parents are known to be heterozygous for an autosomal recessive uncomplicated HSP-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Heterozygous sibs are typically asymptomatic provided the family history is consistent with autosomal recessive inheritance and affected individuals have biallelic pathogenic variants. Caution must be exercised when counseling an individual who has all the signs and symptoms of uncomplicated HSP but no similarly affected relatives and in whom a molecular diagnosis has not been established. Without a molecular diagnosis of HSP, the possibility of a diagnosis other than uncomplicated HSP (e.g., primary lateral sclerosis or an acquired disorder) cannot be ruled out and a mode of inheritance cannot be definitively established. Knowledge of the causative gene does not inform the phenotype in an individual or a family because the phenotypic spectrum within a given genetic disorder can be broad and intrafamilial variability is typical [ 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 general discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having an HSP-related pathogenic variant; however, it is not possible to make specific predictions about the potential severity of disease in offspring. Once the pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for hereditary spastic paraplegia 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 autosomal dominant uncomplicated HSP have an affected parent. • Some individuals diagnosed with autosomal dominant uncomplicated HSP 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. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of a parent before the onset of symptoms, or late onset of the disease in an affected parent. Therefore, • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Parental gonadal mosaicism has been reported in • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Parental gonadal mosaicism has been reported in • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Parental gonadal mosaicism has been reported in • 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%. • The age of onset and degree of disability are highly variable among heterozygous members of the same family. • If the HSP-related pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [ • If the parents 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 an affected individual are presumed to be heterozygous for an autosomal recessive uncomplicated HSP-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 HSP-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. • Heterozygous parents of an individual with autosomal recessive uncomplicated HSP are typically asymptomatic. The only exception reported to date was a family in which the proband had compound heterozygosity for biallelic • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual 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 uncomplicated HSP-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. • Heterozygous sibs are typically asymptomatic provided the family history is consistent with autosomal recessive inheritance and affected individuals have biallelic pathogenic variants. • 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 general discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having an HSP-related pathogenic variant; however, it is not possible to make specific predictions about the potential severity of disease in offspring. ## Mode of Inheritance Uncomplicated (pure) hereditary spastic paraplegia (HSP) can be inherited in an autosomal dominant or autosomal recessive manner. Genetic counseling and risk assessment depend on determination of the specific genetic cause of uncomplicated HSP in an individual. Several genes involved in uncomplicated HSP are associated with both autosomal dominant and autosomal recessive HSP (see ## Autosomal Dominant Uncomplicated HSP – Risk to Family Members Most individuals diagnosed with autosomal dominant uncomplicated HSP have an affected parent. Some individuals diagnosed with autosomal dominant uncomplicated HSP 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. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of a parent before the onset of symptoms, or late onset of the disease in an affected parent. Therefore, If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Parental gonadal mosaicism has been reported in If a parent of the proband is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. The age of onset and degree of disability are highly variable among heterozygous members of the same family. If the HSP-related pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [ If the parents 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 • Most individuals diagnosed with autosomal dominant uncomplicated HSP have an affected parent. • Some individuals diagnosed with autosomal dominant uncomplicated HSP 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. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of a parent before the onset of symptoms, or late onset of the disease in an affected parent. Therefore, • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Parental gonadal mosaicism has been reported in • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Parental gonadal mosaicism has been reported in • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Parental gonadal mosaicism has been reported in • 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%. • The age of onset and degree of disability are highly variable among heterozygous members of the same family. • If the HSP-related pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [ • If the parents 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 Uncomplicated HSP – Risk to Family Members The parents of an affected individual are presumed to be heterozygous for an autosomal recessive uncomplicated HSP-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 HSP-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. Heterozygous parents of an individual with autosomal recessive uncomplicated HSP are typically asymptomatic. The only exception reported to date was a family in which the proband had compound heterozygosity for biallelic If both parents are known to be heterozygous for an autosomal recessive uncomplicated HSP-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Heterozygous sibs are typically asymptomatic provided the family history is consistent with autosomal recessive inheritance and affected individuals have biallelic pathogenic variants. • The parents of an affected individual are presumed to be heterozygous for an autosomal recessive uncomplicated HSP-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 HSP-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. • Heterozygous parents of an individual with autosomal recessive uncomplicated HSP are typically asymptomatic. The only exception reported to date was a family in which the proband had compound heterozygosity for biallelic • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual 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 uncomplicated HSP-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. • Heterozygous sibs are typically asymptomatic provided the family history is consistent with autosomal recessive inheritance and affected individuals have biallelic pathogenic variants. ## Related Genetic Counseling Issues Caution must be exercised when counseling an individual who has all the signs and symptoms of uncomplicated HSP but no similarly affected relatives and in whom a molecular diagnosis has not been established. Without a molecular diagnosis of HSP, the possibility of a diagnosis other than uncomplicated HSP (e.g., primary lateral sclerosis or an acquired disorder) cannot be ruled out and a mode of inheritance cannot be definitively established. Knowledge of the causative gene does not inform the phenotype in an individual or a family because the phenotypic spectrum within a given genetic disorder can be broad and intrafamilial variability is typical [ 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 general discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having an HSP-related pathogenic variant; however, it is not possible to make specific predictions about the potential severity of disease in offspring. • 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 general discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having an HSP-related pathogenic variant; however, it is not possible to make specific predictions about the potential severity of disease in offspring. ## Prenatal Testing and Preimplantation Genetic Testing Once the pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for hereditary spastic paraplegia 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 Australia Tom Wahlig Stiftung Germany Associazione Italiana Vivere la Paraparesi Spastica Italy • • • • Australia • • • • • • • • • Tom Wahlig Stiftung • Germany • • • Associazione Italiana Vivere la Paraparesi Spastica • Italy • ## Chapter Notes Web page: John K Fink, MD; University of Michigan (2000-2018)Peter Hedera, MD, PhD, FACMG (2018-present) 5 June 2025 (bp) Comprehensive update posted live 27 September 2018 (ha) Comprehensive update posted live 6 February 2014 (me) Comprehensive update posted live 11 July 2007 (me) Comprehensive update posted live 22 September 2003 (me) Comprehensive update posted live 15 August 2000 (me) Overview posted live 21 March 2000 (jf) Original submission • 5 June 2025 (bp) Comprehensive update posted live • 27 September 2018 (ha) Comprehensive update posted live • 6 February 2014 (me) Comprehensive update posted live • 11 July 2007 (me) Comprehensive update posted live • 22 September 2003 (me) Comprehensive update posted live • 15 August 2000 (me) Overview posted live • 21 March 2000 (jf) Original submission ## Author Notes Web page: ## Author History John K Fink, MD; University of Michigan (2000-2018)Peter Hedera, MD, PhD, FACMG (2018-present) ## Revision History 5 June 2025 (bp) Comprehensive update posted live 27 September 2018 (ha) Comprehensive update posted live 6 February 2014 (me) Comprehensive update posted live 11 July 2007 (me) Comprehensive update posted live 22 September 2003 (me) Comprehensive update posted live 15 August 2000 (me) Overview posted live 21 March 2000 (jf) Original submission • 5 June 2025 (bp) Comprehensive update posted live • 27 September 2018 (ha) Comprehensive update posted live • 6 February 2014 (me) Comprehensive update posted live • 11 July 2007 (me) Comprehensive update posted live • 22 September 2003 (me) Comprehensive update posted live • 15 August 2000 (me) Overview posted live • 21 March 2000 (jf) Original submission ## References ## Literature Cited	[]	15/8/2000	5/6/2025	11/2/2021	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
hunter	hunter	[ "Hunter Syndrome", "Iduronate-2-Sulfatase Deficiency", "MPS II", "Hunter Syndrome", "MPS II", "Iduronate-2-Sulfatase Deficiency", "Iduronate 2-sulfatase", "IDS", "Mucopolysaccharidosis Type II" ]	Mucopolysaccharidosis Type II	Maurizio Scarpa, Christina Lampe	Summary Mucopolysaccharidosis type II (MPS II; also known as Hunter syndrome) is an X-linked multisystem disorder characterized by glycosaminoglycan (GAG) accumulation. The vast majority of affected individuals are male; on rare occasion heterozygous females manifest findings. Age of onset, disease severity, and rate of progression vary significantly among affected males. In those with the neuronopathic phenotype, central nervous system (CNS) involvement (manifesting primarily as progressive cognitive deterioration), progressive airway disease, and cardiac disease usually results in death in the first or second decade of life. In those with the non-neuronopathic phenotype, the CNS is minimally or not affected. However, the effect of GAG accumulation on other organ systems can be severe. Survival into the early adult years with normal intelligence is common in the non-neuronopathic phenotype. Additional findings in neuronopathic and non-neuronopathic MPS II include: short stature, macrocephaly with or without communicating hydrocephalus, macroglossia, hoarse voice, conductive and sensorineural hearing loss, dysostosis multiplex, spinal stenosis, carpal tunnel syndrome, and hepatosplenomegaly. The diagnosis of MPS II is established in a male proband by identification of absent or reduced iduronate 2-sulfatase (I2S) enzyme activity in leukocytes, fibroblasts, or plasma in the presence of normal activity of at least one other sulfatase; or of a hemizygous pathogenic variant in MPS II is inherited in an X-linked manner. The risk to sibs depends on the genetic status of the mother. If the mother of the proband has an	## Diagnosis The diagnosis of mucopolysaccharidosis type II (MPS II; also known as Hunter syndrome) cannot be established on clinical findings alone. Clinical and radiographic findings vary widely, and the evolution of manifestations is often a better indicator of the diagnosis of MPS II. Recommendations for establishing the diagnosis have been developed by the Hunter Syndrome European Expert Council (HSEEC) using an evidence-based approach [ NBS for MPS II is primarily based on quantification of iduronate 2-sulfatase (I2S) enzyme activity on dried blood spots. I2S enzyme activity below the cutoff reported by the screening laboratory is considered positive and requires follow-up biochemical and/or molecular testing to Note: To date, NBS for MPS II is performed in the United States and Taiwan. MPS II Short stature Hepatosplenomegaly Joint contractures Coarse facies Frequent ear/airway infections Umbilical hernia Note: These clinical and radiographic findings may not be present in early life and are not specific to MPS II. Note: These laboratory findings are not specific to MPS II; the profile is similar to that seen in The diagnosis of MPS II Note: (1) Per ACMG/AMG variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of When the phenotypic and laboratory findings suggest the diagnosis of MPS II, molecular genetic testing approaches can include Note: A 178-bp deletion in the promoter region was identified in two affected individuals with low I2S enzyme activity [ For an introduction to multigene panels click When the diagnosis of MPS II has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Mucopolysaccharidosis Type II See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Single-nucleotide changes and splicing variants account for 65% of all pathogenic variants; small (i.e., intraexon) deletions and insertions account for 17% of all pathogenic variants [ Sequence analysis may not detect complex rearrangements in males or females that result from a common pathogenic inversion between Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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. Complex rearrangements result from recombination with the • Short stature • Hepatosplenomegaly • Joint contractures • Coarse facies • Frequent ear/airway infections • Umbilical hernia • Note: A 178-bp deletion in the promoter region was identified in two affected individuals with low I2S enzyme activity [ • For an introduction to multigene panels click ## Suggestive Findings NBS for MPS II is primarily based on quantification of iduronate 2-sulfatase (I2S) enzyme activity on dried blood spots. I2S enzyme activity below the cutoff reported by the screening laboratory is considered positive and requires follow-up biochemical and/or molecular testing to Note: To date, NBS for MPS II is performed in the United States and Taiwan. MPS II Short stature Hepatosplenomegaly Joint contractures Coarse facies Frequent ear/airway infections Umbilical hernia Note: These clinical and radiographic findings may not be present in early life and are not specific to MPS II. Note: These laboratory findings are not specific to MPS II; the profile is similar to that seen in • Short stature • Hepatosplenomegaly • Joint contractures • Coarse facies • Frequent ear/airway infections • Umbilical hernia ## Scenario 1: Abnormal Newborn Screening (NBS) Result NBS for MPS II is primarily based on quantification of iduronate 2-sulfatase (I2S) enzyme activity on dried blood spots. I2S enzyme activity below the cutoff reported by the screening laboratory is considered positive and requires follow-up biochemical and/or molecular testing to Note: To date, NBS for MPS II is performed in the United States and Taiwan. ## Scenario 2: Symptomatic Individual MPS II Short stature Hepatosplenomegaly Joint contractures Coarse facies Frequent ear/airway infections Umbilical hernia Note: These clinical and radiographic findings may not be present in early life and are not specific to MPS II. Note: These laboratory findings are not specific to MPS II; the profile is similar to that seen in • Short stature • Hepatosplenomegaly • Joint contractures • Coarse facies • Frequent ear/airway infections • Umbilical hernia ## Establishing the Diagnosis The diagnosis of MPS II Note: (1) Per ACMG/AMG variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of When the phenotypic and laboratory findings suggest the diagnosis of MPS II, molecular genetic testing approaches can include Note: A 178-bp deletion in the promoter region was identified in two affected individuals with low I2S enzyme activity [ For an introduction to multigene panels click When the diagnosis of MPS II has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Mucopolysaccharidosis Type II See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Single-nucleotide changes and splicing variants account for 65% of all pathogenic variants; small (i.e., intraexon) deletions and insertions account for 17% of all pathogenic variants [ Sequence analysis may not detect complex rearrangements in males or females that result from a common pathogenic inversion between Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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. Complex rearrangements result from recombination with the • Note: A 178-bp deletion in the promoter region was identified in two affected individuals with low I2S enzyme activity [ • For an introduction to multigene panels click ## Analyte Diagnosis The diagnosis of MPS II ## Molecular Diagnosis Note: (1) Per ACMG/AMG variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of When the phenotypic and laboratory findings suggest the diagnosis of MPS II, molecular genetic testing approaches can include Note: A 178-bp deletion in the promoter region was identified in two affected individuals with low I2S enzyme activity [ For an introduction to multigene panels click When the diagnosis of MPS II has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Mucopolysaccharidosis Type II See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Single-nucleotide changes and splicing variants account for 65% of all pathogenic variants; small (i.e., intraexon) deletions and insertions account for 17% of all pathogenic variants [ Sequence analysis may not detect complex rearrangements in males or females that result from a common pathogenic inversion between Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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. Complex rearrangements result from recombination with the • Note: A 178-bp deletion in the promoter region was identified in two affected individuals with low I2S enzyme activity [ • For an introduction to multigene panels click ## When the phenotypic and laboratory findings suggest the diagnosis of MPS II, molecular genetic testing approaches can include Note: A 178-bp deletion in the promoter region was identified in two affected individuals with low I2S enzyme activity [ For an introduction to multigene panels click • Note: A 178-bp deletion in the promoter region was identified in two affected individuals with low I2S enzyme activity [ • For an introduction to multigene panels click ## When the diagnosis of MPS II has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Mucopolysaccharidosis Type II See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Single-nucleotide changes and splicing variants account for 65% of all pathogenic variants; small (i.e., intraexon) deletions and insertions account for 17% of all pathogenic variants [ Sequence analysis may not detect complex rearrangements in males or females that result from a common pathogenic inversion between Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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. Complex rearrangements result from recombination with the ## Clinical Characteristics Mucopolysaccharidosis type II (MPS II; also known as Hunter syndrome) has multisystem involvement with significant variability in both age of onset and rate of progression. Two phenotypes have been described based on severity of neurologic disease and rate of progression. In those with neuronopathic MPS II, neurologic involvement (manifesting primarily as cognitive deterioration) and progressive airway and cardiac disease usually result in death in the first or second decade of life. In those with non-neuronopathic MPS II, the central nervous system (CNS) is minimally or not affected, although glycosaminoglycan (GAG) accumulation affects other organ systems; survival into the early adult years with normal intelligence is common. Additional findings in both forms of MPS II include: short stature, macrocephaly with or without communicating hydrocephalus, macroglossia, hoarse voice, conductive and sensorineural hearing loss, hepatosplenomegaly, dysostosis multiplex, spinal stenosis, and carpal tunnel syndrome. Mucopolysaccharidosis type II: Frequency of Select Features Adapted from The percentages for some features were specifically reported for individuals younger than age ten years. Optic nerve head swelling (papilledema) in the absence of increased intracranial pressure is present in approximately 20% of affected individuals and subsequent optic atrophy in approximately 11% [ Retinopathy has been reported most commonly in individuals with neuronopathic MPS II, although it can also be present in individuals with non-neuronopathic MPS II. Progressive reduction in electroretinography (ERG) amplitude suggests deterioration in retinal function [ Although glaucoma is not commonly reported in individuals with MPS II, there are instances of increased intraocular pressure due to GAG deposition, which can lead to chronic disc elevation without increased intracranial pressure [ Other ocular findings include bilateral uveal effusions, peripheral pigment epithelial changes, and radial parafoveal folds [ Enzyme replacement therapy does not halt the eventual progression of the ocular involvement [ Teeth are often irregularly shaped and gingival tissue is overgrown. Anterior open bite and ectopic and/or unerupted teeth can be present. Dentigenous cysts can also occur, often causing pain and discomfort. Dentigenous cysts can be difficult to diagnose particularly in males with CNS involvement. Painful dental caries and cysts can cause hyperactivity and aggression in individuals with neuronopathic MPS II [ Conductive and sensorineural hearing loss, complicated by recurrent ear infections, occurs in most affected individuals. Otosclerosis can contribute to the conductive hearing loss. Neurosensory hearing loss can be attributed to compression of the cochlear nerve resulting from arachnoid hyperplasia, reduction in the number of spiral ganglion cells, and degeneration of hair cells. The skeletal abnormalities in MPS II are similar in neuronopathic and non-neuropathic phenotypes but are not specific to MPS II. Termed "dysostosis multiplex," these radiographic findings are found in all MPS disorders and manifest as a generalized thickening of most long bones, particularly the ribs, with irregular epiphyseal ossification centers in many areas. Notching of the vertebral bodies is common. Hip dysplasia is the most common long-term orthopedic problem and can become a significant disability with early-onset arthritis if not treated. Gait abnormalities in individuals with MPS II are common and arise from a complex interplay of skeletal deformities, joint stiffness, and muscle weakness. Approximately 25% of individuals with non-neuropathic MPS II exhibit abnormal gait, with a median age of onset of 5.4 years. Gait issues can develop relatively early in the disease progression, often following initial skeletal manifestations that typically appear by age 3.5 years [ Kyphosis/scoliosis occurs in approximately 33.8% of all individuals with MPS II, with a median age of onset of 6.4 years [ Musculoskeletal pain is more common in individuals with non-neuronopathic MPS II than in individuals with neuronopathic MPS II. Cognitive impairment/decline. Individuals may experience developmental delays or cognitive impairment. This can range from mild learning difficulties to significant intellectual disability. Behavioral issues. Individuals may exhibit behavioral problems such as aggression, hyperactivity, and social withdrawal. Neurologic manifestations. Individuals can show signs of neurologic involvement, including seizures, ataxia, gait disturbances. Presence of sleep disturbance, behavior difficulties, increased activity, seizure-like behavior, perseverative chewing behavior, and inability to achieve bowel and bladder training may be strongly correlated with subsequent cognitive dysfunction [ Behavioral problems occur in individuals with neuronopathic and non-neuronopathic MPS II [ Chronic communicating hydrocephalus may complicate the clinical picture, especially in those with neuronopathic MPS II and deteriorating cognitive ability and seizures. Males with non-neuronopathic MPS II have normal or near-normal intelligence and seizures are uncommon; however, chronic communicating hydrocephalus may still occur. Carpal tunnel syndrome (CTS) is an often-overlooked complication of MPS II. Unlike adults with CTS, most children with MPS II do not report the typical symptoms of CTS. Nonetheless, nerve conduction studies are abnormal. Hand function improves after surgical correction. Spinal stenosis can occur, particularly in the cervical region, with spinal cord compression. Spinal stenosis might occur less frequently in individuals with MPS II than in other mucopolysaccharidoses [ Mucopolysaccharidosis Type II: Frequency of Neurobehavioral/Psychiatric and Neurologic Features by Phenotype and Age Adapted from Limited information is available regarding genotype-phenotype correlations: The pathogenic variant Males with complete absence of functional enzyme as a result of gene deletion or complex gene rearrangements (~17% of affected individuals) invariably manifest the neuronopathic phenotype of MPS II [ Data from a cohort study of Dutch individuals with MPS II suggest that very low or cell-type-specific iduronate 2-sulfatase residual activity is sufficient to prevent the neuronal phenotype of MPS II. While the molecular effects of Penetrance of MPS II in males is complete. Other terms used to describe the phenotypic variability of MPS II include: Mild/attenuated MPS II and severe MPS II; and Slowly progressive MPS II and early progressive MPS II. Several surveys suggest an incidence between 1:100,000 and 1:170,000 male births [ • Cognitive impairment/decline. Individuals may experience developmental delays or cognitive impairment. This can range from mild learning difficulties to significant intellectual disability. • Behavioral issues. Individuals may exhibit behavioral problems such as aggression, hyperactivity, and social withdrawal. • Neurologic manifestations. Individuals can show signs of neurologic involvement, including seizures, ataxia, gait disturbances. • The pathogenic variant • Males with complete absence of functional enzyme as a result of gene deletion or complex gene rearrangements (~17% of affected individuals) invariably manifest the neuronopathic phenotype of MPS II [ • Data from a cohort study of Dutch individuals with MPS II suggest that very low or cell-type-specific iduronate 2-sulfatase residual activity is sufficient to prevent the neuronal phenotype of MPS II. While the molecular effects of • Mild/attenuated MPS II and severe MPS II; and • Slowly progressive MPS II and early progressive MPS II. ## Clinical Description Mucopolysaccharidosis type II (MPS II; also known as Hunter syndrome) has multisystem involvement with significant variability in both age of onset and rate of progression. Two phenotypes have been described based on severity of neurologic disease and rate of progression. In those with neuronopathic MPS II, neurologic involvement (manifesting primarily as cognitive deterioration) and progressive airway and cardiac disease usually result in death in the first or second decade of life. In those with non-neuronopathic MPS II, the central nervous system (CNS) is minimally or not affected, although glycosaminoglycan (GAG) accumulation affects other organ systems; survival into the early adult years with normal intelligence is common. Additional findings in both forms of MPS II include: short stature, macrocephaly with or without communicating hydrocephalus, macroglossia, hoarse voice, conductive and sensorineural hearing loss, hepatosplenomegaly, dysostosis multiplex, spinal stenosis, and carpal tunnel syndrome. Mucopolysaccharidosis type II: Frequency of Select Features Adapted from The percentages for some features were specifically reported for individuals younger than age ten years. Optic nerve head swelling (papilledema) in the absence of increased intracranial pressure is present in approximately 20% of affected individuals and subsequent optic atrophy in approximately 11% [ Retinopathy has been reported most commonly in individuals with neuronopathic MPS II, although it can also be present in individuals with non-neuronopathic MPS II. Progressive reduction in electroretinography (ERG) amplitude suggests deterioration in retinal function [ Although glaucoma is not commonly reported in individuals with MPS II, there are instances of increased intraocular pressure due to GAG deposition, which can lead to chronic disc elevation without increased intracranial pressure [ Other ocular findings include bilateral uveal effusions, peripheral pigment epithelial changes, and radial parafoveal folds [ Enzyme replacement therapy does not halt the eventual progression of the ocular involvement [ Teeth are often irregularly shaped and gingival tissue is overgrown. Anterior open bite and ectopic and/or unerupted teeth can be present. Dentigenous cysts can also occur, often causing pain and discomfort. Dentigenous cysts can be difficult to diagnose particularly in males with CNS involvement. Painful dental caries and cysts can cause hyperactivity and aggression in individuals with neuronopathic MPS II [ Conductive and sensorineural hearing loss, complicated by recurrent ear infections, occurs in most affected individuals. Otosclerosis can contribute to the conductive hearing loss. Neurosensory hearing loss can be attributed to compression of the cochlear nerve resulting from arachnoid hyperplasia, reduction in the number of spiral ganglion cells, and degeneration of hair cells. The skeletal abnormalities in MPS II are similar in neuronopathic and non-neuropathic phenotypes but are not specific to MPS II. Termed "dysostosis multiplex," these radiographic findings are found in all MPS disorders and manifest as a generalized thickening of most long bones, particularly the ribs, with irregular epiphyseal ossification centers in many areas. Notching of the vertebral bodies is common. Hip dysplasia is the most common long-term orthopedic problem and can become a significant disability with early-onset arthritis if not treated. Gait abnormalities in individuals with MPS II are common and arise from a complex interplay of skeletal deformities, joint stiffness, and muscle weakness. Approximately 25% of individuals with non-neuropathic MPS II exhibit abnormal gait, with a median age of onset of 5.4 years. Gait issues can develop relatively early in the disease progression, often following initial skeletal manifestations that typically appear by age 3.5 years [ Kyphosis/scoliosis occurs in approximately 33.8% of all individuals with MPS II, with a median age of onset of 6.4 years [ Musculoskeletal pain is more common in individuals with non-neuronopathic MPS II than in individuals with neuronopathic MPS II. Cognitive impairment/decline. Individuals may experience developmental delays or cognitive impairment. This can range from mild learning difficulties to significant intellectual disability. Behavioral issues. Individuals may exhibit behavioral problems such as aggression, hyperactivity, and social withdrawal. Neurologic manifestations. Individuals can show signs of neurologic involvement, including seizures, ataxia, gait disturbances. Presence of sleep disturbance, behavior difficulties, increased activity, seizure-like behavior, perseverative chewing behavior, and inability to achieve bowel and bladder training may be strongly correlated with subsequent cognitive dysfunction [ Behavioral problems occur in individuals with neuronopathic and non-neuronopathic MPS II [ Chronic communicating hydrocephalus may complicate the clinical picture, especially in those with neuronopathic MPS II and deteriorating cognitive ability and seizures. Males with non-neuronopathic MPS II have normal or near-normal intelligence and seizures are uncommon; however, chronic communicating hydrocephalus may still occur. Carpal tunnel syndrome (CTS) is an often-overlooked complication of MPS II. Unlike adults with CTS, most children with MPS II do not report the typical symptoms of CTS. Nonetheless, nerve conduction studies are abnormal. Hand function improves after surgical correction. Spinal stenosis can occur, particularly in the cervical region, with spinal cord compression. Spinal stenosis might occur less frequently in individuals with MPS II than in other mucopolysaccharidoses [ Mucopolysaccharidosis Type II: Frequency of Neurobehavioral/Psychiatric and Neurologic Features by Phenotype and Age Adapted from • Cognitive impairment/decline. Individuals may experience developmental delays or cognitive impairment. This can range from mild learning difficulties to significant intellectual disability. • Behavioral issues. Individuals may exhibit behavioral problems such as aggression, hyperactivity, and social withdrawal. • Neurologic manifestations. Individuals can show signs of neurologic involvement, including seizures, ataxia, gait disturbances. ## Genotype-Phenotype Correlations Limited information is available regarding genotype-phenotype correlations: The pathogenic variant Males with complete absence of functional enzyme as a result of gene deletion or complex gene rearrangements (~17% of affected individuals) invariably manifest the neuronopathic phenotype of MPS II [ Data from a cohort study of Dutch individuals with MPS II suggest that very low or cell-type-specific iduronate 2-sulfatase residual activity is sufficient to prevent the neuronal phenotype of MPS II. While the molecular effects of • The pathogenic variant • Males with complete absence of functional enzyme as a result of gene deletion or complex gene rearrangements (~17% of affected individuals) invariably manifest the neuronopathic phenotype of MPS II [ • Data from a cohort study of Dutch individuals with MPS II suggest that very low or cell-type-specific iduronate 2-sulfatase residual activity is sufficient to prevent the neuronal phenotype of MPS II. While the molecular effects of ## Penetrance Penetrance of MPS II in males is complete. ## Nomenclature Other terms used to describe the phenotypic variability of MPS II include: Mild/attenuated MPS II and severe MPS II; and Slowly progressive MPS II and early progressive MPS II. • Mild/attenuated MPS II and severe MPS II; and • Slowly progressive MPS II and early progressive MPS II. ## Prevalence Several surveys suggest an incidence between 1:100,000 and 1:170,000 male births [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The differential diagnosis for mucopolysaccharidosis type II (MPS II; also known as Hunter syndrome) includes multiple sulfatase deficiency, mucolipidosis type II and type III alpha/beta, mucolipidosis type III gamma, and essentially all the other MPS disorders (given the significant overlap of clinical presentation and radiologic findings). Selected disorders of interest in the differential diagnosis of MPS II are listed in Genes and Disorders of Interest in the Differential Diagnosis of Mucopolysaccharidosis Type II Dysostosis multiplex (multiple skeletal abnormalities visible on imaging) Coarse facial features such as thickened lips & macroglossia Joint stiffness & contractures that can significantly impact mobility Coarse facial features, hepatosplenomegaly, joint stiffness, skeletal abnormalities Multiple sulfatase deficiency & MPS II differ significantly in their neurologic manifestations, skin manifestations, & age of onset. MPS II typically presents with more pronounced skeletal issues & organ involvement without the severe neurologic decline seen in multiple sulfatase deficiency, particularly in its neonatal form. AR = autosomal recessive; ML = mucolipidosis; MOI = mode of inheritance; MPS = mucopolysaccharidosis • Dysostosis multiplex (multiple skeletal abnormalities visible on imaging) • Coarse facial features such as thickened lips & macroglossia • Joint stiffness & contractures that can significantly impact mobility • Coarse facial features, hepatosplenomegaly, joint stiffness, skeletal abnormalities • Multiple sulfatase deficiency & MPS II differ significantly in their neurologic manifestations, skin manifestations, & age of onset. MPS II typically presents with more pronounced skeletal issues & organ involvement without the severe neurologic decline seen in multiple sulfatase deficiency, particularly in its neonatal form. ## Management Management guidelines for individuals with mucopolysaccharidosis type II (MPS II; also known as Hunter syndrome) have been published [ To establish the extent of disease and needs in an individual diagnosed with MPS II, the evaluations summarized in Mucopolysaccharidosis Type II: Recommended Evaluations Following Initial Diagnosis Assessment of feeding/swallowing issues (incl macroglossia, limited mouth opening) Assessment for adenoid & tonsil hypertrophy Dental assessment for abnormal teeth & dentigenous cysts Audiologic eval Assess for umbilical/inguinal hernia & for chronic diarrhea. Assess liver & spleen size. Echocardiogram to assess for valvular disease & cardiomyopathy EKG to assess arrhythmias Developmental & cognitive assessment Behavioral assessment by neurodevelopment specialist &/or psychiatrist Neurologic eval incl assessment for seizures Assessment for spinal stenosis Community or Social work involvement for parental support Home nursing referral ADL = activities of daily living; CNS = central nervous system; MOI = mode of inheritance; MPS II = mucopolysaccharidosis type II Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Analysis of data from the Hunter Outcome Survey (HOS) showed that survival in idursulfase-treated individuals was longer than in those who were untreated [ Earlier introduction of ERT was associated with improved respiratory outcome in individuals with MPS II at age 16 years. The median predicted forced vital capacity in those who started ERT at younger than age eight years was 69% (range: 34%-86%) and in those who started ERT at older than age eight years was 48% (range: 25%-108%) (P=0.045) [ Since Elaprase Infusion-related reactions that may occur with use of Elaprase Infusion reactions are generally mild and include brief, insignificant decreases or increases in heart rate, blood pressure, or respiratory rate; itching; rash; flushing; and headache. Mild reactions can usually be managed by slowing the infusion rate for several treatments and then slowly returning to the prior rate. Pretreatment with anti-inflammatory drugs or antihistamines, as is often done for ERT in other conditions, is not suggested on the label for Elaprase Severe non-allergic anaphylactoid reactions such as major changes in blood pressure, wheezing, stridor, rigors, or drop in oxygen saturations should be immediately addressed by stopping the infusion and giving appropriate doses of subcutaneous epinephrine, intravenous (IV) diphenhydramine, and hydrocortisone or methylprednisolone. Subsequent infusions should then be given at a significantly reduced rate with pretreatment with prednisone 24 hours and eight hours before the infusion, diphenhydramine and acetaminophen or ibuprofen orally one hour before the infusion, and IV methylprednisolone just before beginning the infusion. Current data are insufficient to indicate whether the incidence or severity of infusion-related reactions is different for individuals younger than age five years with severe respiratory compromise or with severe CNS disease. Further studies and longer follow up are needed to better understand the effects of ERT. A recent attempt to assess the impact of anti-idursulfase antibodies during long-term idursulfase ERT did not establish a clear association between infusion-related adverse events and antibody levels [ Until two decades ago, HSCT had high mortality rates because of (1) the preconditioning regimen prior to HSCT, which caused severe side effects including increased susceptibility to infection and (2) poor donor selection, which resulted in a high risk of graft-vs-host disease [ Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Mucopolysaccharidosis Type II: Treatment of Manifestations Tonsillectomy & adenoidectomy as needed for airway obstruction Early & aggressive treatment of ear infections Pressure-equalizing tubes for recurrent ear infections Hip replacement as needed PT Positive pressure ventilation (CPAP) as needed CT scan of trachea to identify anatomic alterations that may modify trachea structure, ↓ benefit from CPAP, & complicate tracheostomy procedure Tracheostomy should be last option to manage respiratory problems. Anesthesia should be administered in centers familiar w/MPS II given risks assoc w/sedation w/& w/o intubation. Nasopharyngeal intubation is often necessary. When endotracheal intubation is difficult or when sedation is required for brief procedures, laryngeal mask airway may be indicated. CT scan of trachea is always recommended due to anatomic alterations that may modify trachea structure & impair anesthesia procedure. Ankylosis of temporomandibular joint that can restrict oral access to airway; Visualization of vocal cords compromised by macroglossia, GAG-infiltrated soft tissues, & large tonsils & adenoids; Hyperextension of neck secondary to atlantoaxial instability & cervicomedullary compression. Developmental & educational support (See OT & PT Shunting for hydrocephalus as needed Carpal tunnel release as needed Treatment of spinal stenosis per neurosurgeon/orthopedist 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; CPAP = continuous positive airway pressure; ENT = ear, nose, throat; GAG = glycosaminoglycan; MPS = mucopolysaccharidosis; OT = occupational therapy; PT = physical therapy The risk of airway complications may continue following successful surgery. Extubation may be difficult because laryngeal edema, which has been reported up to 27 hours post surgery, may prevent maintenance of a proper airway [ 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 Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with MPS II 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. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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. Guidelines for surveillance have been developed [ Mucopolysaccharidosis Type II: Recommended Surveillance Assess for umbilical/inguinal hernia. Assess for chronic diarrhea. Assess liver & spleen size. Developmental & cognitive assessment Behavioral assessment by neurodevelopment specialist &/or psychiatrist Neurologic exam Assessment for seizures Assessment for manifestations of spinal stenosis Head/neck MRI to document ventricular size & cervicomedullary narrowing Assessment of opening pressure on lumbar puncture ADL = activities of daily living; MPS II = mucopolysaccharidosis type II Iduronate 2-sulfatase (I2S) biochemical testing and/or See A number of interventions are being evaluated for potential use in individuals with MPS II. A Phase II/III open-label, multicenter study ( Other therapies under preclinical investigation include more direct delivery of enzyme into the CNS. Tissue uptake (including the brain and spinal cord) via the transferrin receptor of a fusion protein between iduronate 2-sulfatase (I2S) and a monoclonal antibody against the transferrin receptor are being studied [ Gene editing has been attempted in nine individuals with MPS II, and in one individual a transient increase in plasma I2S approaching normal levels was detected; however, there was no evidence of genome editing [ Mucopolysaccharidosis Type II: Selected Therapies Under Investigation CNS = central nervous system; ERT = enzyme replacement therapy; I2S = iduronate 2-sulfatase Search • Assessment of feeding/swallowing issues (incl macroglossia, limited mouth opening) • Assessment for adenoid & tonsil hypertrophy • Dental assessment for abnormal teeth & dentigenous cysts • Audiologic eval • Assess for umbilical/inguinal hernia & for chronic diarrhea. • Assess liver & spleen size. • Echocardiogram to assess for valvular disease & cardiomyopathy • EKG to assess arrhythmias • Developmental & cognitive assessment • Behavioral assessment by neurodevelopment specialist &/or psychiatrist • Neurologic eval incl assessment for seizures • Assessment for spinal stenosis • Community or • Social work involvement for parental support • Home nursing referral • Tonsillectomy & adenoidectomy as needed for airway obstruction • Early & aggressive treatment of ear infections • Pressure-equalizing tubes for recurrent ear infections • Hip replacement as needed • PT • Positive pressure ventilation (CPAP) as needed • CT scan of trachea to identify anatomic alterations that may modify trachea structure, ↓ benefit from CPAP, & complicate tracheostomy procedure • Tracheostomy should be last option to manage respiratory problems. • Anesthesia should be administered in centers familiar w/MPS II given risks assoc w/sedation w/& w/o intubation. • Nasopharyngeal intubation is often necessary. When endotracheal intubation is difficult or when sedation is required for brief procedures, laryngeal mask airway may be indicated. • CT scan of trachea is always recommended due to anatomic alterations that may modify trachea structure & impair anesthesia procedure. • Ankylosis of temporomandibular joint that can restrict oral access to airway; • Visualization of vocal cords compromised by macroglossia, GAG-infiltrated soft tissues, & large tonsils & adenoids; • Hyperextension of neck secondary to atlantoaxial instability & cervicomedullary compression. • Developmental & educational support (See • OT & PT • Shunting for hydrocephalus as needed • Carpal tunnel release as needed • Treatment of spinal stenosis per neurosurgeon/orthopedist • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox • Assess for umbilical/inguinal hernia. • Assess for chronic diarrhea. • Assess liver & spleen size. • Developmental & cognitive assessment • Behavioral assessment by neurodevelopment specialist &/or psychiatrist • Neurologic exam • Assessment for seizures • Assessment for manifestations of spinal stenosis • Head/neck MRI to document ventricular size & cervicomedullary narrowing • Assessment of opening pressure on lumbar puncture ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with MPS II, the evaluations summarized in Mucopolysaccharidosis Type II: Recommended Evaluations Following Initial Diagnosis Assessment of feeding/swallowing issues (incl macroglossia, limited mouth opening) Assessment for adenoid & tonsil hypertrophy Dental assessment for abnormal teeth & dentigenous cysts Audiologic eval Assess for umbilical/inguinal hernia & for chronic diarrhea. Assess liver & spleen size. Echocardiogram to assess for valvular disease & cardiomyopathy EKG to assess arrhythmias Developmental & cognitive assessment Behavioral assessment by neurodevelopment specialist &/or psychiatrist Neurologic eval incl assessment for seizures Assessment for spinal stenosis Community or Social work involvement for parental support Home nursing referral ADL = activities of daily living; CNS = central nervous system; MOI = mode of inheritance; MPS II = mucopolysaccharidosis type II Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Assessment of feeding/swallowing issues (incl macroglossia, limited mouth opening) • Assessment for adenoid & tonsil hypertrophy • Dental assessment for abnormal teeth & dentigenous cysts • Audiologic eval • Assess for umbilical/inguinal hernia & for chronic diarrhea. • Assess liver & spleen size. • Echocardiogram to assess for valvular disease & cardiomyopathy • EKG to assess arrhythmias • Developmental & cognitive assessment • Behavioral assessment by neurodevelopment specialist &/or psychiatrist • Neurologic eval incl assessment for seizures • Assessment for spinal stenosis • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations Analysis of data from the Hunter Outcome Survey (HOS) showed that survival in idursulfase-treated individuals was longer than in those who were untreated [ Earlier introduction of ERT was associated with improved respiratory outcome in individuals with MPS II at age 16 years. The median predicted forced vital capacity in those who started ERT at younger than age eight years was 69% (range: 34%-86%) and in those who started ERT at older than age eight years was 48% (range: 25%-108%) (P=0.045) [ Since Elaprase Infusion-related reactions that may occur with use of Elaprase Infusion reactions are generally mild and include brief, insignificant decreases or increases in heart rate, blood pressure, or respiratory rate; itching; rash; flushing; and headache. Mild reactions can usually be managed by slowing the infusion rate for several treatments and then slowly returning to the prior rate. Pretreatment with anti-inflammatory drugs or antihistamines, as is often done for ERT in other conditions, is not suggested on the label for Elaprase Severe non-allergic anaphylactoid reactions such as major changes in blood pressure, wheezing, stridor, rigors, or drop in oxygen saturations should be immediately addressed by stopping the infusion and giving appropriate doses of subcutaneous epinephrine, intravenous (IV) diphenhydramine, and hydrocortisone or methylprednisolone. Subsequent infusions should then be given at a significantly reduced rate with pretreatment with prednisone 24 hours and eight hours before the infusion, diphenhydramine and acetaminophen or ibuprofen orally one hour before the infusion, and IV methylprednisolone just before beginning the infusion. Current data are insufficient to indicate whether the incidence or severity of infusion-related reactions is different for individuals younger than age five years with severe respiratory compromise or with severe CNS disease. Further studies and longer follow up are needed to better understand the effects of ERT. A recent attempt to assess the impact of anti-idursulfase antibodies during long-term idursulfase ERT did not establish a clear association between infusion-related adverse events and antibody levels [ Until two decades ago, HSCT had high mortality rates because of (1) the preconditioning regimen prior to HSCT, which caused severe side effects including increased susceptibility to infection and (2) poor donor selection, which resulted in a high risk of graft-vs-host disease [ Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Mucopolysaccharidosis Type II: Treatment of Manifestations Tonsillectomy & adenoidectomy as needed for airway obstruction Early & aggressive treatment of ear infections Pressure-equalizing tubes for recurrent ear infections Hip replacement as needed PT Positive pressure ventilation (CPAP) as needed CT scan of trachea to identify anatomic alterations that may modify trachea structure, ↓ benefit from CPAP, & complicate tracheostomy procedure Tracheostomy should be last option to manage respiratory problems. Anesthesia should be administered in centers familiar w/MPS II given risks assoc w/sedation w/& w/o intubation. Nasopharyngeal intubation is often necessary. When endotracheal intubation is difficult or when sedation is required for brief procedures, laryngeal mask airway may be indicated. CT scan of trachea is always recommended due to anatomic alterations that may modify trachea structure & impair anesthesia procedure. Ankylosis of temporomandibular joint that can restrict oral access to airway; Visualization of vocal cords compromised by macroglossia, GAG-infiltrated soft tissues, & large tonsils & adenoids; Hyperextension of neck secondary to atlantoaxial instability & cervicomedullary compression. Developmental & educational support (See OT & PT Shunting for hydrocephalus as needed Carpal tunnel release as needed Treatment of spinal stenosis per neurosurgeon/orthopedist 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; CPAP = continuous positive airway pressure; ENT = ear, nose, throat; GAG = glycosaminoglycan; MPS = mucopolysaccharidosis; OT = occupational therapy; PT = physical therapy The risk of airway complications may continue following successful surgery. Extubation may be difficult because laryngeal edema, which has been reported up to 27 hours post surgery, may prevent maintenance of a proper airway [ 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 Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with MPS II 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. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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. • Tonsillectomy & adenoidectomy as needed for airway obstruction • Early & aggressive treatment of ear infections • Pressure-equalizing tubes for recurrent ear infections • Hip replacement as needed • PT • Positive pressure ventilation (CPAP) as needed • CT scan of trachea to identify anatomic alterations that may modify trachea structure, ↓ benefit from CPAP, & complicate tracheostomy procedure • Tracheostomy should be last option to manage respiratory problems. • Anesthesia should be administered in centers familiar w/MPS II given risks assoc w/sedation w/& w/o intubation. • Nasopharyngeal intubation is often necessary. When endotracheal intubation is difficult or when sedation is required for brief procedures, laryngeal mask airway may be indicated. • CT scan of trachea is always recommended due to anatomic alterations that may modify trachea structure & impair anesthesia procedure. • Ankylosis of temporomandibular joint that can restrict oral access to airway; • Visualization of vocal cords compromised by macroglossia, GAG-infiltrated soft tissues, & large tonsils & adenoids; • Hyperextension of neck secondary to atlantoaxial instability & cervicomedullary compression. • Developmental & educational support (See • OT & PT • Shunting for hydrocephalus as needed • Carpal tunnel release as needed • Treatment of spinal stenosis per neurosurgeon/orthopedist • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## Targeted Therapies Analysis of data from the Hunter Outcome Survey (HOS) showed that survival in idursulfase-treated individuals was longer than in those who were untreated [ Earlier introduction of ERT was associated with improved respiratory outcome in individuals with MPS II at age 16 years. The median predicted forced vital capacity in those who started ERT at younger than age eight years was 69% (range: 34%-86%) and in those who started ERT at older than age eight years was 48% (range: 25%-108%) (P=0.045) [ Since Elaprase Infusion-related reactions that may occur with use of Elaprase Infusion reactions are generally mild and include brief, insignificant decreases or increases in heart rate, blood pressure, or respiratory rate; itching; rash; flushing; and headache. Mild reactions can usually be managed by slowing the infusion rate for several treatments and then slowly returning to the prior rate. Pretreatment with anti-inflammatory drugs or antihistamines, as is often done for ERT in other conditions, is not suggested on the label for Elaprase Severe non-allergic anaphylactoid reactions such as major changes in blood pressure, wheezing, stridor, rigors, or drop in oxygen saturations should be immediately addressed by stopping the infusion and giving appropriate doses of subcutaneous epinephrine, intravenous (IV) diphenhydramine, and hydrocortisone or methylprednisolone. Subsequent infusions should then be given at a significantly reduced rate with pretreatment with prednisone 24 hours and eight hours before the infusion, diphenhydramine and acetaminophen or ibuprofen orally one hour before the infusion, and IV methylprednisolone just before beginning the infusion. Current data are insufficient to indicate whether the incidence or severity of infusion-related reactions is different for individuals younger than age five years with severe respiratory compromise or with severe CNS disease. Further studies and longer follow up are needed to better understand the effects of ERT. A recent attempt to assess the impact of anti-idursulfase antibodies during long-term idursulfase ERT did not establish a clear association between infusion-related adverse events and antibody levels [ Until two decades ago, HSCT had high mortality rates because of (1) the preconditioning regimen prior to HSCT, which caused severe side effects including increased susceptibility to infection and (2) poor donor selection, which resulted in a high risk of graft-vs-host disease [ ## Supportive Care Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Mucopolysaccharidosis Type II: Treatment of Manifestations Tonsillectomy & adenoidectomy as needed for airway obstruction Early & aggressive treatment of ear infections Pressure-equalizing tubes for recurrent ear infections Hip replacement as needed PT Positive pressure ventilation (CPAP) as needed CT scan of trachea to identify anatomic alterations that may modify trachea structure, ↓ benefit from CPAP, & complicate tracheostomy procedure Tracheostomy should be last option to manage respiratory problems. Anesthesia should be administered in centers familiar w/MPS II given risks assoc w/sedation w/& w/o intubation. Nasopharyngeal intubation is often necessary. When endotracheal intubation is difficult or when sedation is required for brief procedures, laryngeal mask airway may be indicated. CT scan of trachea is always recommended due to anatomic alterations that may modify trachea structure & impair anesthesia procedure. Ankylosis of temporomandibular joint that can restrict oral access to airway; Visualization of vocal cords compromised by macroglossia, GAG-infiltrated soft tissues, & large tonsils & adenoids; Hyperextension of neck secondary to atlantoaxial instability & cervicomedullary compression. Developmental & educational support (See OT & PT Shunting for hydrocephalus as needed Carpal tunnel release as needed Treatment of spinal stenosis per neurosurgeon/orthopedist 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; CPAP = continuous positive airway pressure; ENT = ear, nose, throat; GAG = glycosaminoglycan; MPS = mucopolysaccharidosis; OT = occupational therapy; PT = physical therapy The risk of airway complications may continue following successful surgery. Extubation may be difficult because laryngeal edema, which has been reported up to 27 hours post surgery, may prevent maintenance of a proper airway [ 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 Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with MPS II 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. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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. • Tonsillectomy & adenoidectomy as needed for airway obstruction • Early & aggressive treatment of ear infections • Pressure-equalizing tubes for recurrent ear infections • Hip replacement as needed • PT • Positive pressure ventilation (CPAP) as needed • CT scan of trachea to identify anatomic alterations that may modify trachea structure, ↓ benefit from CPAP, & complicate tracheostomy procedure • Tracheostomy should be last option to manage respiratory problems. • Anesthesia should be administered in centers familiar w/MPS II given risks assoc w/sedation w/& w/o intubation. • Nasopharyngeal intubation is often necessary. When endotracheal intubation is difficult or when sedation is required for brief procedures, laryngeal mask airway may be indicated. • CT scan of trachea is always recommended due to anatomic alterations that may modify trachea structure & impair anesthesia procedure. • Ankylosis of temporomandibular joint that can restrict oral access to airway; • Visualization of vocal cords compromised by macroglossia, GAG-infiltrated soft tissues, & large tonsils & adenoids; • Hyperextension of neck secondary to atlantoaxial instability & cervicomedullary compression. • Developmental & educational support (See • OT & PT • Shunting for hydrocephalus as needed • Carpal tunnel release as needed • Treatment of spinal stenosis per neurosurgeon/orthopedist • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ## Surveillance Guidelines for surveillance have been developed [ Mucopolysaccharidosis Type II: Recommended Surveillance Assess for umbilical/inguinal hernia. Assess for chronic diarrhea. Assess liver & spleen size. Developmental & cognitive assessment Behavioral assessment by neurodevelopment specialist &/or psychiatrist Neurologic exam Assessment for seizures Assessment for manifestations of spinal stenosis Head/neck MRI to document ventricular size & cervicomedullary narrowing Assessment of opening pressure on lumbar puncture ADL = activities of daily living; MPS II = mucopolysaccharidosis type II • Assess for umbilical/inguinal hernia. • Assess for chronic diarrhea. • Assess liver & spleen size. • Developmental & cognitive assessment • Behavioral assessment by neurodevelopment specialist &/or psychiatrist • Neurologic exam • Assessment for seizures • Assessment for manifestations of spinal stenosis • Head/neck MRI to document ventricular size & cervicomedullary narrowing • Assessment of opening pressure on lumbar puncture ## Evaluation of Relatives at Risk Iduronate 2-sulfatase (I2S) biochemical testing and/or See ## Therapies Under Investigation A number of interventions are being evaluated for potential use in individuals with MPS II. A Phase II/III open-label, multicenter study ( Other therapies under preclinical investigation include more direct delivery of enzyme into the CNS. Tissue uptake (including the brain and spinal cord) via the transferrin receptor of a fusion protein between iduronate 2-sulfatase (I2S) and a monoclonal antibody against the transferrin receptor are being studied [ Gene editing has been attempted in nine individuals with MPS II, and in one individual a transient increase in plasma I2S approaching normal levels was detected; however, there was no evidence of genome editing [ Mucopolysaccharidosis Type II: Selected Therapies Under Investigation CNS = central nervous system; ERT = enzyme replacement therapy; I2S = iduronate 2-sulfatase Search ## Genetic Counseling Mucopolysaccharidosis type II (MPS II; also known as Hunter syndrome) is inherited in an X-linked manner. Hemizygous males are affected; heterozygous females are typically asymptomatic. The father of an affected male will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), the affected male may have a Molecular genetic testing of the mother is recommended to evaluate her genetic status and inform recurrence risk assessment. (Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ [gonadal] cells only.) If the proband has a complex chromosomal rearrangement involving If the mother of the proband has an Males who inherit the Females who inherit the If the mother of the proband has a chromosome rearrangement, the risk to sibs is increased and depends on the specific chromosome rearrangement. If the proband represents a simplex case and if the All of their daughters, who will be heterozygotes (carriers) and will usually not be affected; None of their sons. Note: Molecular genetic testing may be able to identify the family member in whom a Identification of the If an affected male is not available for testing, First by sequence analysis; If no If no 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 being carriers. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The father of an affected male will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), the affected male may have a • Molecular genetic testing of the mother is recommended to evaluate her genetic status and inform recurrence risk assessment. (Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ [gonadal] cells only.) If the proband has a complex chromosomal rearrangement involving • If the mother of the proband has an • Males who inherit the • Females who inherit the • Males who inherit the • Females who inherit the • If the mother of the proband has a chromosome rearrangement, the risk to sibs is increased and depends on the specific chromosome rearrangement. • If the proband represents a simplex case and if the • Males who inherit the • Females who inherit the • All of their daughters, who will be heterozygotes (carriers) and will usually not be affected; • None of their sons. • Identification of the • If an affected male is not available for testing, • First by sequence analysis; • If no • If no • First by sequence analysis; • If no • If no • First by sequence analysis; • If no • If no • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is 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. ## Mode of Inheritance Mucopolysaccharidosis type II (MPS II; also known as Hunter syndrome) is inherited in an X-linked manner. Hemizygous males are affected; heterozygous females are typically asymptomatic. ## Risk to Family Members The father of an affected male will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), the affected male may have a Molecular genetic testing of the mother is recommended to evaluate her genetic status and inform recurrence risk assessment. (Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ [gonadal] cells only.) If the proband has a complex chromosomal rearrangement involving If the mother of the proband has an Males who inherit the Females who inherit the If the mother of the proband has a chromosome rearrangement, the risk to sibs is increased and depends on the specific chromosome rearrangement. If the proband represents a simplex case and if the All of their daughters, who will be heterozygotes (carriers) and will usually not be affected; None of their sons. Note: Molecular genetic testing may be able to identify the family member in whom a • The father of an affected male will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), the affected male may have a • Molecular genetic testing of the mother is recommended to evaluate her genetic status and inform recurrence risk assessment. (Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ [gonadal] cells only.) If the proband has a complex chromosomal rearrangement involving • If the mother of the proband has an • Males who inherit the • Females who inherit the • Males who inherit the • Females who inherit the • If the mother of the proband has a chromosome rearrangement, the risk to sibs is increased and depends on the specific chromosome rearrangement. • If the proband represents a simplex case and if the • Males who inherit the • Females who inherit the • All of their daughters, who will be heterozygotes (carriers) and will usually not be affected; • None of their sons. ## Carrier Detection Identification of the If an affected male is not available for testing, First by sequence analysis; If no If no • Identification of the • If an affected male is not available for testing, • First by sequence analysis; • If no • If no • First by sequence analysis; • If no • If no • First by sequence analysis; • If no • If no ## 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 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 or at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources Canada United Kingdom Health Resources & Services Administration • • Canada • • • • • United Kingdom • • • • • • • Health Resources & Services Administration • ## Molecular Genetics Mucopolysaccharidosis Type II: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Mucopolysaccharidosis Type II ( 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 Christina Lampe, MD (2025-present)Rick A Martin, MD; Saint Louis University (2007-2011)Maurizio Scarpa, MD, PhD (2011-present) 16 January 2025 (sw) Comprehensive update posted live 4 October 2018 (sw) Comprehensive update posted live 26 March 2015 (me) Comprehensive update posted live 22 February 2011 (me) Comprehensive update posted live 6 November 2007 (me) Review posted live 8 June 2007 (rm) Original submission • 16 January 2025 (sw) Comprehensive update posted live • 4 October 2018 (sw) Comprehensive update posted live • 26 March 2015 (me) Comprehensive update posted live • 22 February 2011 (me) Comprehensive update posted live • 6 November 2007 (me) Review posted live • 8 June 2007 (rm) Original submission ## Author Notes ## Author History Christina Lampe, MD (2025-present)Rick A Martin, MD; Saint Louis University (2007-2011)Maurizio Scarpa, MD, PhD (2011-present) ## Revision History 16 January 2025 (sw) Comprehensive update posted live 4 October 2018 (sw) Comprehensive update posted live 26 March 2015 (me) Comprehensive update posted live 22 February 2011 (me) Comprehensive update posted live 6 November 2007 (me) Review posted live 8 June 2007 (rm) Original submission • 16 January 2025 (sw) Comprehensive update posted live • 4 October 2018 (sw) Comprehensive update posted live • 26 March 2015 (me) Comprehensive update posted live • 22 February 2011 (me) Comprehensive update posted live • 6 November 2007 (me) Review posted live • 8 June 2007 (rm) Original submission ## Key Sections in This ## References ## Literature Cited	[]	6/11/2007	16/1/2025		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
huntington	huntington	[ "Huntington Chorea", "Huntington Chorea", "Huntingtin", "HTT", "Huntington Disease" ]	Huntington Disease	Nicholas S Caron, Galen EB Wright, Michael R Hayden	Summary Huntington disease (HD) is a progressive disorder of motor, cognitive, and psychiatric disturbances. The mean age of onset is 35 to 44 years, and the median survival time is 15 to 18 years after onset. The diagnosis of HD rests on positive family history, characteristic clinical findings, and the detection of an expansion of 36 or more CAG trinucleotide repeats in HD is inherited in an autosomal dominant manner. Offspring of an individual with a pathogenic variant have a 50% chance of inheriting the disease-causing allele. Predictive testing in asymptomatic adults at risk is available but requires careful thought (including pre- and post-test genetic counseling) as there is currently no cure for the disorder. However, asymptomatic individuals at risk may be eligible to participate in clinical trials. Predictive testing is not considered appropriate for asymptomatic at-risk individuals younger than age 18 years. Prenatal testing by molecular genetic testing and preimplantation genetic testing are possible.	## Diagnosis Huntington disease (HD) Progressive motor disability featuring chorea. Voluntary movement may also be affected. Mental disturbances including cognitive decline, changes in personality, and/or depression Family history consistent with autosomal dominant inheritance Note: The appearance and sequence of motor, cognitive, and psychiatric disturbances can be variable in HD (see The diagnosis of HD Note: Pathogenic (CAG) Molecular Genetic Testing Used in Huntington Disease See See Current clinical sequence-based multigene panels, exome sequencing, and genome sequencing cannot detect pathogenic repeat expansions in this gene. Note: For comprehensive recommendations pertaining to predictive genetic testing for HD, see • Progressive motor disability featuring chorea. Voluntary movement may also be affected. • Mental disturbances including cognitive decline, changes in personality, and/or depression • Family history consistent with autosomal dominant inheritance ## Suggestive Findings Huntington disease (HD) Progressive motor disability featuring chorea. Voluntary movement may also be affected. Mental disturbances including cognitive decline, changes in personality, and/or depression Family history consistent with autosomal dominant inheritance Note: The appearance and sequence of motor, cognitive, and psychiatric disturbances can be variable in HD (see • Progressive motor disability featuring chorea. Voluntary movement may also be affected. • Mental disturbances including cognitive decline, changes in personality, and/or depression • Family history consistent with autosomal dominant inheritance ## Establishing the Diagnosis The diagnosis of HD Note: Pathogenic (CAG) Molecular Genetic Testing Used in Huntington Disease See See Current clinical sequence-based multigene panels, exome sequencing, and genome sequencing cannot detect pathogenic repeat expansions in this gene. Note: For comprehensive recommendations pertaining to predictive genetic testing for HD, see ## Clinical Characteristics During the prodromal phase of Huntington disease (HD) individuals may have subtle changes in motor skills, cognition, and personality (see Categories of Huntington Disease Diagnosis No clinical motor signs/symptoms (motor DCL = 0 or 1) No cognitive signs/symptoms May have changes in imaging, quantitative motor assessments, or other biomarkers No symptomatic treatment indicated Disease-modifying treatment when safe & available Subtle motor signs (usually motor DCL = 2) AND/OR subtle cognitive signs or symptoms Minor decline from individual premorbid level of function possibly detectable, but not required & not detectable on TFC Apathy or depression or other behavioral changes judged related to HD may be present. Usually changes in imaging & quantitative motor assessments May/may not require symptomatic treatment (e.g., for depression) Disease-modifying treatment appropriate Presence of clinical motor &/or cognitive signs & symptoms that have an impact on life, with: Functional changes (e.g., ↓ TFC); Motor DCL = 3 or 4 (or motor DCL of 2 if cognitive changes significant AND evidence of progression) Symptomatic & disease-modifying treatment appropriate Adapted from DCL = diagnostic confidence level (from the UHDRS rating scale); HD = Huntington disease; TFC = total functional capacity Requires motor DCL = 4, plus cognitive changes The mean age of onset for HD is approximately 45 years [ In approximately 25% of individuals with HD, the onset is delayed until after age 50 years, with some after age 70 years. These individuals have chorea, gait disturbances, and dysphagia, but a more prolonged and benign course than the typical individual. In the next stage, chorea becomes more prominent, voluntary activity becomes increasingly difficult, and dysarthria and dysphagia worsen. Most individuals are forced to give up their employment and depend increasingly on others for help, although they are still able to maintain a considerable degree of personal independence. The impairment is usually considerable, sometimes with intermittent outbursts of aggressive behaviors and social disinhibition. In late stages of HD, motor disability becomes severe and the individual is often totally dependent, mute, and incontinent. The median survival time after onset is 15 to 18 years (range: 5 to >25 years). The average age at death is 54 to 55 years [ Onset of Clinical Signs and Symptoms in HD Clumsiness Agitation Irritability Apathy Anxiety Disinhibition Delusions Hallucinations Abnormal eye movements Depression Olfactory dysfunction Dystonia Involuntary movements Trouble w/balance & walking Chorea, twisting & writhing motions, jerks, staggering, swaying, disjointed gait (can seem like intoxication) Trouble w/activities that require manual dexterity Slow voluntary movements; difficulty initiating movement Inability to control speed & force of movement Slow reaction time General weakness Weight loss Speech difficulties Stubbornness Rigidity Bradykinesia (difficulty initiating & continuing movements) Severe chorea (less common) Significant weight loss Inability to walk Inability to speak Swallowing difficulties; danger of choking Inability to care for oneself With advancing disease duration, other involuntary movements such as bradykinesia, rigidity, and dystonia occur. Impairment in voluntary motor function is an early sign. Affected individuals and their families describe clumsiness in common daily activities. Motor speed, fine motor control, and gait are affected. Oculomotor disturbances occur early and worsen progressively. Difficulty in initiating ocular saccades, slow and hypometric saccades, and problems in gaze fixation may be seen in up to 75% of symptomatic individuals [ Memory deficits with greater impairment for retrieval of information occur early, but verbal cues, priming, and sufficient time may lead to partial or correct recall. Early in the disease the memory deficits in HD are usually much less severe than in Alzheimer disease. The overall cognitive and behavioral syndrome in individuals with HD is more similar to frontotemporal dementia than to Alzheimer disease. Attention and concentration are involved early [ Neuropsychologic testing reveals impaired visuospatial abilities, particularly in late stages of the disease. Lack of awareness, especially of one's own disabilities, is common [ Sleep and circadian rhythms are disrupted in individuals with HD [ Intraneuronal inclusions containing huntingtin, the protein expressed from In teenagers, symptoms are more similar to adult HD, in which chorea and severe behavioral disturbances are common initial manifestations [ A significant inverse correlation exists between the number of CAG repeats and the age of onset of HD [ Individuals with adult onset of symptoms usually have an Individuals with juvenile onset of symptoms usually have an Intermediate alleles (ranging from 27 to 35 CAG repeats) usually have not been associated with disease but are prone to CAG repeat instability [ For data on the age-specific likelihood of onset by trinucleotide repeat size, see In addition to age at clinical onset, CAG repeat length has also been shown to predict age at death, but not the duration of the illness [ The rate of deterioration of motor, cognitive, and functional measures increases with larger CAG repeat sizes [ The progression of behavioral symptoms appears not to be related to repeat size [ Homozygotes for fully penetrant HD alleles appear to have a similar age of onset to heterozygotes, but may exhibit an accelerated rate of disease progression [ A significant negative correlation also exists between CAG size and Significant progress has been made in recent years in the identification of these additional genomic modifiers, both at the Alleles with 36 to 39 CAG repeats are considered HD-causing alleles, but exhibit incomplete penetrance. Elderly asymptomatic individuals with CAG repeats in this range are common [ Disease risk varies for the common [(CAG)n-CAA-CAG] interrupted repeat, observed in more than 95% of alleles, and the rare [(CAG)n] uninterrupted repeat, observed in about 1% of alleles [ The loss of the CAA repeat has been termed the loss of interruption (LOI) variant [ Alleles that contain more than 40 CAG repeats are completely penetrant. No asymptomatic elderly individuals with alleles of more than 40 CAG repeats have been reported. Anticipation, the phenomenon in which increasing disease severity or decreasing age of onset is observed in successive generations, is known to occur in HD. Anticipation occurs far more commonly in paternal transmission of the mutated allele. The phenomenon of anticipation arises from instability of the CAG repeat during spermatogenesis [ In the pre-molecular-genetic era, there were many different names for chorea, including St. Vitus's dance and Sydenham's chorea. Juvenile HD, or childhood-onset HD, was previously called the Westphal variant of HD. Individuals who do not yet show symptoms are in the HD prevalence varies across world regions. Populations of European ancestry display an average prevalence of 9.71:100,000 [ Individuals living in the Lake Maracaibo region of Venezuela are believed to have the highest prevalence of HD in the world [ The uneven distribution of HD is at least partially explained by the distribution of specific predisposing alleles and haplotypes in the general population of these ethnic groups [ Reduced-penetrance • No clinical motor signs/symptoms (motor DCL = 0 or 1) • No cognitive signs/symptoms • May have changes in imaging, quantitative motor assessments, or other biomarkers • No symptomatic treatment indicated • Disease-modifying treatment when safe & available • Subtle motor signs (usually motor DCL = 2) AND/OR subtle cognitive signs or symptoms • Minor decline from individual premorbid level of function possibly detectable, but not required & not detectable on TFC • Apathy or depression or other behavioral changes judged related to HD may be present. • Usually changes in imaging & quantitative motor assessments • May/may not require symptomatic treatment (e.g., for depression) • Disease-modifying treatment appropriate • Presence of clinical motor &/or cognitive signs & symptoms that have an impact on life, with: • Functional changes (e.g., ↓ TFC); • Motor DCL = 3 or 4 (or motor DCL of 2 if cognitive changes significant AND evidence of progression) • Functional changes (e.g., ↓ TFC); • Motor DCL = 3 or 4 (or motor DCL of 2 if cognitive changes significant AND evidence of progression) • Symptomatic & disease-modifying treatment appropriate • Functional changes (e.g., ↓ TFC); • Motor DCL = 3 or 4 (or motor DCL of 2 if cognitive changes significant AND evidence of progression) • Clumsiness • Agitation • Irritability • Apathy • Anxiety • Disinhibition • Delusions • Hallucinations • Abnormal eye movements • Depression • Olfactory dysfunction • Dystonia • Involuntary movements • Trouble w/balance & walking • Chorea, twisting & writhing motions, jerks, staggering, swaying, disjointed gait (can seem like intoxication) • Trouble w/activities that require manual dexterity • Slow voluntary movements; difficulty initiating movement • Inability to control speed & force of movement • Slow reaction time • General weakness • Weight loss • Speech difficulties • Stubbornness • Rigidity • Bradykinesia (difficulty initiating & continuing movements) • Severe chorea (less common) • Significant weight loss • Inability to walk • Inability to speak • Swallowing difficulties; danger of choking • Inability to care for oneself • Individuals with adult onset of symptoms usually have an • Individuals with juvenile onset of symptoms usually have an • Intermediate alleles (ranging from 27 to 35 CAG repeats) usually have not been associated with disease but are prone to CAG repeat instability [ ## Clinical Description During the prodromal phase of Huntington disease (HD) individuals may have subtle changes in motor skills, cognition, and personality (see Categories of Huntington Disease Diagnosis No clinical motor signs/symptoms (motor DCL = 0 or 1) No cognitive signs/symptoms May have changes in imaging, quantitative motor assessments, or other biomarkers No symptomatic treatment indicated Disease-modifying treatment when safe & available Subtle motor signs (usually motor DCL = 2) AND/OR subtle cognitive signs or symptoms Minor decline from individual premorbid level of function possibly detectable, but not required & not detectable on TFC Apathy or depression or other behavioral changes judged related to HD may be present. Usually changes in imaging & quantitative motor assessments May/may not require symptomatic treatment (e.g., for depression) Disease-modifying treatment appropriate Presence of clinical motor &/or cognitive signs & symptoms that have an impact on life, with: Functional changes (e.g., ↓ TFC); Motor DCL = 3 or 4 (or motor DCL of 2 if cognitive changes significant AND evidence of progression) Symptomatic & disease-modifying treatment appropriate Adapted from DCL = diagnostic confidence level (from the UHDRS rating scale); HD = Huntington disease; TFC = total functional capacity Requires motor DCL = 4, plus cognitive changes The mean age of onset for HD is approximately 45 years [ In approximately 25% of individuals with HD, the onset is delayed until after age 50 years, with some after age 70 years. These individuals have chorea, gait disturbances, and dysphagia, but a more prolonged and benign course than the typical individual. In the next stage, chorea becomes more prominent, voluntary activity becomes increasingly difficult, and dysarthria and dysphagia worsen. Most individuals are forced to give up their employment and depend increasingly on others for help, although they are still able to maintain a considerable degree of personal independence. The impairment is usually considerable, sometimes with intermittent outbursts of aggressive behaviors and social disinhibition. In late stages of HD, motor disability becomes severe and the individual is often totally dependent, mute, and incontinent. The median survival time after onset is 15 to 18 years (range: 5 to >25 years). The average age at death is 54 to 55 years [ Onset of Clinical Signs and Symptoms in HD Clumsiness Agitation Irritability Apathy Anxiety Disinhibition Delusions Hallucinations Abnormal eye movements Depression Olfactory dysfunction Dystonia Involuntary movements Trouble w/balance & walking Chorea, twisting & writhing motions, jerks, staggering, swaying, disjointed gait (can seem like intoxication) Trouble w/activities that require manual dexterity Slow voluntary movements; difficulty initiating movement Inability to control speed & force of movement Slow reaction time General weakness Weight loss Speech difficulties Stubbornness Rigidity Bradykinesia (difficulty initiating & continuing movements) Severe chorea (less common) Significant weight loss Inability to walk Inability to speak Swallowing difficulties; danger of choking Inability to care for oneself With advancing disease duration, other involuntary movements such as bradykinesia, rigidity, and dystonia occur. Impairment in voluntary motor function is an early sign. Affected individuals and their families describe clumsiness in common daily activities. Motor speed, fine motor control, and gait are affected. Oculomotor disturbances occur early and worsen progressively. Difficulty in initiating ocular saccades, slow and hypometric saccades, and problems in gaze fixation may be seen in up to 75% of symptomatic individuals [ Memory deficits with greater impairment for retrieval of information occur early, but verbal cues, priming, and sufficient time may lead to partial or correct recall. Early in the disease the memory deficits in HD are usually much less severe than in Alzheimer disease. The overall cognitive and behavioral syndrome in individuals with HD is more similar to frontotemporal dementia than to Alzheimer disease. Attention and concentration are involved early [ Neuropsychologic testing reveals impaired visuospatial abilities, particularly in late stages of the disease. Lack of awareness, especially of one's own disabilities, is common [ Sleep and circadian rhythms are disrupted in individuals with HD [ Intraneuronal inclusions containing huntingtin, the protein expressed from In teenagers, symptoms are more similar to adult HD, in which chorea and severe behavioral disturbances are common initial manifestations [ • No clinical motor signs/symptoms (motor DCL = 0 or 1) • No cognitive signs/symptoms • May have changes in imaging, quantitative motor assessments, or other biomarkers • No symptomatic treatment indicated • Disease-modifying treatment when safe & available • Subtle motor signs (usually motor DCL = 2) AND/OR subtle cognitive signs or symptoms • Minor decline from individual premorbid level of function possibly detectable, but not required & not detectable on TFC • Apathy or depression or other behavioral changes judged related to HD may be present. • Usually changes in imaging & quantitative motor assessments • May/may not require symptomatic treatment (e.g., for depression) • Disease-modifying treatment appropriate • Presence of clinical motor &/or cognitive signs & symptoms that have an impact on life, with: • Functional changes (e.g., ↓ TFC); • Motor DCL = 3 or 4 (or motor DCL of 2 if cognitive changes significant AND evidence of progression) • Functional changes (e.g., ↓ TFC); • Motor DCL = 3 or 4 (or motor DCL of 2 if cognitive changes significant AND evidence of progression) • Symptomatic & disease-modifying treatment appropriate • Functional changes (e.g., ↓ TFC); • Motor DCL = 3 or 4 (or motor DCL of 2 if cognitive changes significant AND evidence of progression) • Clumsiness • Agitation • Irritability • Apathy • Anxiety • Disinhibition • Delusions • Hallucinations • Abnormal eye movements • Depression • Olfactory dysfunction • Dystonia • Involuntary movements • Trouble w/balance & walking • Chorea, twisting & writhing motions, jerks, staggering, swaying, disjointed gait (can seem like intoxication) • Trouble w/activities that require manual dexterity • Slow voluntary movements; difficulty initiating movement • Inability to control speed & force of movement • Slow reaction time • General weakness • Weight loss • Speech difficulties • Stubbornness • Rigidity • Bradykinesia (difficulty initiating & continuing movements) • Severe chorea (less common) • Significant weight loss • Inability to walk • Inability to speak • Swallowing difficulties; danger of choking • Inability to care for oneself ## Genotype-Phenotype Correlations A significant inverse correlation exists between the number of CAG repeats and the age of onset of HD [ Individuals with adult onset of symptoms usually have an Individuals with juvenile onset of symptoms usually have an Intermediate alleles (ranging from 27 to 35 CAG repeats) usually have not been associated with disease but are prone to CAG repeat instability [ For data on the age-specific likelihood of onset by trinucleotide repeat size, see In addition to age at clinical onset, CAG repeat length has also been shown to predict age at death, but not the duration of the illness [ The rate of deterioration of motor, cognitive, and functional measures increases with larger CAG repeat sizes [ The progression of behavioral symptoms appears not to be related to repeat size [ Homozygotes for fully penetrant HD alleles appear to have a similar age of onset to heterozygotes, but may exhibit an accelerated rate of disease progression [ A significant negative correlation also exists between CAG size and Significant progress has been made in recent years in the identification of these additional genomic modifiers, both at the • Individuals with adult onset of symptoms usually have an • Individuals with juvenile onset of symptoms usually have an • Intermediate alleles (ranging from 27 to 35 CAG repeats) usually have not been associated with disease but are prone to CAG repeat instability [ ## Penetrance Alleles with 36 to 39 CAG repeats are considered HD-causing alleles, but exhibit incomplete penetrance. Elderly asymptomatic individuals with CAG repeats in this range are common [ Disease risk varies for the common [(CAG)n-CAA-CAG] interrupted repeat, observed in more than 95% of alleles, and the rare [(CAG)n] uninterrupted repeat, observed in about 1% of alleles [ The loss of the CAA repeat has been termed the loss of interruption (LOI) variant [ Alleles that contain more than 40 CAG repeats are completely penetrant. No asymptomatic elderly individuals with alleles of more than 40 CAG repeats have been reported. ## Anticipation Anticipation, the phenomenon in which increasing disease severity or decreasing age of onset is observed in successive generations, is known to occur in HD. Anticipation occurs far more commonly in paternal transmission of the mutated allele. The phenomenon of anticipation arises from instability of the CAG repeat during spermatogenesis [ ## Nomenclature In the pre-molecular-genetic era, there were many different names for chorea, including St. Vitus's dance and Sydenham's chorea. Juvenile HD, or childhood-onset HD, was previously called the Westphal variant of HD. Individuals who do not yet show symptoms are in the ## Prevalence HD prevalence varies across world regions. Populations of European ancestry display an average prevalence of 9.71:100,000 [ Individuals living in the Lake Maracaibo region of Venezuela are believed to have the highest prevalence of HD in the world [ The uneven distribution of HD is at least partially explained by the distribution of specific predisposing alleles and haplotypes in the general population of these ethnic groups [ Reduced-penetrance ## Genetically Related (Allelic) Disorders Biallelic pathogenic missense variants in ## Differential Diagnosis Huntington disease (HD) falls into the differential diagnosis of chorea, dementia, and psychiatric disturbances. The differential diagnosis of several HD-like disorders is summarized here and reviewed elsewhere [ Inherited Conditions to Consider in the Differential Diagnosis of Huntington Disease Movement disorders Dementia Psychiatric disturbances Myoclonus Tremor Torticollis Early onset Slow progression Progressive movement disorder Progressive cognitive & behavior changes Myopathy ↑ serum CK Acanthocytosis Seizures common Mean age of onset ~30 yrs Cognitive impairment Psychiatric symptoms Acanthocytosis Compensated hemolysis McLeod blood group phenotype Chorea Dementia Psychiatric disturbances Progressive movement disorders & dementia Psychiatric disturbances Nonprogressive chorea Not assoc w/dementia Typically late onset Progressive dementia Movement disorders Behavior changes Psychiatric symptoms fCJD progresses more rapidly. Myoclonus is a prominent involuntary movement. Late onset Progressive movement disorders, dementia, & behavior changes Psychiatric disturbances AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system; MOI = mode of inheritance; XL = X-linked HDL1 is caused by a specific pathogenic variant (8 extra octapeptide repeats) in the prion protein gene, The diagnosis of HD in children is straightforward in a family with a history of HD. In simplex cases (an affected individual with no known family history of HD), • Movement disorders • Dementia • Psychiatric disturbances • Myoclonus • Tremor • Torticollis • Early onset • Slow progression • Progressive movement disorder • Progressive cognitive & behavior changes • Myopathy • ↑ serum CK • Acanthocytosis • Seizures common • Mean age of onset ~30 yrs • Cognitive impairment • Psychiatric symptoms • Acanthocytosis • Compensated hemolysis • McLeod blood group phenotype • Chorea • Dementia • Psychiatric disturbances • Progressive movement disorders & dementia • Psychiatric disturbances • Nonprogressive chorea • Not assoc w/dementia • Typically late onset • Progressive dementia • Movement disorders • Behavior changes • Psychiatric symptoms • fCJD progresses more rapidly. • Myoclonus is a prominent involuntary movement. • Late onset • Progressive movement disorders, dementia, & behavior changes • Psychiatric disturbances ## Management To establish the extent of disease and needs in an individual diagnosed with Huntington disease (HD), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended: Physical examination Neurologic assessment Assessment of the full range of motor, cognitive, and psychiatric symptoms associated with HD. Among a range of clinical scoring systems that have been described, the Unified Huntington's Disease Rating Scale (UHDRS) provides a reliable and consistent assessment of the clinical features and progression of HD. Consultation with a clinical geneticist and/or genetic counselor Pharmacologic therapy is limited to symptomatic treatment [ Choreic movements can be partially suppressed by typical (haloperidol) and atypical (olanzapine) neuroleptics; benzodiazepines; or the monoamine-depleting agent tetrabenazine [ Anti-parkinsonian agents may ameliorate hypokinesia and rigidity, but may increase chorea. Psychiatric disturbances such as depression, psychotic symptoms, and outbursts of aggression generally respond well to psychotropic drugs or some types of anti-seizure medication. Valproic acid has improved myoclonic hyperkinesia in Huntington disease [ Supportive care with attention to nursing, diet, special equipment, and eligibility for state and federal benefits is much appreciated by individuals with HD and their families. Numerous social challenges beset individuals with HD and their families; practical help, emotional support, and counseling can provide relief [ Significant secondary complications of HD include the following: The complications typically observed with any individual requiring long-term supportive care The side effects associated with various pharmacologic treatments. Drug side effects are dependent on a variety of factors including the compound involved, the dosage, and the individual; with the medications typically used in HD, side effects may include depression, sedation, nausea, restlessness, headache, neutropenia, and tardive dyskinesia. For some individuals, the side effects of certain therapeutics may be worse than the symptoms; such individuals would benefit from being removed from the treatment, having the dose reduced, or being "rested" regularly from the treatment. Current medications used to treat chorea are particularly prone to significant side effects. Individuals with mild-to-moderate chorea may be better assisted with nonpharmacologic therapies such as movement training and speech therapy. Depression. Standard treatment is appropriate when indicated [ Regular evaluations should be made to address the appearance and severity of chorea, rigidity, gait abnormalities, depression, behavioral changes, and cognitive decline [ The Behavior Observation Scale Huntington (BOSH) is a scale developed for the rapid and longitudinal assessment of functional abilities of persons with HD in a nursing home environment [ L-dopa-containing compounds may increase chorea. Alcohol and smoking are discouraged. See A wide range of potential therapeutics are under investigation in both animal models of HD and human clinical trials [ Pharmacologic agents being investigated include inhibitors of: apoptosis, excitotoxicity, huntingtin aggregation, huntingtin proteolysis, huntingtin phosphorylation, inflammation, oxidative damage, phosphodiesterase activity, histone deacetylase, and transglutaminase activity; as well as compounds that modulate mitochondrial function, chaperone activity, transcription, and neurotrophic support. Therapeutics that have shown improvements in preclinical animal models of HD and have been advanced to clinical trials include minocycline, sodium butyrate, essential fatty acids, racemide, creatine, cystamine, riluzole, memantine, resveratrol, cannabis extract (THC and CBD), coenzyme Q Gene-silencing approaches to target the cause of HD have been shown to be safe and efficacious in preclinical animal studies and are currently undergoing or on the verge of entering clinical trials. These include approaches using RNA interference (RNAi) or antisense oligonucleotides (ASOs) [ Cell transplantation studies in HD have shown variable results with small numbers of individuals [ Numerous human clinical trials are planned or under way for HD and are listed at Search A number of candidate molecular biomarkers of disease onset and clinical progression have been assessed in HD patient cohorts, yet only a few have been validated. Mutated huntingtin levels in CSF have been shown to correlate with disease stage in HD [ • Physical examination • Neurologic assessment • Assessment of the full range of motor, cognitive, and psychiatric symptoms associated with HD. Among a range of clinical scoring systems that have been described, the Unified Huntington's Disease Rating Scale (UHDRS) provides a reliable and consistent assessment of the clinical features and progression of HD. • Consultation with a clinical geneticist and/or genetic counselor • Choreic movements can be partially suppressed by typical (haloperidol) and atypical (olanzapine) neuroleptics; benzodiazepines; or the monoamine-depleting agent tetrabenazine [ • Anti-parkinsonian agents may ameliorate hypokinesia and rigidity, but may increase chorea. • Psychiatric disturbances such as depression, psychotic symptoms, and outbursts of aggression generally respond well to psychotropic drugs or some types of anti-seizure medication. • Valproic acid has improved myoclonic hyperkinesia in Huntington disease [ • The complications typically observed with any individual requiring long-term supportive care • The side effects associated with various pharmacologic treatments. Drug side effects are dependent on a variety of factors including the compound involved, the dosage, and the individual; with the medications typically used in HD, side effects may include depression, sedation, nausea, restlessness, headache, neutropenia, and tardive dyskinesia. For some individuals, the side effects of certain therapeutics may be worse than the symptoms; such individuals would benefit from being removed from the treatment, having the dose reduced, or being "rested" regularly from the treatment. Current medications used to treat chorea are particularly prone to significant side effects. Individuals with mild-to-moderate chorea may be better assisted with nonpharmacologic therapies such as movement training and speech therapy. • Depression. Standard treatment is appropriate when indicated [ • Pharmacologic agents being investigated include inhibitors of: apoptosis, excitotoxicity, huntingtin aggregation, huntingtin proteolysis, huntingtin phosphorylation, inflammation, oxidative damage, phosphodiesterase activity, histone deacetylase, and transglutaminase activity; as well as compounds that modulate mitochondrial function, chaperone activity, transcription, and neurotrophic support. • Therapeutics that have shown improvements in preclinical animal models of HD and have been advanced to clinical trials include minocycline, sodium butyrate, essential fatty acids, racemide, creatine, cystamine, riluzole, memantine, resveratrol, cannabis extract (THC and CBD), coenzyme Q • Gene-silencing approaches to target the cause of HD have been shown to be safe and efficacious in preclinical animal studies and are currently undergoing or on the verge of entering clinical trials. These include approaches using RNA interference (RNAi) or antisense oligonucleotides (ASOs) [ • Cell transplantation studies in HD have shown variable results with small numbers of individuals [ ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Huntington disease (HD), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended: Physical examination Neurologic assessment Assessment of the full range of motor, cognitive, and psychiatric symptoms associated with HD. Among a range of clinical scoring systems that have been described, the Unified Huntington's Disease Rating Scale (UHDRS) provides a reliable and consistent assessment of the clinical features and progression of HD. Consultation with a clinical geneticist and/or genetic counselor • Physical examination • Neurologic assessment • Assessment of the full range of motor, cognitive, and psychiatric symptoms associated with HD. Among a range of clinical scoring systems that have been described, the Unified Huntington's Disease Rating Scale (UHDRS) provides a reliable and consistent assessment of the clinical features and progression of HD. • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations Pharmacologic therapy is limited to symptomatic treatment [ Choreic movements can be partially suppressed by typical (haloperidol) and atypical (olanzapine) neuroleptics; benzodiazepines; or the monoamine-depleting agent tetrabenazine [ Anti-parkinsonian agents may ameliorate hypokinesia and rigidity, but may increase chorea. Psychiatric disturbances such as depression, psychotic symptoms, and outbursts of aggression generally respond well to psychotropic drugs or some types of anti-seizure medication. Valproic acid has improved myoclonic hyperkinesia in Huntington disease [ Supportive care with attention to nursing, diet, special equipment, and eligibility for state and federal benefits is much appreciated by individuals with HD and their families. Numerous social challenges beset individuals with HD and their families; practical help, emotional support, and counseling can provide relief [ • Choreic movements can be partially suppressed by typical (haloperidol) and atypical (olanzapine) neuroleptics; benzodiazepines; or the monoamine-depleting agent tetrabenazine [ • Anti-parkinsonian agents may ameliorate hypokinesia and rigidity, but may increase chorea. • Psychiatric disturbances such as depression, psychotic symptoms, and outbursts of aggression generally respond well to psychotropic drugs or some types of anti-seizure medication. • Valproic acid has improved myoclonic hyperkinesia in Huntington disease [ ## Prevention of Secondary Complications Significant secondary complications of HD include the following: The complications typically observed with any individual requiring long-term supportive care The side effects associated with various pharmacologic treatments. Drug side effects are dependent on a variety of factors including the compound involved, the dosage, and the individual; with the medications typically used in HD, side effects may include depression, sedation, nausea, restlessness, headache, neutropenia, and tardive dyskinesia. For some individuals, the side effects of certain therapeutics may be worse than the symptoms; such individuals would benefit from being removed from the treatment, having the dose reduced, or being "rested" regularly from the treatment. Current medications used to treat chorea are particularly prone to significant side effects. Individuals with mild-to-moderate chorea may be better assisted with nonpharmacologic therapies such as movement training and speech therapy. Depression. Standard treatment is appropriate when indicated [ • The complications typically observed with any individual requiring long-term supportive care • The side effects associated with various pharmacologic treatments. Drug side effects are dependent on a variety of factors including the compound involved, the dosage, and the individual; with the medications typically used in HD, side effects may include depression, sedation, nausea, restlessness, headache, neutropenia, and tardive dyskinesia. For some individuals, the side effects of certain therapeutics may be worse than the symptoms; such individuals would benefit from being removed from the treatment, having the dose reduced, or being "rested" regularly from the treatment. Current medications used to treat chorea are particularly prone to significant side effects. Individuals with mild-to-moderate chorea may be better assisted with nonpharmacologic therapies such as movement training and speech therapy. • Depression. Standard treatment is appropriate when indicated [ ## Surveillance Regular evaluations should be made to address the appearance and severity of chorea, rigidity, gait abnormalities, depression, behavioral changes, and cognitive decline [ The Behavior Observation Scale Huntington (BOSH) is a scale developed for the rapid and longitudinal assessment of functional abilities of persons with HD in a nursing home environment [ ## Agents/Circumstances to Avoid L-dopa-containing compounds may increase chorea. Alcohol and smoking are discouraged. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation A wide range of potential therapeutics are under investigation in both animal models of HD and human clinical trials [ Pharmacologic agents being investigated include inhibitors of: apoptosis, excitotoxicity, huntingtin aggregation, huntingtin proteolysis, huntingtin phosphorylation, inflammation, oxidative damage, phosphodiesterase activity, histone deacetylase, and transglutaminase activity; as well as compounds that modulate mitochondrial function, chaperone activity, transcription, and neurotrophic support. Therapeutics that have shown improvements in preclinical animal models of HD and have been advanced to clinical trials include minocycline, sodium butyrate, essential fatty acids, racemide, creatine, cystamine, riluzole, memantine, resveratrol, cannabis extract (THC and CBD), coenzyme Q Gene-silencing approaches to target the cause of HD have been shown to be safe and efficacious in preclinical animal studies and are currently undergoing or on the verge of entering clinical trials. These include approaches using RNA interference (RNAi) or antisense oligonucleotides (ASOs) [ Cell transplantation studies in HD have shown variable results with small numbers of individuals [ Numerous human clinical trials are planned or under way for HD and are listed at Search • Pharmacologic agents being investigated include inhibitors of: apoptosis, excitotoxicity, huntingtin aggregation, huntingtin proteolysis, huntingtin phosphorylation, inflammation, oxidative damage, phosphodiesterase activity, histone deacetylase, and transglutaminase activity; as well as compounds that modulate mitochondrial function, chaperone activity, transcription, and neurotrophic support. • Therapeutics that have shown improvements in preclinical animal models of HD and have been advanced to clinical trials include minocycline, sodium butyrate, essential fatty acids, racemide, creatine, cystamine, riluzole, memantine, resveratrol, cannabis extract (THC and CBD), coenzyme Q • Gene-silencing approaches to target the cause of HD have been shown to be safe and efficacious in preclinical animal studies and are currently undergoing or on the verge of entering clinical trials. These include approaches using RNA interference (RNAi) or antisense oligonucleotides (ASOs) [ • Cell transplantation studies in HD have shown variable results with small numbers of individuals [ ## Other A number of candidate molecular biomarkers of disease onset and clinical progression have been assessed in HD patient cohorts, yet only a few have been validated. Mutated huntingtin levels in CSF have been shown to correlate with disease stage in HD [ ## Genetic Counseling Huntington disease (HD) is inherited in an autosomal dominant manner. Most individuals diagnosed with HD have an affected parent. The family history of some individuals diagnosed with HD may appear to be negative for one of the following reasons: Failure to recognize the disorder in family members Early death of the parent before the onset of symptoms The presence of an intermediate allele (range: 27-35 CAG repeats) or an Late onset of the disease in the affected parent Molecular genetic testing is recommended for the parents of a proband who appears to represent a simplex case (i.e., a single occurrence in a family). If a parent has an If a parent has an If a parent has an intermediate CAG size-specific estimates for repeat instability in sperm have been reported to enable genetic counselors to provide more accurate risk assessment for persons who receive an intermediate allele predictive test result [ At conception, each child of an individual with HD as a result of heterozygosity for a CAG repeat expansion in Each child of an affected individual who is homozygous for CAG repeat expansion in At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Asymptomatic individuals at risk may also be eligible to participate in clinical trials. Others may have different motivations including simply the "need to know." Testing of asymptomatic at-risk adult family members usually involves pretest interviews in which the motives for requesting the test, the individual's knowledge of HD, the possible impact of positive and negative test results, and neurologic status are assessed. Those seeking testing should be counseled about problems they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Interestingly, a study has found that genetic testing does not increase the risk for discrimination; perceived genetic discrimination is more likely due to the family history of HD regardless of gene status, rather than due to the specific results of the HD genetic test [ Short-term follow up of the participants in the Canadian Predictive Testing Program has revealed that predictive testing for HD may maintain or even improve the psychological well-being of at-risk individuals even though some had negative experiences. About 10% of the group who were determined to be at decreased risk had serious difficulties adapting to their new status. The major issue for these individuals is the realization that they are facing an unplanned future. Overall, the demand for testing of at-risk asymptomatic adults has been lower than expected in studies conducted before the availability of direct molecular genetic testing. Consistent with use of medical services and genetic testing in general, women are more likely than men to undergo predictive testing for HD [ In their study of psychological distress in the partners of asymptomatic individuals who had inherited an HD-causing allele, 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 HD, it is appropriate to consider testing of symptomatic individuals regardless of age. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing when the testing is being considered for the purpose of pregnancy termination or for 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 HD have an affected parent. • The family history of some individuals diagnosed with HD may appear to be negative for one of the following reasons: • Failure to recognize the disorder in family members • Early death of the parent before the onset of symptoms • The presence of an intermediate allele (range: 27-35 CAG repeats) or an • Late onset of the disease in the affected parent • Failure to recognize the disorder in family members • Early death of the parent before the onset of symptoms • The presence of an intermediate allele (range: 27-35 CAG repeats) or an • Late onset of the disease in the affected parent • Molecular genetic testing is recommended for the parents of a proband who appears to represent a simplex case (i.e., a single occurrence in a family). • Failure to recognize the disorder in family members • Early death of the parent before the onset of symptoms • The presence of an intermediate allele (range: 27-35 CAG repeats) or an • Late onset of the disease in the affected parent • If a parent has an • If a parent has an • If a parent has an intermediate • CAG size-specific estimates for repeat instability in sperm have been reported to enable genetic counselors to provide more accurate risk assessment for persons who receive an intermediate allele predictive test result [ • CAG size-specific estimates for repeat instability in sperm have been reported to enable genetic counselors to provide more accurate risk assessment for persons who receive an intermediate allele predictive test result [ • CAG size-specific estimates for repeat instability in sperm have been reported to enable genetic counselors to provide more accurate risk assessment for persons who receive an intermediate allele predictive test result [ • At conception, each child of an individual with HD as a result of heterozygosity for a CAG repeat expansion in • Each child of an affected individual who is homozygous for CAG repeat expansion in • At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Asymptomatic individuals at risk may also be eligible to participate in clinical trials. Others may have different motivations including simply the "need to know." Testing of asymptomatic at-risk adult family members usually involves pretest interviews in which the motives for requesting the test, the individual's knowledge of HD, the possible impact of positive and negative test results, and neurologic status are assessed. Those seeking testing should be counseled about problems they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Interestingly, a study has found that genetic testing does not increase the risk for discrimination; perceived genetic discrimination is more likely due to the family history of HD regardless of gene status, rather than due to the specific results of the HD genetic test [ • Short-term follow up of the participants in the Canadian Predictive Testing Program has revealed that predictive testing for HD may maintain or even improve the psychological well-being of at-risk individuals even though some had negative experiences. About 10% of the group who were determined to be at decreased risk had serious difficulties adapting to their new status. The major issue for these individuals is the realization that they are facing an unplanned future. Overall, the demand for testing of at-risk asymptomatic adults has been lower than expected in studies conducted before the availability of direct molecular genetic testing. Consistent with use of medical services and genetic testing in general, women are more likely than men to undergo predictive testing for HD [ • In their study of psychological distress in the partners of asymptomatic individuals who had inherited an HD-causing allele, • 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. • Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy. ## Mode of Inheritance Huntington disease (HD) is inherited in an autosomal dominant manner. ## Risk to Family Members Most individuals diagnosed with HD have an affected parent. The family history of some individuals diagnosed with HD may appear to be negative for one of the following reasons: Failure to recognize the disorder in family members Early death of the parent before the onset of symptoms The presence of an intermediate allele (range: 27-35 CAG repeats) or an Late onset of the disease in the affected parent Molecular genetic testing is recommended for the parents of a proband who appears to represent a simplex case (i.e., a single occurrence in a family). If a parent has an If a parent has an If a parent has an intermediate CAG size-specific estimates for repeat instability in sperm have been reported to enable genetic counselors to provide more accurate risk assessment for persons who receive an intermediate allele predictive test result [ At conception, each child of an individual with HD as a result of heterozygosity for a CAG repeat expansion in Each child of an affected individual who is homozygous for CAG repeat expansion in • Most individuals diagnosed with HD have an affected parent. • The family history of some individuals diagnosed with HD may appear to be negative for one of the following reasons: • Failure to recognize the disorder in family members • Early death of the parent before the onset of symptoms • The presence of an intermediate allele (range: 27-35 CAG repeats) or an • Late onset of the disease in the affected parent • Failure to recognize the disorder in family members • Early death of the parent before the onset of symptoms • The presence of an intermediate allele (range: 27-35 CAG repeats) or an • Late onset of the disease in the affected parent • Molecular genetic testing is recommended for the parents of a proband who appears to represent a simplex case (i.e., a single occurrence in a family). • Failure to recognize the disorder in family members • Early death of the parent before the onset of symptoms • The presence of an intermediate allele (range: 27-35 CAG repeats) or an • Late onset of the disease in the affected parent • If a parent has an • If a parent has an • If a parent has an intermediate • CAG size-specific estimates for repeat instability in sperm have been reported to enable genetic counselors to provide more accurate risk assessment for persons who receive an intermediate allele predictive test result [ • CAG size-specific estimates for repeat instability in sperm have been reported to enable genetic counselors to provide more accurate risk assessment for persons who receive an intermediate allele predictive test result [ • CAG size-specific estimates for repeat instability in sperm have been reported to enable genetic counselors to provide more accurate risk assessment for persons who receive an intermediate allele predictive test result [ • At conception, each child of an individual with HD as a result of heterozygosity for a CAG repeat expansion in • Each child of an affected individual who is homozygous for CAG repeat expansion in ## Related Genetic Counseling Issues At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Asymptomatic individuals at risk may also be eligible to participate in clinical trials. Others may have different motivations including simply the "need to know." Testing of asymptomatic at-risk adult family members usually involves pretest interviews in which the motives for requesting the test, the individual's knowledge of HD, the possible impact of positive and negative test results, and neurologic status are assessed. Those seeking testing should be counseled about problems they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Interestingly, a study has found that genetic testing does not increase the risk for discrimination; perceived genetic discrimination is more likely due to the family history of HD regardless of gene status, rather than due to the specific results of the HD genetic test [ Short-term follow up of the participants in the Canadian Predictive Testing Program has revealed that predictive testing for HD may maintain or even improve the psychological well-being of at-risk individuals even though some had negative experiences. About 10% of the group who were determined to be at decreased risk had serious difficulties adapting to their new status. The major issue for these individuals is the realization that they are facing an unplanned future. Overall, the demand for testing of at-risk asymptomatic adults has been lower than expected in studies conducted before the availability of direct molecular genetic testing. Consistent with use of medical services and genetic testing in general, women are more likely than men to undergo predictive testing for HD [ In their study of psychological distress in the partners of asymptomatic individuals who had inherited an HD-causing allele, 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 HD, it is appropriate to consider testing of symptomatic individuals regardless of age. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy. • At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Asymptomatic individuals at risk may also be eligible to participate in clinical trials. Others may have different motivations including simply the "need to know." Testing of asymptomatic at-risk adult family members usually involves pretest interviews in which the motives for requesting the test, the individual's knowledge of HD, the possible impact of positive and negative test results, and neurologic status are assessed. Those seeking testing should be counseled about problems they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Interestingly, a study has found that genetic testing does not increase the risk for discrimination; perceived genetic discrimination is more likely due to the family history of HD regardless of gene status, rather than due to the specific results of the HD genetic test [ • Short-term follow up of the participants in the Canadian Predictive Testing Program has revealed that predictive testing for HD may maintain or even improve the psychological well-being of at-risk individuals even though some had negative experiences. About 10% of the group who were determined to be at decreased risk had serious difficulties adapting to their new status. The major issue for these individuals is the realization that they are facing an unplanned future. Overall, the demand for testing of at-risk asymptomatic adults has been lower than expected in studies conducted before the availability of direct molecular genetic testing. Consistent with use of medical services and genetic testing in general, women are more likely than men to undergo predictive testing for HD [ • In their study of psychological distress in the partners of asymptomatic individuals who had inherited an HD-causing allele, • 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. • Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy. ## Prenatal Testing and Preimplantation Genetic Testing Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing when the testing is being considered for the purpose of pregnancy termination or for early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources Germany Canada Canada University of Washington Medical Center • • Germany • • • • • • • Canada • • • • • • • Canada • • • • University of Washington Medical Center • • • • • • • ## Molecular Genetics Huntington Disease: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Huntington Disease ( Of note, huntingtin acts as a scaffold to facilitate several essential functions in the cell, including cytoskeletal dynamics, endocytosis, vesicular trafficking (BDNF), energy metabolism, protein turnover, and gene expression (transcription and RNA processing). In the presence of a CAG expansion, many of its roles are disrupted, likely contributing to the disease phenotype [ Methods to Characterize The design of a triplet-primed PCR (TP-PCR) assay may include conventional PCR primers to size normal repeats and detect expanded repeats in a single assay. The TP-PCR assay itself does not determine repeat size, even alleles in the normal range. Methods to detect and approximate the size of expanded repeats include long-range PCR sized by gel 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 CAG repeat; thus, testing by TP-PCR or expanded repeat analysis is required to detect a repeat expansion. PCR-based methods detect alleles up to about 115 CAG repeats [ Repeats at the lower end of this range may not show the characteristic stutter pattern that indicates an expanded allele. Southern blotting for the CAG repeat expansion has been described [ Notable Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis Of note, huntingtin acts as a scaffold to facilitate several essential functions in the cell, including cytoskeletal dynamics, endocytosis, vesicular trafficking (BDNF), energy metabolism, protein turnover, and gene expression (transcription and RNA processing). In the presence of a CAG expansion, many of its roles are disrupted, likely contributing to the disease phenotype [ Methods to Characterize The design of a triplet-primed PCR (TP-PCR) assay may include conventional PCR primers to size normal repeats and detect expanded repeats in a single assay. The TP-PCR assay itself does not determine repeat size, even alleles in the normal range. Methods to detect and approximate the size of expanded repeats include long-range PCR sized by gel 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 CAG repeat; thus, testing by TP-PCR or expanded repeat analysis is required to detect a repeat expansion. PCR-based methods detect alleles up to about 115 CAG repeats [ Repeats at the lower end of this range may not show the characteristic stutter pattern that indicates an expanded allele. Southern blotting for the CAG repeat expansion has been described [ Notable Variants listed in the table have been provided by the authors. ## Chapter Notes Booklets available through the Loss and Grief: Coping with the Death of a Loved One and with Other Losses Related to Huntington Disease A Physician's Guide to the Management of Huntington Disease (3rd edition) Caregiver's Handbook for Advanced Stages of Huntington Disease Juvenile Huntington Disease: A Resource for Families, Health Professionals and Caregivers Understanding Behaviour in Huntington Disease: A Guide for Professionals (3rd edition) Personal Perspectives on Genetic Testing for Huntington Disease Understanding Huntington Disease: A Resource for Families Nicholas S Caron, PhD (2018-present)Rona K Graham, PhD; University of Sherbrooke, Quebec (2007-2018) Brendan Haigh, PhD; University of British Columbia (1998-2007) Michael R Hayden, MB, ChB, PhD, FRCP(C), FRSC (1998-present) Mahbubul Huq, PhD; University of British Columbia (1998-2007) Simon C Warby, PhD; University of Montreal (2007-2018)Galen EB Wright, PhD (2018-present) 11 June 2020 (sw) Comprehensive update posted live 5 July 2018 (sw) Comprehensive update posted live 11 December 2014 (me) Comprehensive update posted live 22 April 2010 (me) Comprehensive update posted live 19 July 2007 (me) Comprehensive update posted live 30 August 2005 (cd) Revision: correction of CAG repeat ranges 15 February 2005 (me) Comprehensive update posted live 25 May 2004 (cd) Revisions 23 October 1998 (pb) Review posted live 16 May 1998 (mh) Original submission • Loss and Grief: Coping with the Death of a Loved One and with Other Losses Related to Huntington Disease • A Physician's Guide to the Management of Huntington Disease (3rd edition) • Caregiver's Handbook for Advanced Stages of Huntington Disease • Juvenile Huntington Disease: A Resource for Families, Health Professionals and Caregivers • Understanding Behaviour in Huntington Disease: A Guide for Professionals (3rd edition) • Personal Perspectives on Genetic Testing for Huntington Disease • Understanding Huntington Disease: A Resource for Families • 11 June 2020 (sw) Comprehensive update posted live • 5 July 2018 (sw) Comprehensive update posted live • 11 December 2014 (me) Comprehensive update posted live • 22 April 2010 (me) Comprehensive update posted live • 19 July 2007 (me) Comprehensive update posted live • 30 August 2005 (cd) Revision: correction of CAG repeat ranges • 15 February 2005 (me) Comprehensive update posted live • 25 May 2004 (cd) Revisions • 23 October 1998 (pb) Review posted live • 16 May 1998 (mh) Original submission ## Author Notes Booklets available through the Loss and Grief: Coping with the Death of a Loved One and with Other Losses Related to Huntington Disease A Physician's Guide to the Management of Huntington Disease (3rd edition) Caregiver's Handbook for Advanced Stages of Huntington Disease Juvenile Huntington Disease: A Resource for Families, Health Professionals and Caregivers Understanding Behaviour in Huntington Disease: A Guide for Professionals (3rd edition) Personal Perspectives on Genetic Testing for Huntington Disease Understanding Huntington Disease: A Resource for Families • Loss and Grief: Coping with the Death of a Loved One and with Other Losses Related to Huntington Disease • A Physician's Guide to the Management of Huntington Disease (3rd edition) • Caregiver's Handbook for Advanced Stages of Huntington Disease • Juvenile Huntington Disease: A Resource for Families, Health Professionals and Caregivers • Understanding Behaviour in Huntington Disease: A Guide for Professionals (3rd edition) • Personal Perspectives on Genetic Testing for Huntington Disease • Understanding Huntington Disease: A Resource for Families ## Author History Nicholas S Caron, PhD (2018-present)Rona K Graham, PhD; University of Sherbrooke, Quebec (2007-2018) Brendan Haigh, PhD; University of British Columbia (1998-2007) Michael R Hayden, MB, ChB, PhD, FRCP(C), FRSC (1998-present) Mahbubul Huq, PhD; University of British Columbia (1998-2007) Simon C Warby, PhD; University of Montreal (2007-2018)Galen EB Wright, PhD (2018-present) ## Revision History 11 June 2020 (sw) Comprehensive update posted live 5 July 2018 (sw) Comprehensive update posted live 11 December 2014 (me) Comprehensive update posted live 22 April 2010 (me) Comprehensive update posted live 19 July 2007 (me) Comprehensive update posted live 30 August 2005 (cd) Revision: correction of CAG repeat ranges 15 February 2005 (me) Comprehensive update posted live 25 May 2004 (cd) Revisions 23 October 1998 (pb) Review posted live 16 May 1998 (mh) Original submission • 11 June 2020 (sw) Comprehensive update posted live • 5 July 2018 (sw) Comprehensive update posted live • 11 December 2014 (me) Comprehensive update posted live • 22 April 2010 (me) Comprehensive update posted live • 19 July 2007 (me) Comprehensive update posted live • 30 August 2005 (cd) Revision: correction of CAG repeat ranges • 15 February 2005 (me) Comprehensive update posted live • 25 May 2004 (cd) Revisions • 23 October 1998 (pb) Review posted live • 16 May 1998 (mh) Original submission ## References American College of Medical Genetics/American Society of Human Genetics Huntington Disease Genetic Testing Working Group. Laboratory guidelines for Huntington disease genetic testing. Am J Hum Genet. 1998;62:1243-7. [ 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 International Huntington Association and the World Federation of Neurology Research Group on Huntington's Chorea. Guidelines for the molecular genetics predictive test in Huntington's disease. Neurology. 1994;44:1533-6. [ International Huntington Association and World Federation of Neurology. Guidelines for the molecular genetic predictive test in Huntington's disease. Available National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available World Federation of Neurology Research Committee Research Group on Huntington's Chorea. Ethical issues policy statement on Huntington's chorea molecular genetics predictive test. J Neurol Sci. 1989;94:327-32. [ • American College of Medical Genetics/American Society of Human Genetics Huntington Disease Genetic Testing Working Group. Laboratory guidelines for Huntington disease genetic testing. Am J Hum Genet. 1998;62:1243-7. [ • 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 • International Huntington Association and the World Federation of Neurology Research Group on Huntington's Chorea. Guidelines for the molecular genetics predictive test in Huntington's disease. Neurology. 1994;44:1533-6. [ • International Huntington Association and World Federation of Neurology. Guidelines for the molecular genetic predictive test in Huntington's disease. Available • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available • World Federation of Neurology Research Committee Research Group on Huntington's Chorea. Ethical issues policy statement on Huntington's chorea molecular genetics predictive test. J Neurol Sci. 1989;94:327-32. [ ## Published Guidelines / Consensus Statements American College of Medical Genetics/American Society of Human Genetics Huntington Disease Genetic Testing Working Group. Laboratory guidelines for Huntington disease genetic testing. Am J Hum Genet. 1998;62:1243-7. [ 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 International Huntington Association and the World Federation of Neurology Research Group on Huntington's Chorea. Guidelines for the molecular genetics predictive test in Huntington's disease. Neurology. 1994;44:1533-6. [ International Huntington Association and World Federation of Neurology. Guidelines for the molecular genetic predictive test in Huntington's disease. Available National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available World Federation of Neurology Research Committee Research Group on Huntington's Chorea. Ethical issues policy statement on Huntington's chorea molecular genetics predictive test. J Neurol Sci. 1989;94:327-32. [ • American College of Medical Genetics/American Society of Human Genetics Huntington Disease Genetic Testing Working Group. Laboratory guidelines for Huntington disease genetic testing. Am J Hum Genet. 1998;62:1243-7. [ • 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 • International Huntington Association and the World Federation of Neurology Research Group on Huntington's Chorea. Guidelines for the molecular genetics predictive test in Huntington's disease. Neurology. 1994;44:1533-6. [ • International Huntington Association and World Federation of Neurology. Guidelines for the molecular genetic predictive test in Huntington's disease. Available • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available • World Federation of Neurology Research Committee Research Group on Huntington's Chorea. Ethical issues policy statement on Huntington's chorea molecular genetics predictive test. J Neurol Sci. 1989;94:327-32. [ ## Literature Cited Natural history of Huntington disease (HD). Presymptomatic individuals are free from signs and symptoms of HD. During the prodromal phase, subtle signs and symptoms may be present prior to the diagnosis of HD, which is usually based on motor symptoms. During manifest HD, chorea may be one of the most prominent features, followed by a slow progression of motor and cognitive impairments. Modified from	[]	23/10/1998	11/6/2020	30/8/2005	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
huppke-brendel	huppke-brendel	[ "Acetyl-coenzyme A transporter 1", "SLC33A1", "Huppke-Brendel Syndrome" ]	Huppke-Brendel Syndrome	Bindu Parayil Sankaran, Shwetha Chiplunkar, VP Vandana, Madhu Nagappa, Periyasamy Govindaraj, AB Taly	Summary Huppke-Brendel syndrome (HBS) is characterized by bilateral congenital cataracts, sensorineural hearing loss, and severe developmental delay. To date, 11 individuals (ten children and one adult) with HBS have been reported in the literature. All children presented in infancy with axial hypotonia; motor delay was apparent in the first few months of life with a lack of head control and paucity of limb movement. Seizures have been reported infrequently. In all individuals described to date, serum copper and ceruloplasmin levels were very low or undetectable. Brain MRI examination showed hypomyelination, cerebellar hypoplasia (mainly affecting the vermis), and wide subarachnoid spaces. None of the individuals reported to date could sit or walk independently. All affected children died between age ten months and six years. The only adult reported to date had a history of developmental delay, moderately impaired intellectual development, partial hearing loss from childhood, spastic ataxia, hypotonia, and unilateral tremor of parkinsonian type. Low serum copper and ceruloplasmin levels and increased urinary copper levels were reported. Brain MRI showed global atrophy including cerebellar atrophy. The diagnosis of HBS is established in a proband with characteristic features (bilateral congenital cataracts, sensorineural hearing loss, severe developmental delay, very low serum copper and ceruloplasmin levels) and biallelic pathogenic variants in HBS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an	## Diagnosis Formal diagnostic criteria for Huppke-Brendel syndrome (HBS) have not been established. HBS Bilateral congenital cataracts Nystagmus Sensorineural hearing loss Severe developmental delay / intellectual disability and regression of acquired milestones Hypotonia Seizures Poor weight gain and growth deficiency Cerebellar hypoplasia / cerebellar atrophy Cerebral atrophy Hypomyelination/dysmyelination White matter volume loss Wide subarachnoid spaces Posterior cranial fossa cyst Low serum copper (usually 10%-20% of normal for age) Low serum ceruloplasmin (undetectable or very low) Note: Identification of low serum copper and ceruloplasmin levels may be problematic in infants younger than age six months, given the normally low serum concentration in all children at this age. The diagnosis of HBS 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 HBS, molecular genetic testing approaches can include For an introduction to multigene panels click When the diagnosis of HBS is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Huppke-Brendel Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. To date, no large intragenic deletions/duplications have been reported in individuals with Huppke-Brendel syndrome. • Bilateral congenital cataracts • Nystagmus • Sensorineural hearing loss • Severe developmental delay / intellectual disability and regression of acquired milestones • Hypotonia • Seizures • Poor weight gain and growth deficiency • Cerebellar hypoplasia / cerebellar atrophy • Cerebral atrophy • Hypomyelination/dysmyelination • White matter volume loss • Wide subarachnoid spaces • Posterior cranial fossa cyst • Low serum copper (usually 10%-20% of normal for age) • Low serum ceruloplasmin (undetectable or very low) • For an introduction to multigene panels click ## Suggestive Findings HBS Bilateral congenital cataracts Nystagmus Sensorineural hearing loss Severe developmental delay / intellectual disability and regression of acquired milestones Hypotonia Seizures Poor weight gain and growth deficiency Cerebellar hypoplasia / cerebellar atrophy Cerebral atrophy Hypomyelination/dysmyelination White matter volume loss Wide subarachnoid spaces Posterior cranial fossa cyst Low serum copper (usually 10%-20% of normal for age) Low serum ceruloplasmin (undetectable or very low) Note: Identification of low serum copper and ceruloplasmin levels may be problematic in infants younger than age six months, given the normally low serum concentration in all children at this age. • Bilateral congenital cataracts • Nystagmus • Sensorineural hearing loss • Severe developmental delay / intellectual disability and regression of acquired milestones • Hypotonia • Seizures • Poor weight gain and growth deficiency • Cerebellar hypoplasia / cerebellar atrophy • Cerebral atrophy • Hypomyelination/dysmyelination • White matter volume loss • Wide subarachnoid spaces • Posterior cranial fossa cyst • Low serum copper (usually 10%-20% of normal for age) • Low serum ceruloplasmin (undetectable or very low) ## Establishing the Diagnosis The diagnosis of HBS 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 HBS, molecular genetic testing approaches can include For an introduction to multigene panels click When the diagnosis of HBS is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Huppke-Brendel Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. To date, no large intragenic deletions/duplications have been reported in individuals with Huppke-Brendel syndrome. • For an introduction to multigene panels click ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of HBS, 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 HBS is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Huppke-Brendel Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. To date, no large intragenic deletions/duplications have been reported in individuals with Huppke-Brendel syndrome. ## Clinical Characteristics Huppke-Brendel syndrome (HBS) is characterized by congenital cataracts, sensorineural hearing loss, and severe developmental delay in all reported children. One adult presented with less severe features. To date, 11 individuals (ten children and one adult) with HBS have been reported in the literature [ Two reported children had seizures. Burst suppression pattern has been described in the EEG of one individual [ Dyskinetic movements of the head, trunk, and limbs were noted in one affected individual at age 14 months [ Deep tendon reflexes were normal and symmetric. Secondary hypothyroidism (1 individual) [ Micropenis with bilaterally descended testes and hypopigmented hair (1 individual) [ Subsarcolemmal proliferation and vacuolization in few type 1 fibers are reported. No typical ragged red fibers, ragged blue fibers, or COX-negative fibers are seen [ Biochemical measurements of the respiratory chain enzymes showed significantly reduced activity of COX, with 30% residual activity in one individual [ The number of individuals with confirmed pathogenic variants in HBS may also be referred to as congenital cataracts, hearing loss, and neurodegeneration (CCHLND). Prevalence of HBS is unknown. Only 11 affected individuals (ten children and one adult) have been reported to date. • Secondary hypothyroidism (1 individual) [ • Micropenis with bilaterally descended testes and hypopigmented hair (1 individual) [ • Subsarcolemmal proliferation and vacuolization in few type 1 fibers are reported. No typical ragged red fibers, ragged blue fibers, or COX-negative fibers are seen [ • Biochemical measurements of the respiratory chain enzymes showed significantly reduced activity of COX, with 30% residual activity in one individual [ ## Clinical Description Huppke-Brendel syndrome (HBS) is characterized by congenital cataracts, sensorineural hearing loss, and severe developmental delay in all reported children. One adult presented with less severe features. To date, 11 individuals (ten children and one adult) with HBS have been reported in the literature [ Two reported children had seizures. Burst suppression pattern has been described in the EEG of one individual [ Dyskinetic movements of the head, trunk, and limbs were noted in one affected individual at age 14 months [ Deep tendon reflexes were normal and symmetric. Secondary hypothyroidism (1 individual) [ Micropenis with bilaterally descended testes and hypopigmented hair (1 individual) [ Subsarcolemmal proliferation and vacuolization in few type 1 fibers are reported. No typical ragged red fibers, ragged blue fibers, or COX-negative fibers are seen [ Biochemical measurements of the respiratory chain enzymes showed significantly reduced activity of COX, with 30% residual activity in one individual [ • Secondary hypothyroidism (1 individual) [ • Micropenis with bilaterally descended testes and hypopigmented hair (1 individual) [ • Subsarcolemmal proliferation and vacuolization in few type 1 fibers are reported. No typical ragged red fibers, ragged blue fibers, or COX-negative fibers are seen [ • Biochemical measurements of the respiratory chain enzymes showed significantly reduced activity of COX, with 30% residual activity in one individual [ ## Genotype-Phenotype Correlations The number of individuals with confirmed pathogenic variants in ## Nomenclature HBS may also be referred to as congenital cataracts, hearing loss, and neurodegeneration (CCHLND). ## Prevalence Prevalence of HBS is unknown. Only 11 affected individuals (ten children and one adult) have been reported to date. ## Genetically Related (Allelic) Disorders A heterozygous ## Differential Diagnosis Disorders with low copper and ceruloplasmin in the differential diagnosis of Huppke-Brendel Syndrome are listed in Differential Diagnosis of Huppke-Brendel Syndrome: Disorders of Copper Metabolism ↓ serum ceruloplasmin & total copper levels are common. Hearing loss, DD/ID, cataracts (2 persons), sparse hair, hypotonia Low serum copper & ceruloplasmin concentration Hypotonia, sparse & hypopigmented hair Kinky hair Seizures are a predominant manifestation. White matter signal changes on brain MRI & tortuous blood vessels on brain MR angiogram Not assoc w/cataracts or hearing loss Low serum copper & ceruloplasmin concentration ↑ urinary copper excretion Liver disease Movement disorder Kayser-Fleischer rings Low serum ceruloplasmin concentration Hypotonia, DD Low serum copper & ceruloplasmin concentration Neurologic manifestations: ataxia, involuntary movements Retinal degeneration Diabetes mellitus Low serum ceruloplasmin concentration Low serum copper concentration in persons w/severe phenotype Mild DD Not assoc w/cataracts or hearing loss AR = autosomal recessive; DD = developmental delay; HBS = Huppke-Brendel syndrome; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked • ↓ serum ceruloplasmin & total copper levels are common. • Hearing loss, DD/ID, cataracts (2 persons), sparse hair, hypotonia • Low serum copper & ceruloplasmin concentration • Hypotonia, sparse & hypopigmented hair • Kinky hair • Seizures are a predominant manifestation. • White matter signal changes on brain MRI & tortuous blood vessels on brain MR angiogram • Not assoc w/cataracts or hearing loss • Low serum copper & ceruloplasmin concentration • ↑ urinary copper excretion • Liver disease • Movement disorder • Kayser-Fleischer rings • Low serum ceruloplasmin concentration • Hypotonia, DD • Low serum copper & ceruloplasmin concentration • Neurologic manifestations: ataxia, involuntary movements • Retinal degeneration • Diabetes mellitus • Low serum ceruloplasmin concentration • Low serum copper concentration in persons w/severe phenotype • Mild DD • Not assoc w/cataracts or hearing loss ## Management No clinical practice guidelines for Huppke-Brendel syndrome (HBS) 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 HBS, the evaluations summarized in Huppke-Brendel Syndrome: Recommended Evaluations Following Initial Diagnosis Complete neurologic assessment EEG if seizures are suspected To incl eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Gross motor & fine motor skills Contractures, scoliosis Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Community or Social work involvement for parental support Home nursing referral ADL = activities of daily living; HBS = Huppke-Brendel syndrome; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) There is no cure for HBS. 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 Huppke-Brendel Syndrome: Treatment of Manifestations Children: through early intervention programs &/or school district Adults: low vision clinic &/or community vision services / OT / mobility services Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers Treatment of scoliosis per orthopedist PT to maintain muscle function & prevent contractures 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 IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Huppke-Brendel Syndrome: Recommended Surveillance Measure growth parameters. Evaluate nutritional status & safety of oral intake. Physical medicine, OT/PT assessment of mobility, self-help skills Assess for scoliosis & contractures. OT = occupational therapy; PT = physical therapy It is appropriate to evaluate at-risk newborn sibs for HBS in order to identify as early as possible those who would benefit from prompt removal of cataracts as well as feeding and developmental support. Evaluations can include the following: Clinical exam, ophthalmologic exam for cataracts, and audiologic evaluation in an at-risk newborn prior to molecular testing or while waiting for molecular results; Molecular genetic testing for the Note: Serum copper and ceruloplasmin levels may not be informative in a newborn because serum ceruloplasmin and, to a lesser degree, serum copper are very low in normal neonates (even more so in premature infants); further, the depletion of copper stores may not be noticeable in the first few months of life even in individuals with known disorders of copper transport. See Treatment with copper histidinate in three affected individuals did not result in an increase in serum copper or ceruloplasmin. Clinical improvement was reported in one individual who died at age four years. Therapeutic trials with acetylation therapy, consisting of N-acetyl cysteine and ketogenic diet, did not normalize the concentration of N-acetylated amino acids in cerebrospinal fluid or plasma and no clinical improvement was noted. Search • Complete neurologic assessment • EEG if seizures are suspected • To incl eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Gross motor & fine motor skills • Contractures, scoliosis • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Community or • Social work involvement for parental support • Home nursing referral • Children: through early intervention programs &/or school district • Adults: low vision clinic &/or community vision services / OT / mobility services • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Treatment of scoliosis per orthopedist • PT to maintain muscle function & prevent contractures • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox • Measure growth parameters. • Evaluate nutritional status & safety of oral intake. • Physical medicine, OT/PT assessment of mobility, self-help skills • Assess for scoliosis & contractures. • Clinical exam, ophthalmologic exam for cataracts, and audiologic evaluation in an at-risk newborn prior to molecular testing or while waiting for molecular results; • Molecular genetic testing for the ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with HBS, the evaluations summarized in Huppke-Brendel Syndrome: Recommended Evaluations Following Initial Diagnosis Complete neurologic assessment EEG if seizures are suspected To incl eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Gross motor & fine motor skills Contractures, scoliosis Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Community or Social work involvement for parental support Home nursing referral ADL = activities of daily living; HBS = Huppke-Brendel syndrome; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Complete neurologic assessment • EEG if seizures are suspected • To incl eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Gross motor & fine motor skills • Contractures, scoliosis • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations There is no cure for HBS. 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 Huppke-Brendel Syndrome: Treatment of Manifestations Children: through early intervention programs &/or school district Adults: low vision clinic &/or community vision services / OT / mobility services Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers Treatment of scoliosis per orthopedist PT to maintain muscle function & prevent contractures 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 IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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: through early intervention programs &/or school district • Adults: low vision clinic &/or community vision services / OT / mobility services • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Treatment of scoliosis per orthopedist • PT to maintain muscle function & prevent contractures • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## Developmental Delay / Intellectual Disability Management Issues IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Motor Dysfunction Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Huppke-Brendel Syndrome: Recommended Surveillance Measure growth parameters. Evaluate nutritional status & safety of oral intake. Physical medicine, OT/PT assessment of mobility, self-help skills Assess for scoliosis & contractures. OT = occupational therapy; PT = physical therapy • Measure growth parameters. • Evaluate nutritional status & safety of oral intake. • Physical medicine, OT/PT assessment of mobility, self-help skills • Assess for scoliosis & contractures. ## Evaluation of Relatives at Risk It is appropriate to evaluate at-risk newborn sibs for HBS in order to identify as early as possible those who would benefit from prompt removal of cataracts as well as feeding and developmental support. Evaluations can include the following: Clinical exam, ophthalmologic exam for cataracts, and audiologic evaluation in an at-risk newborn prior to molecular testing or while waiting for molecular results; Molecular genetic testing for the Note: Serum copper and ceruloplasmin levels may not be informative in a newborn because serum ceruloplasmin and, to a lesser degree, serum copper are very low in normal neonates (even more so in premature infants); further, the depletion of copper stores may not be noticeable in the first few months of life even in individuals with known disorders of copper transport. See • Clinical exam, ophthalmologic exam for cataracts, and audiologic evaluation in an at-risk newborn prior to molecular testing or while waiting for molecular results; • Molecular genetic testing for the ## Therapies Under Investigation Treatment with copper histidinate in three affected individuals did not result in an increase in serum copper or ceruloplasmin. Clinical improvement was reported in one individual who died at age four years. Therapeutic trials with acetylation therapy, consisting of N-acetyl cysteine and ketogenic diet, did not normalize the concentration of N-acetylated amino acids in cerebrospinal fluid or plasma and no clinical improvement was noted. Search ## Genetic Counseling Huppke-Brendel syndrome (HBS) is inherited in an autosomal recessive manner. The parents of an affected child are presumed to be heterozygous for an Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Carrier testing for at-risk relatives requires prior identification of the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are 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 carriers or are at risk of being carriers. ## Mode of Inheritance Huppke-Brendel syndrome (HBS) is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected child are presumed to be heterozygous for an Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The parents of an affected child are presumed to be heterozygous for an • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources No specific resources for Huppke-Brendel Syndrome have been identified by ## Molecular Genetics Huppke-Brendel Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Huppke-Brendel Syndrome ( The relationship between AT-1 and low serum copper and ceruloplasmin levels is unclear at present. One theory is that ceruloplasmin, which is a glycoprotein, requires AT-1-dependent transient acetylation for proper function. Studies in HepG2 cells with reduced AT-1 expression demonstrated 30% less ceruloplasmin excretion consistent with AT-1 deficiency causing reduced ceruloplasmin levels [ Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis The relationship between AT-1 and low serum copper and ceruloplasmin levels is unclear at present. One theory is that ceruloplasmin, which is a glycoprotein, requires AT-1-dependent transient acetylation for proper function. Studies in HepG2 cells with reduced AT-1 expression demonstrated 30% less ceruloplasmin excretion consistent with AT-1 deficiency causing reduced ceruloplasmin levels [ Variants listed in the table have been provided by the authors. ## Chapter Notes 3 April 2025 (sw) Comprehensive update posted live 13 June 2019 (sw) Review posted live 10 May 2018 (bps) Original submission • 3 April 2025 (sw) Comprehensive update posted live • 13 June 2019 (sw) Review posted live • 10 May 2018 (bps) Original submission ## Revision History 3 April 2025 (sw) Comprehensive update posted live 13 June 2019 (sw) Review posted live 10 May 2018 (bps) Original submission • 3 April 2025 (sw) Comprehensive update posted live • 13 June 2019 (sw) Review posted live • 10 May 2018 (bps) Original submission ## References ## Literature Cited Brain MRI in a child with Huppke-Brendel syndrome at age four months A, B. T C. T	[]	13/6/2019	3/4/2025		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
husa	husa	[ "Familial Atypical Hemolytic-Uremic Syndrome", "Familial Atypical Hemolytic-Uremic Syndrome", "Complement C3", "Complement factor B", "Complement factor H", "Complement factor H-related protein 1", "Complement factor H-related protein 3", "Complement factor H-related protein 4", "Complement factor I", "Diacylglycerol kinase epsilon", "Membrane cofactor protein", "Thrombomodulin", "Vitronectin", "C3", "CD46", "CFB", "CFH", "CFHR1", "CFHR3", "CFHR4", "CFI", "DGKE", "THBD", "VTN", "Genetic Atypical Hemolytic-Uremic Syndrome" ]	Genetic Atypical Hemolytic-Uremic Syndrome	Marina Noris, Elena Bresin, Caterina Mele, Giuseppe Remuzzi	Summary Hemolytic-uremic syndrome (HUS) is characterized by hemolytic anemia, thrombocytopenia, and renal failure caused by platelet thrombi in the microcirculation of the kidney and other organs. The onset of atypical HUS (aHUS) ranges from the neonatal period to adulthood. Genetic aHUS accounts for an estimated 60% of all aHUS. Individuals with genetic aHUS frequently experience relapse even after complete recovery following the presenting episode; 60% of genetic aHUS progresses to end-stage renal disease (ESRD). The diagnosis of genetic aHUS is established in a proband with aHUS by identification of a pathogenic variant(s) in one or more of the genes known to be associated with genetic aHUS. The genes associated with genetic aHUS include Every month in the first year after an aHUS episode, then every three to six months in the following years, particularly for those with normal renal function or chronic renal insufficiency as they are at risk for relapse; and In relatives with the pathogenic variant following exposure to potential triggering events. Predisposition to aHUS associated with pathogenic variants in Once the aHUS-related pathogenic variant(s) have been identified in an affected family member, prenatal testing and preimplantation genetic testing for the familial pathogenic variant(s) are possible.	## Diagnosis Genetic atypical hemolytic-uremic syndrome (aHUS) One or more members of the same family have been diagnosed with aHUS at least six months apart and exposure to a common triggering infectious agent has been excluded. An individual has an HUS relapse even after complete recovery from the presenting episode. An underlying environmental factor such as drugs, systemic disease, viral agents, or bacterial agents that do not result in Shiga-like exotoxins can be identified. For information about laboratory findings and renal histology related to typical and atypical HUS, click The diagnosis of genetic aHUS Heterozygous pathogenic variant in one or more of the following genes: Homozygous or compound heterozygous pathogenic variants in Modifiers that increase the penetrance and/or severity of aHUS but may not cause aHUS when present without one of the established molecular causes (see Homozygous deletion of Molecular testing approaches can include Note: The high degree of sequence identity between Note: Molecular testing should include analysis of genetic modifiers including A multigene panel that includes other genes of interest (see 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 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Atypical Hemolytic-Uremic Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No large deletions or duplications involving In one child, complete paternal uniparental isodisomy of chromosome 1 with homozygosity for a splice defect of exon 10 resulted in severe deficiency of Several Two • One or more members of the same family have been diagnosed with aHUS at least six months apart and exposure to a common triggering infectious agent has been excluded. • An individual has an HUS relapse even after complete recovery from the presenting episode. • An underlying environmental factor such as drugs, systemic disease, viral agents, or bacterial agents that do not result in Shiga-like exotoxins can be identified. • Heterozygous pathogenic variant in one or more of the following genes: • Homozygous or compound heterozygous pathogenic variants in • Homozygous deletion of • Note: The high degree of sequence identity between • Note: Molecular testing should include analysis of genetic modifiers including • A multigene panel that includes other genes of interest (see • 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 • For an introduction to comprehensive genomic testing click ## Suggestive Findings Genetic atypical hemolytic-uremic syndrome (aHUS) One or more members of the same family have been diagnosed with aHUS at least six months apart and exposure to a common triggering infectious agent has been excluded. An individual has an HUS relapse even after complete recovery from the presenting episode. An underlying environmental factor such as drugs, systemic disease, viral agents, or bacterial agents that do not result in Shiga-like exotoxins can be identified. For information about laboratory findings and renal histology related to typical and atypical HUS, click • One or more members of the same family have been diagnosed with aHUS at least six months apart and exposure to a common triggering infectious agent has been excluded. • An individual has an HUS relapse even after complete recovery from the presenting episode. • An underlying environmental factor such as drugs, systemic disease, viral agents, or bacterial agents that do not result in Shiga-like exotoxins can be identified. ## Establishing the Diagnosis The diagnosis of genetic aHUS Heterozygous pathogenic variant in one or more of the following genes: Homozygous or compound heterozygous pathogenic variants in Modifiers that increase the penetrance and/or severity of aHUS but may not cause aHUS when present without one of the established molecular causes (see Homozygous deletion of Molecular testing approaches can include Note: The high degree of sequence identity between Note: Molecular testing should include analysis of genetic modifiers including A multigene panel that includes other genes of interest (see 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 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Atypical Hemolytic-Uremic Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No large deletions or duplications involving In one child, complete paternal uniparental isodisomy of chromosome 1 with homozygosity for a splice defect of exon 10 resulted in severe deficiency of Several Two • Heterozygous pathogenic variant in one or more of the following genes: • Homozygous or compound heterozygous pathogenic variants in • Homozygous deletion of • Note: The high degree of sequence identity between • Note: Molecular testing should include analysis of genetic modifiers including • A multigene panel that includes other genes of interest (see • 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 • For an introduction to comprehensive genomic testing click ## Clinical Characteristics The onset of atypical hemolytic-uremic syndrome (aHUS) ranges from the neonatal period to adulthood. Collectively, aHUS is associated with poor outcome. Individuals with genetic aHUS frequently relapse even after complete recovery following the presenting episode. Sixty percent of genetic aHUS progresses to end-stage renal disease (ESRD) [ Genetic aHUS accounts for an estimated 60% of all aHUS [ The phenotype of aHUS ranges from mild (with complete recovery of renal function) to severe (resulting in ESRD or death). The course and outcome of the disease are influenced by the gene in which pathogenic variants occur: No genotype-phenotype correlations have been identified. Genetic aHUS is also referred to as hereditary HUS, familial aHUS, and complement mutation-associated HUS. Genetic aHUS accounts for an estimated 60% of all aHUS. ## Clinical Description The onset of atypical hemolytic-uremic syndrome (aHUS) ranges from the neonatal period to adulthood. Collectively, aHUS is associated with poor outcome. Individuals with genetic aHUS frequently relapse even after complete recovery following the presenting episode. Sixty percent of genetic aHUS progresses to end-stage renal disease (ESRD) [ Genetic aHUS accounts for an estimated 60% of all aHUS [ ## Phenotype Correlations by Gene The phenotype of aHUS ranges from mild (with complete recovery of renal function) to severe (resulting in ESRD or death). The course and outcome of the disease are influenced by the gene in which pathogenic variants occur: ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been identified. ## Penetrance ## Nomenclature Genetic aHUS is also referred to as hereditary HUS, familial aHUS, and complement mutation-associated HUS. ## Prevalence Genetic aHUS accounts for an estimated 60% of all aHUS. ## Genetically Related (Allelic) Disorders Biallelic or heterozygous pathogenic variants in No phenotypes other than those discussed in this ## Differential Diagnosis Typical HUS triggered by Stx- Note: STEC isolation and detection of LPS antibodies are not routinely available and require a few days to complete. Approximately 80% of TTP is triggered by deficient activity of ADAMTS13. ADAMTS13 deficiency can be constitutive, as a result of biallelic Individuals with aHUS associated with homozygous pathogenic variants in ## Management Guidelines for the initial assessment and early management of children with aHUS have been published [ To establish the extent of disease and needs in an individual diagnosed with genetic atypical hemolytic-uremic syndrome (aHUS), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Genetic Atypical Hemolytic-Uremic Syndrome Creatinine clearance (i.e., GFR) Serum concentration of creatinine resources Urinalysis Platelet count Erythrocyte count Histologic eval of blood smear for schistocytes Leukocyte count Serum LDH concentration Haptoglobin Serum C3 & C4 concentrations Plasma concentrations of Bb & sC5b-9 Serum concentrations of CFH & CFI CD46 expression on leukocytes GFR = glomerular filtration rate; LDH = lactate dehydrogenase; MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse Plasma exchange usually involves exchanging 1-2 plasma volumes (40 mL/kg) per session in adults and 50-100 mL/kg in children. Typically, plasma exchange is initially undertaken daily; the duration and frequency of treatment is then determined by the clinical response. Treatment can be intensified by increasing the volume of plasma replaced. Twice-daily exchange of one plasma volume is probably the treatment of choice for those with refractory disease in order to minimize the recycling of infused plasma. Plasma infusion is the first-line therapy when plasma exchange or eculizumab therapies are not available. In plasma infusion 30-40 mL/kg of plasma is administered initially, followed by 10-20 mL/kg/day. Plasma infusion should be used to treat or prevent recurrent episodes. Platelet count and serum LDH concentration are the most sensitive markers for monitoring response to plasma therapy. Plasma treatment should be continued until platelet count and serum LDH concentration remain normal after therapy is discontinued. Discontinuation of plasma therapy is the only way to know if complete remission has been achieved. Immediate exacerbation of disease activity (principally manifested by falling platelet count that requires the resumption of daily plasma therapy) occurs in 29%-82% of individuals after treatment is discontinued. Thus, many cycles of stopping and resuming plasma therapy may occur, in which case therapy with eculizumab should be considered. Plasma infusion or exchange has been used in individuals with aHUS and A dozen case reports showed that early plasma therapy, generally consisting of daily plasma exchange followed by maintenance plasma exchange/infusion, could prevent relapses and preserve renal function at follow up for up to six years [ In the authors' series [ In the French cohort [ In individuals with Molecular genetic testing can help to define graft prognosis; thus, all affected individuals should undergo such testing prior to transplantation. Simultaneous kidney and liver transplantation has been performed in two young children with aHUS and In six other individuals with Eculizumab prophylaxis may prevent disease recurrences in individuals with pathogenic variants affecting circulating factors ( Individuals with pathogenic variants in Individuals with anti-CFH antibodies, pathogenic variants in The major adverse effect of eculizumab is the increased risk for meningococcal infection [ Vaccination against In those who are not vaccinated two weeks prior to therapy with eculizumab, daily prophylactic antibiotics (e.g., oral penicillin or a macrolide) should be administered for two weeks following vaccination. Since currently available vaccines do not cover all In children treated with eculizumab, vaccination against Every month in the first year after an aHUS episode, then every three to six months in the following years, particularly for persons with normal renal function or chronic renal insufficiency, as they are at risk for relapse Note: Individuals with ESRD usually do not relapse. Every two weeks for those rare individuals with homozygous Note: The proposed time intervals for checking hemoglobin, platelet count, and serum concentrations of creatinine, LDH, C3, C4, and haptoglobin are suggestions [Authors, personal observation]; each center may follow different guidelines based on their own experience. Discontinue cyclosporine or tacrolimus when aHUS develops following challenge with the medication. Fresh frozen plasma should be avoided (i.e., plasma therapy is contraindicated) in persons with aHUS induced by Avoid potential precipitants of aHUS, including the following known triggers: Pregnancy Medications: some chemotherapeutic agents (e.g., mitomycin, cisplatin, daunorubicin, bleomycin, cytosine arabinoside, gemcitabine), immunotherapeutic agents (e.g., cyclosporin, tacrolimus, muromonab-CD Note: Testing of family members needs to be done with caution because presence of the family-specific pathogenic variant(s) is predisposing rather than causative, and thus is only one of several risk factors required for development of aHUS. Predictions based on a single risk factor in unaffected individuals are unreliable; thus, risk cannot be quantified for a given individual. The following are appropriate for relatives in whom the family-specific pathogenic variant(s) have been identified: Monitoring of hemoglobin, platelet count, and serum concentrations of creatinine, LDH, C3, C4, and haptoglobin, when exposed to potential triggering events such as severe infections, inflammation, and pregnancy (See Avoidance of known precipitants of aHUS (See Note: No monitoring is needed for the relatives of individuals with typical HUS (i.e., individuals with HUS triggered by an infective agent such as certain strains of See Women with a history of aHUS are at increased risk for aHUS flare during pregnancy and an even greater risk in the postpartum period. Pregnancy-associated aHUS (P-aHUS) occurred in 21 of 100 adult women with aHUS, with 79% presenting postpartum [ On the basis of these results, women with complement dysregulation should be informed of the 20% risk for P-aHUS, and pregnancy in these women should be closely monitored. A clinical trial is currently evaluating the efficacy and safety of Search Splenectomy, while inducing remission in some persons with plasma resistance, is ineffective and actually increases morbidity and mortality in others. Other treatments, including antiplatelet agents, prostacyclin, heparin or fibrinolytic agents, steroids, and intravenous immunoglobulins, have been attempted in both plasma resistance and plasma dependence with no consistent benefit [ • Creatinine clearance (i.e., GFR) • Serum concentration of creatinine resources • Urinalysis • Platelet count • Erythrocyte count • Histologic eval of blood smear for schistocytes • Leukocyte count • Serum LDH concentration • Haptoglobin • Serum C3 & C4 concentrations • Plasma concentrations of Bb & sC5b-9 • Serum concentrations of CFH & CFI • CD46 expression on leukocytes • Plasma exchange usually involves exchanging 1-2 plasma volumes (40 mL/kg) per session in adults and 50-100 mL/kg in children. Typically, plasma exchange is initially undertaken daily; the duration and frequency of treatment is then determined by the clinical response. • Treatment can be intensified by increasing the volume of plasma replaced. Twice-daily exchange of one plasma volume is probably the treatment of choice for those with refractory disease in order to minimize the recycling of infused plasma. • Plasma infusion is the first-line therapy when plasma exchange or eculizumab therapies are not available. In plasma infusion 30-40 mL/kg of plasma is administered initially, followed by 10-20 mL/kg/day. Plasma infusion should be used to treat or prevent recurrent episodes. • • Plasma infusion or exchange has been used in individuals with aHUS and • A dozen case reports showed that early plasma therapy, generally consisting of daily plasma exchange followed by maintenance plasma exchange/infusion, could prevent relapses and preserve renal function at follow up for up to six years [ • In the authors' series [ • In the French cohort [ • In individuals with • Plasma infusion or exchange has been used in individuals with aHUS and • A dozen case reports showed that early plasma therapy, generally consisting of daily plasma exchange followed by maintenance plasma exchange/infusion, could prevent relapses and preserve renal function at follow up for up to six years [ • In the authors' series [ • In the French cohort [ • In individuals with • Plasma infusion or exchange has been used in individuals with aHUS and • A dozen case reports showed that early plasma therapy, generally consisting of daily plasma exchange followed by maintenance plasma exchange/infusion, could prevent relapses and preserve renal function at follow up for up to six years [ • In the authors' series [ • In the French cohort [ • In individuals with • Simultaneous kidney and liver transplantation has been performed in two young children with aHUS and • In six other individuals with • Individuals with pathogenic variants in • Individuals with anti-CFH antibodies, pathogenic variants in • Vaccination against • In those who are not vaccinated two weeks prior to therapy with eculizumab, daily prophylactic antibiotics (e.g., oral penicillin or a macrolide) should be administered for two weeks following vaccination. • Since currently available vaccines do not cover all • Every month in the first year after an aHUS episode, then every three to six months in the following years, particularly for persons with normal renal function or chronic renal insufficiency, as they are at risk for relapse • Note: Individuals with ESRD usually do not relapse. • Every two weeks for those rare individuals with homozygous • Pregnancy • Medications: some chemotherapeutic agents (e.g., mitomycin, cisplatin, daunorubicin, bleomycin, cytosine arabinoside, gemcitabine), immunotherapeutic agents (e.g., cyclosporin, tacrolimus, muromonab-CD • Monitoring of hemoglobin, platelet count, and serum concentrations of creatinine, LDH, C3, C4, and haptoglobin, when exposed to potential triggering events such as severe infections, inflammation, and pregnancy (See • Avoidance of known precipitants of aHUS (See • Splenectomy, while inducing remission in some persons with plasma resistance, is ineffective and actually increases morbidity and mortality in others. • Other treatments, including antiplatelet agents, prostacyclin, heparin or fibrinolytic agents, steroids, and intravenous immunoglobulins, have been attempted in both plasma resistance and plasma dependence with no consistent benefit [ ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with genetic atypical hemolytic-uremic syndrome (aHUS), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Genetic Atypical Hemolytic-Uremic Syndrome Creatinine clearance (i.e., GFR) Serum concentration of creatinine resources Urinalysis Platelet count Erythrocyte count Histologic eval of blood smear for schistocytes Leukocyte count Serum LDH concentration Haptoglobin Serum C3 & C4 concentrations Plasma concentrations of Bb & sC5b-9 Serum concentrations of CFH & CFI CD46 expression on leukocytes GFR = glomerular filtration rate; LDH = lactate dehydrogenase; MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Creatinine clearance (i.e., GFR) • Serum concentration of creatinine resources • Urinalysis • Platelet count • Erythrocyte count • Histologic eval of blood smear for schistocytes • Leukocyte count • Serum LDH concentration • Haptoglobin • Serum C3 & C4 concentrations • Plasma concentrations of Bb & sC5b-9 • Serum concentrations of CFH & CFI • CD46 expression on leukocytes ## Treatment of Manifestations Plasma exchange usually involves exchanging 1-2 plasma volumes (40 mL/kg) per session in adults and 50-100 mL/kg in children. Typically, plasma exchange is initially undertaken daily; the duration and frequency of treatment is then determined by the clinical response. Treatment can be intensified by increasing the volume of plasma replaced. Twice-daily exchange of one plasma volume is probably the treatment of choice for those with refractory disease in order to minimize the recycling of infused plasma. Plasma infusion is the first-line therapy when plasma exchange or eculizumab therapies are not available. In plasma infusion 30-40 mL/kg of plasma is administered initially, followed by 10-20 mL/kg/day. Plasma infusion should be used to treat or prevent recurrent episodes. Platelet count and serum LDH concentration are the most sensitive markers for monitoring response to plasma therapy. Plasma treatment should be continued until platelet count and serum LDH concentration remain normal after therapy is discontinued. Discontinuation of plasma therapy is the only way to know if complete remission has been achieved. Immediate exacerbation of disease activity (principally manifested by falling platelet count that requires the resumption of daily plasma therapy) occurs in 29%-82% of individuals after treatment is discontinued. Thus, many cycles of stopping and resuming plasma therapy may occur, in which case therapy with eculizumab should be considered. Plasma infusion or exchange has been used in individuals with aHUS and A dozen case reports showed that early plasma therapy, generally consisting of daily plasma exchange followed by maintenance plasma exchange/infusion, could prevent relapses and preserve renal function at follow up for up to six years [ In the authors' series [ In the French cohort [ In individuals with Molecular genetic testing can help to define graft prognosis; thus, all affected individuals should undergo such testing prior to transplantation. Simultaneous kidney and liver transplantation has been performed in two young children with aHUS and In six other individuals with • Plasma exchange usually involves exchanging 1-2 plasma volumes (40 mL/kg) per session in adults and 50-100 mL/kg in children. Typically, plasma exchange is initially undertaken daily; the duration and frequency of treatment is then determined by the clinical response. • Treatment can be intensified by increasing the volume of plasma replaced. Twice-daily exchange of one plasma volume is probably the treatment of choice for those with refractory disease in order to minimize the recycling of infused plasma. • Plasma infusion is the first-line therapy when plasma exchange or eculizumab therapies are not available. In plasma infusion 30-40 mL/kg of plasma is administered initially, followed by 10-20 mL/kg/day. Plasma infusion should be used to treat or prevent recurrent episodes. • • Plasma infusion or exchange has been used in individuals with aHUS and • A dozen case reports showed that early plasma therapy, generally consisting of daily plasma exchange followed by maintenance plasma exchange/infusion, could prevent relapses and preserve renal function at follow up for up to six years [ • In the authors' series [ • In the French cohort [ • In individuals with • Plasma infusion or exchange has been used in individuals with aHUS and • A dozen case reports showed that early plasma therapy, generally consisting of daily plasma exchange followed by maintenance plasma exchange/infusion, could prevent relapses and preserve renal function at follow up for up to six years [ • In the authors' series [ • In the French cohort [ • In individuals with • Plasma infusion or exchange has been used in individuals with aHUS and • A dozen case reports showed that early plasma therapy, generally consisting of daily plasma exchange followed by maintenance plasma exchange/infusion, could prevent relapses and preserve renal function at follow up for up to six years [ • In the authors' series [ • In the French cohort [ • In individuals with • Simultaneous kidney and liver transplantation has been performed in two young children with aHUS and • In six other individuals with ## Prevention of Primary Manifestations Eculizumab prophylaxis may prevent disease recurrences in individuals with pathogenic variants affecting circulating factors ( ## Prevention of Secondary Complications Individuals with pathogenic variants in Individuals with anti-CFH antibodies, pathogenic variants in The major adverse effect of eculizumab is the increased risk for meningococcal infection [ Vaccination against In those who are not vaccinated two weeks prior to therapy with eculizumab, daily prophylactic antibiotics (e.g., oral penicillin or a macrolide) should be administered for two weeks following vaccination. Since currently available vaccines do not cover all In children treated with eculizumab, vaccination against • Individuals with pathogenic variants in • Individuals with anti-CFH antibodies, pathogenic variants in • Vaccination against • In those who are not vaccinated two weeks prior to therapy with eculizumab, daily prophylactic antibiotics (e.g., oral penicillin or a macrolide) should be administered for two weeks following vaccination. • Since currently available vaccines do not cover all ## Surveillance Every month in the first year after an aHUS episode, then every three to six months in the following years, particularly for persons with normal renal function or chronic renal insufficiency, as they are at risk for relapse Note: Individuals with ESRD usually do not relapse. Every two weeks for those rare individuals with homozygous Note: The proposed time intervals for checking hemoglobin, platelet count, and serum concentrations of creatinine, LDH, C3, C4, and haptoglobin are suggestions [Authors, personal observation]; each center may follow different guidelines based on their own experience. • Every month in the first year after an aHUS episode, then every three to six months in the following years, particularly for persons with normal renal function or chronic renal insufficiency, as they are at risk for relapse • Note: Individuals with ESRD usually do not relapse. • Every two weeks for those rare individuals with homozygous ## Agents/Circumstances to Avoid Discontinue cyclosporine or tacrolimus when aHUS develops following challenge with the medication. Fresh frozen plasma should be avoided (i.e., plasma therapy is contraindicated) in persons with aHUS induced by Avoid potential precipitants of aHUS, including the following known triggers: Pregnancy Medications: some chemotherapeutic agents (e.g., mitomycin, cisplatin, daunorubicin, bleomycin, cytosine arabinoside, gemcitabine), immunotherapeutic agents (e.g., cyclosporin, tacrolimus, muromonab-CD • Pregnancy • Medications: some chemotherapeutic agents (e.g., mitomycin, cisplatin, daunorubicin, bleomycin, cytosine arabinoside, gemcitabine), immunotherapeutic agents (e.g., cyclosporin, tacrolimus, muromonab-CD ## Evaluation of Relatives at Risk Note: Testing of family members needs to be done with caution because presence of the family-specific pathogenic variant(s) is predisposing rather than causative, and thus is only one of several risk factors required for development of aHUS. Predictions based on a single risk factor in unaffected individuals are unreliable; thus, risk cannot be quantified for a given individual. The following are appropriate for relatives in whom the family-specific pathogenic variant(s) have been identified: Monitoring of hemoglobin, platelet count, and serum concentrations of creatinine, LDH, C3, C4, and haptoglobin, when exposed to potential triggering events such as severe infections, inflammation, and pregnancy (See Avoidance of known precipitants of aHUS (See Note: No monitoring is needed for the relatives of individuals with typical HUS (i.e., individuals with HUS triggered by an infective agent such as certain strains of See • Monitoring of hemoglobin, platelet count, and serum concentrations of creatinine, LDH, C3, C4, and haptoglobin, when exposed to potential triggering events such as severe infections, inflammation, and pregnancy (See • Avoidance of known precipitants of aHUS (See ## Pregnancy Management Women with a history of aHUS are at increased risk for aHUS flare during pregnancy and an even greater risk in the postpartum period. Pregnancy-associated aHUS (P-aHUS) occurred in 21 of 100 adult women with aHUS, with 79% presenting postpartum [ On the basis of these results, women with complement dysregulation should be informed of the 20% risk for P-aHUS, and pregnancy in these women should be closely monitored. ## Therapies Under Investigation A clinical trial is currently evaluating the efficacy and safety of Search ## Other Splenectomy, while inducing remission in some persons with plasma resistance, is ineffective and actually increases morbidity and mortality in others. Other treatments, including antiplatelet agents, prostacyclin, heparin or fibrinolytic agents, steroids, and intravenous immunoglobulins, have been attempted in both plasma resistance and plasma dependence with no consistent benefit [ • Splenectomy, while inducing remission in some persons with plasma resistance, is ineffective and actually increases morbidity and mortality in others. • Other treatments, including antiplatelet agents, prostacyclin, heparin or fibrinolytic agents, steroids, and intravenous immunoglobulins, have been attempted in both plasma resistance and plasma dependence with no consistent benefit [ ## Genetic Counseling Predisposition to atypical HUS (aHUS) associated with pathogenic variants in Atypical HUS associated with pathogenic variants in Rare polygenic inheritance occurs [ Almost all individuals with autosomal dominant aHUS inherited an aHUS-related pathogenic variant from a heterozygous parent. Some parents who are heterozygous for an aHUS-related pathogenic variant are affected; however, the majority of heterozygous parents are unaffected and their child is the only family member known to have aHUS [ Rarely, individuals diagnosed with autosomal dominant aHUS have the disorder as the result of a If both parents of a proband with a known pathogenic variant are unaffected, molecular genetic testing is recommended for the parents of the proband. If a pathogenic variant is identified in a parent, the parent is at risk of developing aHUS and of transmitting the pathogenic variant to other offspring. 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 individuals with autosomal dominant aHUS may appear to be negative because of reduced penetrance in an asymptomatic parent, early death of a parent, or late onset in a parent (or close relative). 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 known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Because of reduced penetrance, sibs who inherit the pathogenic variant may or may not develop aHUS (see Clinical severity and disease phenotype often differ among individuals with the same pathogenic variants. Although age of onset and/or disease progression and outcome cannot be predicted in sibs who inherit a familial pathogenic variant, the penetrance and/or severity of aHUS are known to be increased in individuals who inherit both a familial aHUS-related pathogenic variant and a genetic modifier (modifiers increase the penetrance and/or severity of aHUS but may not cause aHUS when present without one of the established molecular causes [see If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% based on the theoretic possibility of parental germline mosaicism. The parents of a child with autosomal recessive aHUS are obligate heterozygotes (i.e., presumed to be carriers of one pathogenic variant based on family history). Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an aHUS-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, the following possibilities should be considered: One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband; uniparental isodisomy has been reported in two probands [ Heterozygotes are usually asymptomatic. Rare instances of heterozygotes developing aHUS in adulthood have been reported [ If both parents are known to be heterozygous for an autosomal recessive aHUS-related pathogenic variant, each sib of a proband has a 25% chance of inheriting two pathogenic variants, a 50% chance of inheriting one pathogenic variant, and a 25% chance of inheriting neither pathogenic variant. Sibs who inherit biallelic Age of onset and/or disease progression and outcome cannot be predicted in sibs who inherit biallelic pathogenic variants in other aHUS-related genes, as clinical severity and disease phenotype often differ among individuals with the same pathogenic variants because of the role of environmental triggers and/or genetic modifiers. Heterozygotes are usually asymptomatic. Rare instances of heterozygotes developing aHUS in adulthood have been reported [ Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family. Polygenic aHUS is caused by the simultaneous presence of two pathogenic variants: one pathogenic variant in one complement-regulatory gene and another pathogenic variant in a different complement-regulatory gene. Typically, one parent has a pathogenic variant in one complement-regulatory gene and the other parent has a pathogenic variant in a different complement-regulatory gene. However, both parents should undergo confirmatory genetic testing because it is possible that one parent has both pathogenic variants and is asymptomatic. In the families reported to date with polygenic inheritance, heterozygotes have usually been asymptomatic. 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 aHUS-related pathogenic variant(s) have been identified in an affected family member, prenatal testing and preimplantation genetic testing for the familial pathogenic variant(s) 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. • Almost all individuals with autosomal dominant aHUS inherited an aHUS-related pathogenic variant from a heterozygous parent. Some parents who are heterozygous for an aHUS-related pathogenic variant are affected; however, the majority of heterozygous parents are unaffected and their child is the only family member known to have aHUS [ • Rarely, individuals diagnosed with autosomal dominant aHUS have the disorder as the result of a • If both parents of a proband with a known pathogenic variant are unaffected, molecular genetic testing is recommended for the parents of the proband. If a pathogenic variant is identified in a parent, the parent is at risk of developing aHUS and of transmitting the pathogenic variant to other offspring. • 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 individuals with autosomal dominant aHUS may appear to be negative because of reduced penetrance in an asymptomatic parent, early death of a parent, or late onset in a parent (or close relative). 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 (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If a parent of the proband is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Because of reduced penetrance, sibs who inherit the pathogenic variant may or may not develop aHUS (see • Clinical severity and disease phenotype often differ among individuals with the same pathogenic variants. Although age of onset and/or disease progression and outcome cannot be predicted in sibs who inherit a familial pathogenic variant, the penetrance and/or severity of aHUS are known to be increased in individuals who inherit both a familial aHUS-related pathogenic variant and a genetic modifier (modifiers increase the penetrance and/or severity of aHUS but may not cause aHUS when present without one of the established molecular causes [see • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% based on the theoretic possibility of parental germline mosaicism. • The parents of a child with autosomal recessive aHUS are obligate heterozygotes (i.e., presumed to be carriers of one pathogenic variant based on family history). • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an aHUS-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, the following possibilities should be considered: • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband; uniparental isodisomy has been reported in two probands [ • 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; uniparental isodisomy has been reported in two probands [ • Heterozygotes are usually asymptomatic. Rare instances of heterozygotes developing aHUS in adulthood have been reported [ • 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; uniparental isodisomy has been reported in two probands [ • If both parents are known to be heterozygous for an autosomal recessive aHUS-related pathogenic variant, each sib of a proband has a 25% chance of inheriting two pathogenic variants, a 50% chance of inheriting one pathogenic variant, and a 25% chance of inheriting neither pathogenic variant. • Sibs who inherit biallelic • Age of onset and/or disease progression and outcome cannot be predicted in sibs who inherit biallelic pathogenic variants in other aHUS-related genes, as clinical severity and disease phenotype often differ among individuals with the same pathogenic variants because of the role of environmental triggers and/or genetic modifiers. • Sibs who inherit biallelic • Age of onset and/or disease progression and outcome cannot be predicted in sibs who inherit biallelic pathogenic variants in other aHUS-related genes, as clinical severity and disease phenotype often differ among individuals with the same pathogenic variants because of the role of environmental triggers and/or genetic modifiers. • Heterozygotes are usually asymptomatic. Rare instances of heterozygotes developing aHUS in adulthood have been reported [ • Sibs who inherit biallelic • Age of onset and/or disease progression and outcome cannot be predicted in sibs who inherit biallelic pathogenic variants in other aHUS-related genes, as clinical severity and disease phenotype often differ among individuals with the same pathogenic variants because of the role of environmental triggers and/or genetic modifiers. • Typically, one parent has a pathogenic variant in one complement-regulatory gene and the other parent has a pathogenic variant in a different complement-regulatory gene. However, both parents should undergo confirmatory genetic testing because it is possible that one parent has both pathogenic variants and is asymptomatic. • In the families reported to date with polygenic inheritance, heterozygotes have usually been asymptomatic. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance Predisposition to atypical HUS (aHUS) associated with pathogenic variants in Atypical HUS associated with pathogenic variants in Rare polygenic inheritance occurs [ ## Autosomal Dominant Inheritance – Risk to Family Members Almost all individuals with autosomal dominant aHUS inherited an aHUS-related pathogenic variant from a heterozygous parent. Some parents who are heterozygous for an aHUS-related pathogenic variant are affected; however, the majority of heterozygous parents are unaffected and their child is the only family member known to have aHUS [ Rarely, individuals diagnosed with autosomal dominant aHUS have the disorder as the result of a If both parents of a proband with a known pathogenic variant are unaffected, molecular genetic testing is recommended for the parents of the proband. If a pathogenic variant is identified in a parent, the parent is at risk of developing aHUS and of transmitting the pathogenic variant to other offspring. 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 individuals with autosomal dominant aHUS may appear to be negative because of reduced penetrance in an asymptomatic parent, early death of a parent, or late onset in a parent (or close relative). 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 known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Because of reduced penetrance, sibs who inherit the pathogenic variant may or may not develop aHUS (see Clinical severity and disease phenotype often differ among individuals with the same pathogenic variants. Although age of onset and/or disease progression and outcome cannot be predicted in sibs who inherit a familial pathogenic variant, the penetrance and/or severity of aHUS are known to be increased in individuals who inherit both a familial aHUS-related pathogenic variant and a genetic modifier (modifiers increase the penetrance and/or severity of aHUS but may not cause aHUS when present without one of the established molecular causes [see If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% based on the theoretic possibility of parental germline mosaicism. • Almost all individuals with autosomal dominant aHUS inherited an aHUS-related pathogenic variant from a heterozygous parent. Some parents who are heterozygous for an aHUS-related pathogenic variant are affected; however, the majority of heterozygous parents are unaffected and their child is the only family member known to have aHUS [ • Rarely, individuals diagnosed with autosomal dominant aHUS have the disorder as the result of a • If both parents of a proband with a known pathogenic variant are unaffected, molecular genetic testing is recommended for the parents of the proband. If a pathogenic variant is identified in a parent, the parent is at risk of developing aHUS and of transmitting the pathogenic variant to other offspring. • 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 individuals with autosomal dominant aHUS may appear to be negative because of reduced penetrance in an asymptomatic parent, early death of a parent, or late onset in a parent (or close relative). 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 (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If a parent of the proband is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Because of reduced penetrance, sibs who inherit the pathogenic variant may or may not develop aHUS (see • Clinical severity and disease phenotype often differ among individuals with the same pathogenic variants. Although age of onset and/or disease progression and outcome cannot be predicted in sibs who inherit a familial pathogenic variant, the penetrance and/or severity of aHUS are known to be increased in individuals who inherit both a familial aHUS-related pathogenic variant and a genetic modifier (modifiers increase the penetrance and/or severity of aHUS but may not cause aHUS when present without one of the established molecular causes [see • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% based on the theoretic possibility of parental germline mosaicism. ## Autosomal Recessive Inheritance – Risk to Family Members The parents of a child with autosomal recessive aHUS are obligate heterozygotes (i.e., presumed to be carriers of one pathogenic variant based on family history). Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an aHUS-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, the following possibilities should be considered: One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband; uniparental isodisomy has been reported in two probands [ Heterozygotes are usually asymptomatic. Rare instances of heterozygotes developing aHUS in adulthood have been reported [ If both parents are known to be heterozygous for an autosomal recessive aHUS-related pathogenic variant, each sib of a proband has a 25% chance of inheriting two pathogenic variants, a 50% chance of inheriting one pathogenic variant, and a 25% chance of inheriting neither pathogenic variant. Sibs who inherit biallelic Age of onset and/or disease progression and outcome cannot be predicted in sibs who inherit biallelic pathogenic variants in other aHUS-related genes, as clinical severity and disease phenotype often differ among individuals with the same pathogenic variants because of the role of environmental triggers and/or genetic modifiers. Heterozygotes are usually asymptomatic. Rare instances of heterozygotes developing aHUS in adulthood have been reported [ Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family. • The parents of a child with autosomal recessive aHUS are obligate heterozygotes (i.e., presumed to be carriers of one pathogenic variant based on family history). • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an aHUS-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, the following possibilities should be considered: • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband; uniparental isodisomy has been reported in two probands [ • 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; uniparental isodisomy has been reported in two probands [ • Heterozygotes are usually asymptomatic. Rare instances of heterozygotes developing aHUS in adulthood have been reported [ • 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; uniparental isodisomy has been reported in two probands [ • If both parents are known to be heterozygous for an autosomal recessive aHUS-related pathogenic variant, each sib of a proband has a 25% chance of inheriting two pathogenic variants, a 50% chance of inheriting one pathogenic variant, and a 25% chance of inheriting neither pathogenic variant. • Sibs who inherit biallelic • Age of onset and/or disease progression and outcome cannot be predicted in sibs who inherit biallelic pathogenic variants in other aHUS-related genes, as clinical severity and disease phenotype often differ among individuals with the same pathogenic variants because of the role of environmental triggers and/or genetic modifiers. • Sibs who inherit biallelic • Age of onset and/or disease progression and outcome cannot be predicted in sibs who inherit biallelic pathogenic variants in other aHUS-related genes, as clinical severity and disease phenotype often differ among individuals with the same pathogenic variants because of the role of environmental triggers and/or genetic modifiers. • Heterozygotes are usually asymptomatic. Rare instances of heterozygotes developing aHUS in adulthood have been reported [ • Sibs who inherit biallelic • Age of onset and/or disease progression and outcome cannot be predicted in sibs who inherit biallelic pathogenic variants in other aHUS-related genes, as clinical severity and disease phenotype often differ among individuals with the same pathogenic variants because of the role of environmental triggers and/or genetic modifiers. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family. ## Polygenic Inheritance – Risk to Family Members Polygenic aHUS is caused by the simultaneous presence of two pathogenic variants: one pathogenic variant in one complement-regulatory gene and another pathogenic variant in a different complement-regulatory gene. Typically, one parent has a pathogenic variant in one complement-regulatory gene and the other parent has a pathogenic variant in a different complement-regulatory gene. However, both parents should undergo confirmatory genetic testing because it is possible that one parent has both pathogenic variants and is asymptomatic. In the families reported to date with polygenic inheritance, heterozygotes have usually been asymptomatic. • Typically, one parent has a pathogenic variant in one complement-regulatory gene and the other parent has a pathogenic variant in a different complement-regulatory gene. However, both parents should undergo confirmatory genetic testing because it is possible that one parent has both pathogenic variants and is asymptomatic. • In the families reported to date with polygenic inheritance, heterozygotes have usually been asymptomatic. ## 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 aHUS-related pathogenic variant(s) have been identified in an affected family member, prenatal testing and preimplantation genetic testing for the familial pathogenic variant(s) 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 3 Information Way Bethesda MD 20892-3580 Italy Mario Negri Institute for Pharmacological Research Clinical Research Center for Rare Diseases "Aldo e Cele Daccò" Villa Camozzi - Via Camozzi, 3 Ranica 24020 Italy • • • • 3 Information Way • Bethesda MD 20892-3580 • • • Italy • • • • • • • Mario Negri Institute for Pharmacological Research • Clinical Research Center for Rare Diseases "Aldo e Cele Daccò" • Villa Camozzi - Via Camozzi, 3 • Ranica 24020 • Italy • ## Molecular Genetics Genetic Atypical Hemolytic-Uremic Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Genetic Atypical Hemolytic-Uremic Syndrome ( Hyperactivation of the complement system is the pathogenetic mechanism leading to the endothelial damage and the microvascular thrombosis in aHUS [ Genetic Atypical Hemolytic-Uremic Syndrome: Mechanism of Disease Causation by Gene Genetic Atypical Hemolytic-Uremic Syndrome: Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis Hyperactivation of the complement system is the pathogenetic mechanism leading to the endothelial damage and the microvascular thrombosis in aHUS [ Genetic Atypical Hemolytic-Uremic Syndrome: Mechanism of Disease Causation by Gene Genetic Atypical Hemolytic-Uremic Syndrome: Variants listed in the table have been provided by the authors. ## Chapter Notes Marina Noris, PhDLaboratory of Immunology and Genetics of Rare DiseasesIstituto di Ricerche Farmacologiche Mario Negri–IRCCSVilla Camozzi, via Camozzi 3, 24020 Ranica (Bergamo), ItalyPhone: 0039 035 4535362Fax: 0039 035 4535377Email: Elena Bresin, MD (2007-present)Jessica Caprioli, Biol Sci D; Mario Negri Institute for Pharmacological Research (2007-2013)Caterina Mele, Biol Sci D (2007-present)Marina Noris, PhD (2007-present)Giuseppe Remuzzi, MD (2007-present) 23 September 2021 (sw) Comprehensive update posted live 9 June 2016 (sw) Comprehensive update posted live 8 August 2013 (me) Comprehensive update posted live 10 March 2011 (me) Comprehensive update posted live 20 November 2008 (cd) Revision: deletion/duplication testing for 17 December 2007 (cd) Revision: sequence analysis available for 16 November 2007 (me) Review posted live 27 March 2007 (mn) Original submission • 23 September 2021 (sw) Comprehensive update posted live • 9 June 2016 (sw) Comprehensive update posted live • 8 August 2013 (me) Comprehensive update posted live • 10 March 2011 (me) Comprehensive update posted live • 20 November 2008 (cd) Revision: deletion/duplication testing for • 17 December 2007 (cd) Revision: sequence analysis available for • 16 November 2007 (me) Review posted live • 27 March 2007 (mn) Original submission ## Author Notes Marina Noris, PhDLaboratory of Immunology and Genetics of Rare DiseasesIstituto di Ricerche Farmacologiche Mario Negri–IRCCSVilla Camozzi, via Camozzi 3, 24020 Ranica (Bergamo), ItalyPhone: 0039 035 4535362Fax: 0039 035 4535377Email: ## Author History Elena Bresin, MD (2007-present)Jessica Caprioli, Biol Sci D; Mario Negri Institute for Pharmacological Research (2007-2013)Caterina Mele, Biol Sci D (2007-present)Marina Noris, PhD (2007-present)Giuseppe Remuzzi, MD (2007-present) ## Revision History 23 September 2021 (sw) Comprehensive update posted live 9 June 2016 (sw) Comprehensive update posted live 8 August 2013 (me) Comprehensive update posted live 10 March 2011 (me) Comprehensive update posted live 20 November 2008 (cd) Revision: deletion/duplication testing for 17 December 2007 (cd) Revision: sequence analysis available for 16 November 2007 (me) Review posted live 27 March 2007 (mn) Original submission • 23 September 2021 (sw) Comprehensive update posted live • 9 June 2016 (sw) Comprehensive update posted live • 8 August 2013 (me) Comprehensive update posted live • 10 March 2011 (me) Comprehensive update posted live • 20 November 2008 (cd) Revision: deletion/duplication testing for • 17 December 2007 (cd) Revision: sequence analysis available for • 16 November 2007 (me) Review posted live • 27 March 2007 (mn) Original submission ## References ## Published Guidelines/Consensus Statements ## Literature Cited	[ "C Loirat, F Fakhouri, G Ariceta, N Besbas, M Bitzan, A Bjerre, R Coppo, F Emma, S Johnson, D Karpman, D Landau, CB Langman, AL Lapeyraque, C Licht, C Nester, C Pecoraro, M Riedl, NC van de Kar, J Van de Walle, M Vivarelli, V Frémeaux-Bacchi. An international consensus approach to the management of atypical hemolytic uremic syndrome in children.. Pediatr Nephrol. 2016;31:15-39" ]	16/11/2007	23/9/2021	20/11/2008	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
hyal2-def	hyal2-def	[ "Orofacial Clefting and Cor Triatriatum Sinister Syndrome", "Orofacial Clefting and Cor Triatriatum Sinister Syndrome", "Hyaluronidase-2", "HYAL2", "HYAL2 Deficiency" ]	HYAL2 Deficiency	James Fasham, Olivia K Wenger, Andrew H Crosby, Emma L Baple	Summary HYAL2 deficiency is characterized by cardiac anomalies, cleft lip and palate (unilateral or bilateral), ophthalmic findings (including mild-to-severe myopia up to −16.75 diopters and increased risk of retinal detachment), hearing loss (typically conductive), and skeletal findings (including pectus excavatum and digital anomalies). Intellect is typically normal. To date, 17 individuals from seven families have been reported with HYAL2 deficiency. The diagnosis of HYAL2 deficiency is established in a proband with suggestive findings and biallelic pathogenic variants in HYAL2 deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an	## Diagnosis No consensus clinical diagnostic criteria for HYAL2 deficiency have been published. HYAL2 deficiency Characteristic facial features (See Congenital cardiac anomalies (including coarctation of the aorta, mitral/pulmonary valve atresia, hypoplastic left ventricle, tetralogy of Fallot, double outlet right ventricle, hypoplastic pulmonary and aortopulmonary arteries with agenesis of the ductus venosus) Cleft lip and palate (CLP), either unilateral or bilateral Ophthalmologic features including: Mild-to-severe myopia (up to −16.75 diopters), which can be asymmetric. When myopia is severe, complications include myopic macular degeneration and increased risk of retinal detachment. Cataracts (posterior subcapsular cataract and wedge-shaped cortical cataract), suggesting that the high myopia may be part of a hereditary vitreoretinal degeneration phenotype Ptosis (mild to moderate, bilateral). It is not currently known whether this is stationary or progressive. Hearing loss. Typically conductive, diagnosed on newborn hearing screening or soon after birth and associated with CLP. Sensorineural hearing loss is described but rare. Skeletal findings (including pectus excavatum and digital anomalies such as broad halluces and thumbs) The diagnosis of HYAL2 deficiency Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Note: Targeted analysis for the For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in HYAL2 Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • Characteristic facial features (See • Congenital cardiac anomalies (including coarctation of the aorta, mitral/pulmonary valve atresia, hypoplastic left ventricle, tetralogy of Fallot, double outlet right ventricle, hypoplastic pulmonary and aortopulmonary arteries with agenesis of the ductus venosus) • Cleft lip and palate (CLP), either unilateral or bilateral • Ophthalmologic features including: • Mild-to-severe myopia (up to −16.75 diopters), which can be asymmetric. When myopia is severe, complications include myopic macular degeneration and increased risk of retinal detachment. • Cataracts (posterior subcapsular cataract and wedge-shaped cortical cataract), suggesting that the high myopia may be part of a hereditary vitreoretinal degeneration phenotype • Ptosis (mild to moderate, bilateral). It is not currently known whether this is stationary or progressive. • Mild-to-severe myopia (up to −16.75 diopters), which can be asymmetric. When myopia is severe, complications include myopic macular degeneration and increased risk of retinal detachment. • Cataracts (posterior subcapsular cataract and wedge-shaped cortical cataract), suggesting that the high myopia may be part of a hereditary vitreoretinal degeneration phenotype • Ptosis (mild to moderate, bilateral). It is not currently known whether this is stationary or progressive. • Hearing loss. Typically conductive, diagnosed on newborn hearing screening or soon after birth and associated with CLP. Sensorineural hearing loss is described but rare. • Skeletal findings (including pectus excavatum and digital anomalies such as broad halluces and thumbs) • Mild-to-severe myopia (up to −16.75 diopters), which can be asymmetric. When myopia is severe, complications include myopic macular degeneration and increased risk of retinal detachment. • Cataracts (posterior subcapsular cataract and wedge-shaped cortical cataract), suggesting that the high myopia may be part of a hereditary vitreoretinal degeneration phenotype • Ptosis (mild to moderate, bilateral). It is not currently known whether this is stationary or progressive. ## Suggestive Findings HYAL2 deficiency Characteristic facial features (See Congenital cardiac anomalies (including coarctation of the aorta, mitral/pulmonary valve atresia, hypoplastic left ventricle, tetralogy of Fallot, double outlet right ventricle, hypoplastic pulmonary and aortopulmonary arteries with agenesis of the ductus venosus) Cleft lip and palate (CLP), either unilateral or bilateral Ophthalmologic features including: Mild-to-severe myopia (up to −16.75 diopters), which can be asymmetric. When myopia is severe, complications include myopic macular degeneration and increased risk of retinal detachment. Cataracts (posterior subcapsular cataract and wedge-shaped cortical cataract), suggesting that the high myopia may be part of a hereditary vitreoretinal degeneration phenotype Ptosis (mild to moderate, bilateral). It is not currently known whether this is stationary or progressive. Hearing loss. Typically conductive, diagnosed on newborn hearing screening or soon after birth and associated with CLP. Sensorineural hearing loss is described but rare. Skeletal findings (including pectus excavatum and digital anomalies such as broad halluces and thumbs) • Characteristic facial features (See • Congenital cardiac anomalies (including coarctation of the aorta, mitral/pulmonary valve atresia, hypoplastic left ventricle, tetralogy of Fallot, double outlet right ventricle, hypoplastic pulmonary and aortopulmonary arteries with agenesis of the ductus venosus) • Cleft lip and palate (CLP), either unilateral or bilateral • Ophthalmologic features including: • Mild-to-severe myopia (up to −16.75 diopters), which can be asymmetric. When myopia is severe, complications include myopic macular degeneration and increased risk of retinal detachment. • Cataracts (posterior subcapsular cataract and wedge-shaped cortical cataract), suggesting that the high myopia may be part of a hereditary vitreoretinal degeneration phenotype • Ptosis (mild to moderate, bilateral). It is not currently known whether this is stationary or progressive. • Mild-to-severe myopia (up to −16.75 diopters), which can be asymmetric. When myopia is severe, complications include myopic macular degeneration and increased risk of retinal detachment. • Cataracts (posterior subcapsular cataract and wedge-shaped cortical cataract), suggesting that the high myopia may be part of a hereditary vitreoretinal degeneration phenotype • Ptosis (mild to moderate, bilateral). It is not currently known whether this is stationary or progressive. • Hearing loss. Typically conductive, diagnosed on newborn hearing screening or soon after birth and associated with CLP. Sensorineural hearing loss is described but rare. • Skeletal findings (including pectus excavatum and digital anomalies such as broad halluces and thumbs) • Mild-to-severe myopia (up to −16.75 diopters), which can be asymmetric. When myopia is severe, complications include myopic macular degeneration and increased risk of retinal detachment. • Cataracts (posterior subcapsular cataract and wedge-shaped cortical cataract), suggesting that the high myopia may be part of a hereditary vitreoretinal degeneration phenotype • Ptosis (mild to moderate, bilateral). It is not currently known whether this is stationary or progressive. ## Establishing the Diagnosis The diagnosis of HYAL2 deficiency Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Note: Targeted analysis for the For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in HYAL2 Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Option 1 Note: Targeted analysis for the For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in HYAL2 Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Clinical Characteristics HYAL2 deficiency is characterized by congenital cardiac anomalies, cleft lip and palate that can be unilateral or bilateral, distinctive ophthalmic findings (including mild-to-severe myopia up to −16.75 diopters and increased risk of retinal detachment), hearing loss that is typically conductive, and skeletal findings (including pectus excavatum and digital anomalies). Intellect is typically normal. To date, 17 individuals from seven families have been identified with HYAL2 deficiency [ HYAL2 Deficiency: Frequency of Selected Features Based on Limited clinical details are available for some of the reported individuals included in this table. The denominator of each fraction represents the total number of individuals in whom the corresponding finding was reported. Denominator unknown Ventricular septal defect (4 individuals) Tetralogy of Fallot (2 individuals) Aortic regurgitation (2 individuals) Hypoplastic left ventricle Coarctation of the aorta Mitral valve atresia Pulmonary valve atresia Aortic stenosis Pulmonary hypertension Double outlet right ventricle Persistent left superior vena cava Left cor triatriatum Broad thumbs and/or halluces (6/17) Syndactyly of fingers or toes (5/17), most commonly bilateral toe 2-3 syndactyly Finger webbing Hypoplastic nails Fifth finger clinodactyly Bilateral cryptorchidism was described once [ When congenital heart disease is absent or amenable to surgical treatment, survival does not seem impacted. The oldest reported individuals are ages 19 and 20 years. Although no genotype-phenotype correlations have been conclusively identified, the phenotypes reported in three compound heterozygous individuals with a nonsense variant and a missense variant on homologous alleles suggests that nonsense variants may be associated with more severe congenital cardiac anomalies and severe myopia. These include the two sibs described in Clinical Description, To date 17 individuals from seven families with HYAL2 deficiency have been identified [ The • Ventricular septal defect (4 individuals) • Tetralogy of Fallot (2 individuals) • Aortic regurgitation (2 individuals) • Hypoplastic left ventricle • Coarctation of the aorta • Mitral valve atresia • Pulmonary valve atresia • Aortic stenosis • Pulmonary hypertension • Double outlet right ventricle • Persistent left superior vena cava • Left cor triatriatum • Broad thumbs and/or halluces (6/17) • Syndactyly of fingers or toes (5/17), most commonly bilateral toe 2-3 syndactyly • Finger webbing • Hypoplastic nails • Fifth finger clinodactyly ## Clinical Description HYAL2 deficiency is characterized by congenital cardiac anomalies, cleft lip and palate that can be unilateral or bilateral, distinctive ophthalmic findings (including mild-to-severe myopia up to −16.75 diopters and increased risk of retinal detachment), hearing loss that is typically conductive, and skeletal findings (including pectus excavatum and digital anomalies). Intellect is typically normal. To date, 17 individuals from seven families have been identified with HYAL2 deficiency [ HYAL2 Deficiency: Frequency of Selected Features Based on Limited clinical details are available for some of the reported individuals included in this table. The denominator of each fraction represents the total number of individuals in whom the corresponding finding was reported. Denominator unknown Ventricular septal defect (4 individuals) Tetralogy of Fallot (2 individuals) Aortic regurgitation (2 individuals) Hypoplastic left ventricle Coarctation of the aorta Mitral valve atresia Pulmonary valve atresia Aortic stenosis Pulmonary hypertension Double outlet right ventricle Persistent left superior vena cava Left cor triatriatum Broad thumbs and/or halluces (6/17) Syndactyly of fingers or toes (5/17), most commonly bilateral toe 2-3 syndactyly Finger webbing Hypoplastic nails Fifth finger clinodactyly Bilateral cryptorchidism was described once [ When congenital heart disease is absent or amenable to surgical treatment, survival does not seem impacted. The oldest reported individuals are ages 19 and 20 years. • Ventricular septal defect (4 individuals) • Tetralogy of Fallot (2 individuals) • Aortic regurgitation (2 individuals) • Hypoplastic left ventricle • Coarctation of the aorta • Mitral valve atresia • Pulmonary valve atresia • Aortic stenosis • Pulmonary hypertension • Double outlet right ventricle • Persistent left superior vena cava • Left cor triatriatum • Broad thumbs and/or halluces (6/17) • Syndactyly of fingers or toes (5/17), most commonly bilateral toe 2-3 syndactyly • Finger webbing • Hypoplastic nails • Fifth finger clinodactyly ## Genotype-Phenotype Correlations Although no genotype-phenotype correlations have been conclusively identified, the phenotypes reported in three compound heterozygous individuals with a nonsense variant and a missense variant on homologous alleles suggests that nonsense variants may be associated with more severe congenital cardiac anomalies and severe myopia. These include the two sibs described in Clinical Description, ## Prevalence To date 17 individuals from seven families with HYAL2 deficiency have been identified [ The ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The differential diagnosis of HYAL2 deficiency includes other syndromic clefting disorders; see Selected Genes of Interest in the Differential Diagnosis of HYAL2 Deficiency Hypertelorism, nasal anomalies, midline orofacial clefts Congenital cardiac defects incl tetralogy of Fallot Abnormalities of hair incl V-shaped "widow's peak" anterior hairline Severe myopia absent Pectus excavatum absent Cleft palate, myopia, retinal detachment, auditory issues Characteristic facial features Skeletal abnormalities Craniosynostosis Presentation in males is usually mild. AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked Stickler syndrome caused by pathogenic variants • Hypertelorism, nasal anomalies, midline orofacial clefts • Congenital cardiac defects incl tetralogy of Fallot • Abnormalities of hair incl V-shaped "widow's peak" anterior hairline • Severe myopia absent • Pectus excavatum absent • Characteristic facial features • Skeletal abnormalities • Craniosynostosis • Presentation in males is usually mild. ## Management Clinical advice and practice guidelines for HYAL2 deficiency have been proposed [ To establish the extent of disease and needs in an individual diagnosed with HYAL2 deficiency, the evaluations summarized in HYAL2 Deficiency: Recommended Evaluations Following Initial Diagnosis Community or Social work involvement for parental support; Home nursing referral. MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse There is no cure for HYAL2 deficiency. HYAL2 Deficiency: Treatment of Manifestations Children: through early intervention programs &/or school district Adults: low vision clinic &/or community vision services / OT / mobility services Timely treatment of otitis media secondary to eustachian tube dysfunction due to cleft palate to prevent secondary hearing loss Some persons may require placement of pressure-equalizing tubes. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. CLP = cleft lip and palate; OT = occupational therapy Enteral feeding tubes may be needed if there is concern for aspiration or if the affected individual is unable to take in adequate calories for growth. Some children with more significant respiratory issues may require surgical feeding tubes and/or procedures to protect their lungs from microaspiration. HYAL2 deficiency is primarily a developmental disorder and as such progressive complications are not expected. However, because the complications of congenital anomalies may become apparent with time, the evaluations summarized in HYAL2 Deficiency: Recommended Surveillance Multidisciplinary craniofacial team follow up Equipment & techniques for feeding infants w/cleft palate Audiology eval as needed Infants: visit frequency determined by feeding & respiratory issues Children: varies depending on comorbidities; at least annually Measurement of growth parameters Eval of nutritional status & safety of oral intake Speech assessment by speech-language pathologist familiar w/cleft palate Consider speech therapy & augmentative communication devices. Routine long-term follow up of children without detectable cardiac anomalies is not required. See Search • Community or • Social work involvement for parental support; • Home nursing referral. • Children: through early intervention programs &/or school district • Adults: low vision clinic &/or community vision services / OT / mobility services • Timely treatment of otitis media secondary to eustachian tube dysfunction due to cleft palate to prevent secondary hearing loss • Some persons may require placement of pressure-equalizing tubes. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Multidisciplinary craniofacial team follow up • Equipment & techniques for feeding infants w/cleft palate • Audiology eval as needed • Infants: visit frequency determined by feeding & respiratory issues • Children: varies depending on comorbidities; at least annually • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Speech assessment by speech-language pathologist familiar w/cleft palate • Consider speech therapy & augmentative communication devices. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with HYAL2 deficiency, the evaluations summarized in HYAL2 Deficiency: Recommended Evaluations Following Initial Diagnosis Community or Social work involvement for parental support; Home nursing referral. MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations There is no cure for HYAL2 deficiency. HYAL2 Deficiency: Treatment of Manifestations Children: through early intervention programs &/or school district Adults: low vision clinic &/or community vision services / OT / mobility services Timely treatment of otitis media secondary to eustachian tube dysfunction due to cleft palate to prevent secondary hearing loss Some persons may require placement of pressure-equalizing tubes. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. CLP = cleft lip and palate; OT = occupational therapy Enteral feeding tubes may be needed if there is concern for aspiration or if the affected individual is unable to take in adequate calories for growth. Some children with more significant respiratory issues may require surgical feeding tubes and/or procedures to protect their lungs from microaspiration. • Children: through early intervention programs &/or school district • Adults: low vision clinic &/or community vision services / OT / mobility services • Timely treatment of otitis media secondary to eustachian tube dysfunction due to cleft palate to prevent secondary hearing loss • Some persons may require placement of pressure-equalizing tubes. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ## Surveillance HYAL2 deficiency is primarily a developmental disorder and as such progressive complications are not expected. However, because the complications of congenital anomalies may become apparent with time, the evaluations summarized in HYAL2 Deficiency: Recommended Surveillance Multidisciplinary craniofacial team follow up Equipment & techniques for feeding infants w/cleft palate Audiology eval as needed Infants: visit frequency determined by feeding & respiratory issues Children: varies depending on comorbidities; at least annually Measurement of growth parameters Eval of nutritional status & safety of oral intake Speech assessment by speech-language pathologist familiar w/cleft palate Consider speech therapy & augmentative communication devices. Routine long-term follow up of children without detectable cardiac anomalies is not required. • Multidisciplinary craniofacial team follow up • Equipment & techniques for feeding infants w/cleft palate • Audiology eval as needed • Infants: visit frequency determined by feeding & respiratory issues • Children: varies depending on comorbidities; at least annually • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Speech assessment by speech-language pathologist familiar w/cleft palate • Consider speech therapy & augmentative communication devices. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling HYAL2 deficiency is inherited in an autosomal recessive manner. The parents of an affected child are presumed to be heterozygous for an Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an Intrafamilial clinical variability has been observed among related individuals with HYAL2 deficiency (e.g., cleft palate and/or cardiac anomalies in some but not all affected family members) [ Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Carrier testing for at-risk relatives requires prior identification of the The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Carrier testing for reproductive partners of known carriers could be considered, particularly if both partners are 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 deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual 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 • Intrafamilial clinical variability has been observed among related individuals with HYAL2 deficiency (e.g., cleft palate and/or cardiac anomalies in some but not all affected family members) [ • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • Carrier testing for reproductive partners of known carriers could be considered, particularly if both partners are of the same ethnic background. An ## Mode of Inheritance HYAL2 deficiency is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected child are presumed to be heterozygous for an Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an Intrafamilial clinical variability has been observed among related individuals with HYAL2 deficiency (e.g., cleft palate and/or cardiac anomalies in some but not all affected family members) [ 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 • Intrafamilial clinical variability has been observed among related individuals with HYAL2 deficiency (e.g., cleft palate and/or cardiac anomalies in some but not all affected family members) [ • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Carrier testing for reproductive partners of known carriers could be considered, particularly if both partners are of the same ethnic background. An • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • Carrier testing for reproductive partners of known carriers could be considered, particularly if both partners are 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 United Kingdom • • • • • • United Kingdom • ## Molecular Genetics HYAL2 Deficiency: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for HYAL2 Deficiency ( Hyaluronidase-2 (HYAL2) is proposed to act as a hyaluronidase enzyme, catalyzing the degradation of the high-molecular-weight glycosaminoglycan hyaluronan. HYAL2 undergoes complex post-translational modification before achieving its final topology as a mature GPI-anchored cell surface glycoprotein. The translational steps required to generate mature HYAL2 begin in the endoplasmic reticulum (ER), where even conservative amino acid substitutions may lead to ER-associated degradation and HYAL2 deficiency [ In silico three-dimensional homology modeling of Nonsense-mediated mRNA decay and loss of functional protein Missense variants that either: Result in protein instability resulting in low total cell HYAL2 levels; Disrupt the localization of HYAL2 resulting in low cell surface HYAL2 levels. Variants listed in the table have been provided by the authors. • Nonsense-mediated mRNA decay and loss of functional protein • Missense variants that either: • Result in protein instability resulting in low total cell HYAL2 levels; • Disrupt the localization of HYAL2 resulting in low cell surface HYAL2 levels. • Result in protein instability resulting in low total cell HYAL2 levels; • Disrupt the localization of HYAL2 resulting in low cell surface HYAL2 levels. • Result in protein instability resulting in low total cell HYAL2 levels; • Disrupt the localization of HYAL2 resulting in low cell surface HYAL2 levels. ## Molecular Pathogenesis Hyaluronidase-2 (HYAL2) is proposed to act as a hyaluronidase enzyme, catalyzing the degradation of the high-molecular-weight glycosaminoglycan hyaluronan. HYAL2 undergoes complex post-translational modification before achieving its final topology as a mature GPI-anchored cell surface glycoprotein. The translational steps required to generate mature HYAL2 begin in the endoplasmic reticulum (ER), where even conservative amino acid substitutions may lead to ER-associated degradation and HYAL2 deficiency [ In silico three-dimensional homology modeling of Nonsense-mediated mRNA decay and loss of functional protein Missense variants that either: Result in protein instability resulting in low total cell HYAL2 levels; Disrupt the localization of HYAL2 resulting in low cell surface HYAL2 levels. Variants listed in the table have been provided by the authors. • Nonsense-mediated mRNA decay and loss of functional protein • Missense variants that either: • Result in protein instability resulting in low total cell HYAL2 levels; • Disrupt the localization of HYAL2 resulting in low cell surface HYAL2 levels. • Result in protein instability resulting in low total cell HYAL2 levels; • Disrupt the localization of HYAL2 resulting in low cell surface HYAL2 levels. • Result in protein instability resulting in low total cell HYAL2 levels; • Disrupt the localization of HYAL2 resulting in low cell surface HYAL2 levels. ## Chapter Notes Further information on our work with the Amish community can be found at First and foremost, the authors would like to thank the patients and their families as well as the collaborators who have been involved in defining this emerging multisystem disorder. We would particularly like to acknowledge Professor Barbara Triggs-Raine (University of Manitoba) and her group, especially Ms Promita Ghosh, without whom we would have been unable to begin to define the pathomechanism of the condition. This work was in part supported by the Medical Research Council, Medical Research Foundation, Newlife Foundation for Disabled Children, GW4-CAT Wellcome Trust, Fondazione Bambino Gesù, Vite Coraggiose, the Natural Science and Engineering Research Council of Canada, Genomic Answers for Kids, National Center for Advancing Translational Sciences of the National Institutes of Health, Institute for Translational Medicine and Therapeutics of the Perelman School of Medicine at the University of Pennsylvania, the National Human Genome Research Institute / National Heart, Lung and Blood Institute, Baylor-Hopkins Center for Mendelian Genomics, and Solve-RD. 21 September 2023 (bp) Review posted live 19 December 2022 (eb) Original submission • 21 September 2023 (bp) Review posted live • 19 December 2022 (eb) Original submission ## Author Notes Further information on our work with the Amish community can be found at ## Acknowledgments First and foremost, the authors would like to thank the patients and their families as well as the collaborators who have been involved in defining this emerging multisystem disorder. We would particularly like to acknowledge Professor Barbara Triggs-Raine (University of Manitoba) and her group, especially Ms Promita Ghosh, without whom we would have been unable to begin to define the pathomechanism of the condition. This work was in part supported by the Medical Research Council, Medical Research Foundation, Newlife Foundation for Disabled Children, GW4-CAT Wellcome Trust, Fondazione Bambino Gesù, Vite Coraggiose, the Natural Science and Engineering Research Council of Canada, Genomic Answers for Kids, National Center for Advancing Translational Sciences of the National Institutes of Health, Institute for Translational Medicine and Therapeutics of the Perelman School of Medicine at the University of Pennsylvania, the National Human Genome Research Institute / National Heart, Lung and Blood Institute, Baylor-Hopkins Center for Mendelian Genomics, and Solve-RD. ## Revision History 21 September 2023 (bp) Review posted live 19 December 2022 (eb) Original submission • 21 September 2023 (bp) Review posted live • 19 December 2022 (eb) Original submission ## References ## Literature Cited Photographs of individuals with HYAL2 deficiency. Key features include frontal bossing, hypertelorism, broad and flattened nasal tip, and auricular anomalies (cupped ears, overfolded helices, preauricular pit) in almost all individuals. Additional variable features include frontal bossing, ptosis, a broad nasal tip, and micrognathia. Reproduced with permission from Digital anomalies and pectus excavatum in individuals with HYAL2 deficiency Reproduced with permission from	[]	21/9/2023			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
hyper-card	hyper-card	[ "Actin, alpha cardiac muscle 1", "Alpha-actinin-2", "Alpha-protein kinase 3", "Ankyrin repeat domain-containing protein 1", "Calreticulin-3", "Cysteine and glycine-rich protein 3", "E3 ubiquitin-protein ligase TRIM63", "Junctophilin-2", "Krueppel-like factor 10", "Myomesin-1", "Myopalladin", "Myosin light chain 3", "Myosin light chain kinase 2, skeletal/cardiac muscle", "Myosin regulatory light chain 2, ventricular/cardiac muscle isoform", "Myosin-6", "Myosin-7", "Myosin-binding protein C, cardiac-type", "Myozenin-2", "Nexilin", "Obscurin", "PDZ and LIM domain protein 3", "Phospholamban", "Ryanodine receptor 2", "Telethonin", "Titin", "Tropomyosin alpha-1 chain", "Troponin C, slow skeletal and cardiac muscles", "Troponin I, cardiac muscle", "Troponin T, cardiac muscle", "Vinculin", "ACTC1", "ACTN2", "ALPK3", "ANKRD1", "CALR3", "CSRP3", "JPH2", "KLF10", "MYBPC3", "MYH6", "MYH7", "MYL2", "MYL3", "MYLK2", "MYOM1", "MYOZ2", "MYPN", "NEXN", "OBSCN", "PDLIM3", "PLN", "RYR2", "TCAP", "TNNC1", "TNNI3", "TNNT2", "TPM1", "TRIM63", "TTN", "VCL", "Nonsyndromic Hypertrophic Cardiomyopathy", "Overview" ]	Nonsyndromic Hypertrophic Cardiomyopathy Overview	Allison L Cirino, Nadine Channaoui, Carolyn Ho	Summary The purpose of this overview is to: Define the Review the Review the Provide an Review the Inform	## Clinical Characteristics of Hypertrophic Cardiomyopathy Hypertrophic cardiomyopathy (HCM) is typically defined by the presence of unexplained left ventricular hypertrophy (LVH) with a maximum left ventricular (LV) wall thickness ≥15 mm in adults or an LV wall thickness z score >3 in children [ The diagnosis of HCM is most often established with noninvasive cardiac imaging, including echocardiography and/or cardiac MRI. While asymmetric septal hypertrophy is the most common pattern of hypertrophy, the degree and location of hypertrophy vary. LVH can be concentric, confined to other walls, or involving the LV apex. Findings on transthoracic echocardiography may also include: Systolic anterior motion (SAM) of the mitral valve with associated LV outflow tract obstruction and mitral regurgitation; Mid-ventricular obstruction as a result of systolic cavity obliteration; Diastolic dysfunction, including restrictive physiology. Note: Normal LV wall thickness with impaired LV relaxation can be detected in individuals with a pathogenic variant in a gene that encodes a component of the sarcomere, suggesting that diastolic dysfunction is an early manifestation of HCM due to a pathogenic variant in one of the genes encoding a component of the sarcomere rather than a secondary consequence of LVH. Although LVH and a clinical diagnosis of HCM often become apparent during adolescence or early adulthood, onset can be earlier (in infancy and childhood) or later in life. Common symptoms include shortness of breath (particularly with exertion), chest pain, palpitations, orthostasis, presyncope, and syncope. Left ventricular outflow tract obstruction (LVOTO) is one of the most characteristic features of HCM. At least 25%-30% of persons with HCM have detectable intracavitary obstruction (defined as peak gradient ≥30 mm Hg) at rest or with provocation (e.g., reduction of preload or afterload) [ Individuals with HCM are at an increased risk for atrial fibrillation (AF), which can have significant morbidity due to increased risk of thromboembolism and symptomatic deterioration. The prevalence of AF increases with age and duration of disease. The overall prevalence of AF in individuals with HCM is ~20%, but prevalence is ~60% by age 60 years for individuals diagnosed with HCM by age 40 years [ Left ventricular systolic dysfunction (LVSD), defined as left ventricular ejection fraction (LVEF) <50%, is seen in approximately 8% of individuals with HCM [ SCD, most likely related to ventricular tachycardia / ventricular fibrillation, is an important but relatively rare consequence of HCM. In a large cohort of individuals with HCM, 6% experienced SCD, resuscitated cardiac arrest, or treatment with implantable cardioverter-defibrillator (ICD) [ SCD may be the first manifestation of disease [ HCM is a well-described but rare cause of SCD in competitive athletes in the United States (US), with a reported prevalence of ~5%-14%. [ SCD occurs most often in adolescents or young adults but may occur at any age and the risk persists throughout life, particularly for persons with HCM caused by a pathogenic variant in one of the genes encoding a component of the sarcomere. Penetrance is estimated to be 50%-62% in at-risk relatives who were heterozygous for the familial HCM-related pathogenic variant [ • While asymmetric septal hypertrophy is the most common pattern of hypertrophy, the degree and location of hypertrophy vary. LVH can be concentric, confined to other walls, or involving the LV apex. • Findings on transthoracic echocardiography may also include: • Systolic anterior motion (SAM) of the mitral valve with associated LV outflow tract obstruction and mitral regurgitation; • Mid-ventricular obstruction as a result of systolic cavity obliteration; • Diastolic dysfunction, including restrictive physiology. Note: Normal LV wall thickness with impaired LV relaxation can be detected in individuals with a pathogenic variant in a gene that encodes a component of the sarcomere, suggesting that diastolic dysfunction is an early manifestation of HCM due to a pathogenic variant in one of the genes encoding a component of the sarcomere rather than a secondary consequence of LVH. • Systolic anterior motion (SAM) of the mitral valve with associated LV outflow tract obstruction and mitral regurgitation; • Mid-ventricular obstruction as a result of systolic cavity obliteration; • Diastolic dysfunction, including restrictive physiology. Note: Normal LV wall thickness with impaired LV relaxation can be detected in individuals with a pathogenic variant in a gene that encodes a component of the sarcomere, suggesting that diastolic dysfunction is an early manifestation of HCM due to a pathogenic variant in one of the genes encoding a component of the sarcomere rather than a secondary consequence of LVH. • Systolic anterior motion (SAM) of the mitral valve with associated LV outflow tract obstruction and mitral regurgitation; • Mid-ventricular obstruction as a result of systolic cavity obliteration; • Diastolic dysfunction, including restrictive physiology. Note: Normal LV wall thickness with impaired LV relaxation can be detected in individuals with a pathogenic variant in a gene that encodes a component of the sarcomere, suggesting that diastolic dysfunction is an early manifestation of HCM due to a pathogenic variant in one of the genes encoding a component of the sarcomere rather than a secondary consequence of LVH. • SCD may be the first manifestation of disease [ • HCM is a well-described but rare cause of SCD in competitive athletes in the United States (US), with a reported prevalence of ~5%-14%. [ • SCD occurs most often in adolescents or young adults but may occur at any age and the risk persists throughout life, particularly for persons with HCM caused by a pathogenic variant in one of the genes encoding a component of the sarcomere. ## Penetrance Penetrance is estimated to be 50%-62% in at-risk relatives who were heterozygous for the familial HCM-related pathogenic variant [ ## Genetic Causes of Nonsyndromic Hypertrophic Cardiomyopathy Pathogenic variants in one of the genes encoding a component of the sarcomere (i.e., sarcomeric pathogenic variant) are the predominant cause of nonsyndromic hypertrophic cardiomyopathy (HCM) [ The Note: Pathogenic variants identified in genes classified by ClinGen as having only "moderate" or "limited" evidence supporting a causal relationship with HCM should be interpreted with thorough consideration of genotype-phenotype correlation. For example, presence or absence of a pathogenic variant in a gene where causation of HCM has only limited evidence may not be clinically informative in phenotypically unaffected family members. Nonsyndromic Hypertrophic Cardiomyopathy Genes LVNC Atrial septal defect LVNC Restrictive cardiomyopathy Myosin storage myopathy LVNC Scapuloperoneal myopathy Restrictive cardiomyopathy LVNC Restrictive cardiomyopathy Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome AD = autosomal dominant; AR = autosomal recessive; ARVC = arrhythmogenic right ventricular cardiomyopathy; CPVT = catecholaminergic polymorphic ventricular tachycardia; DCM = dilated cardiomyopathy; LVNC = left ventricular noncompaction; MT = mitochondrial; MOI = mode of inheritance Genes are ordered first by validity classification and then alphabetically. Prevalence data listed for genes included in Allelic disorders = other phenotypes caused by pathogenic variants in the same gene There are multiple Dutch founder pathogenic variants in • LVNC • Atrial septal defect • LVNC • Restrictive cardiomyopathy • Myosin storage myopathy • LVNC • Scapuloperoneal myopathy • Restrictive cardiomyopathy • LVNC • Restrictive cardiomyopathy • Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome ## Differential Diagnosis of Nonsyndromic Hypertrophic Cardiomyopathy Other causes of hypertrophic cardiomyopathy (HCM) include acquired left ventricular hypertrophy and syndromic HCM. Acquired LVH can be pathologic, occurring in response to pressure overload (e.g., systemic hypertension, aortic stenosis). This type of adverse remodeling can lead to diastolic abnormalities and heart failure. Physiologic hypertrophy (athlete's heart) may result from rigorous athletic training, particularly in sports with a high static / strength building component of exercise. Such training may result in increased left ventricular wall thickness accompanied by increased left ventricular cavity size. This type of remodeling is thought to be adaptive and not associated with adverse consequences. Both pathologic and physiologic forms of acquired hypertrophy can regress if the underlying stimulus is removed (e.g., by adequate treatment of high blood pressure or a period of detraining for an athlete). Syndromic Hypertrophic Cardiomyopathy – A Select List Characteristic facies Short stature Variable developmental delay Broad, webbed neck Unusual chest shape Conduction disease Hearing loss Slowly progressive ataxia w/onset age <25 yrs Dysarthria Muscle weakness Poor feeding Macroglossia Motor delay / muscle weakness Respiratory difficulty LVNC, DCM, restrictive cardiomyopathy Arrhythmia Myofibrillar myopathy Neurogenic scapuloperoneal syndrome Limb girdle muscular dystrophy Conduction abnormalities Joint contractures Slowly progressive muscle weakness & wasting Restrictive cardiomyopathy Myofibrillar myopathy Periodic crises of pain in extremities Angiokeratomas Hypohidrosis Ocular abnormalities Proteinuria & deterioration of kidney function Skeletal myopathy Retinal dystrophy Electrophysiologic abnormalities Neonatal hypoglycemia Vacuolar myopathy Mild facial dysmorphia &/or macroglossia Slowly progressive peripheral sensorimotor neuropathy & autonomic neuropathy Vitreous opacities CNS amyloidosis AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system; DCM = dilated cardiomyopathy; HCM = hypertrophic cardiomyopathy; LVNC = left ventricular noncompaction; MOI = mode of inheritance; XL = X-linked The RASopathies are a group of syndromes that have overlapping clinical features resulting from a common pathogenetic mechanism [ Noonan syndrome is most often inherited in an autosomal dominant manner. Noonan syndrome caused by pathogenic variants in • Characteristic facies • Short stature • Variable developmental delay • Broad, webbed neck • Unusual chest shape • Conduction disease • Hearing loss • Slowly progressive ataxia w/onset age <25 yrs • Dysarthria • Muscle weakness • Poor feeding • Macroglossia • Motor delay / muscle weakness • Respiratory difficulty • LVNC, DCM, restrictive cardiomyopathy • Arrhythmia • Myofibrillar myopathy • Neurogenic scapuloperoneal syndrome • Limb girdle muscular dystrophy • Conduction abnormalities • Joint contractures • Slowly progressive muscle weakness & wasting • Restrictive cardiomyopathy • Myofibrillar myopathy • Periodic crises of pain in extremities • Angiokeratomas • Hypohidrosis • Ocular abnormalities • Proteinuria & deterioration of kidney function • Skeletal myopathy • Retinal dystrophy • Electrophysiologic abnormalities • Neonatal hypoglycemia • Vacuolar myopathy • Mild facial dysmorphia &/or macroglossia • Slowly progressive peripheral sensorimotor neuropathy & autonomic neuropathy • Vitreous opacities • CNS amyloidosis ## Acquired Left Ventricular Hypertrophy (LVH) Acquired LVH can be pathologic, occurring in response to pressure overload (e.g., systemic hypertension, aortic stenosis). This type of adverse remodeling can lead to diastolic abnormalities and heart failure. Physiologic hypertrophy (athlete's heart) may result from rigorous athletic training, particularly in sports with a high static / strength building component of exercise. Such training may result in increased left ventricular wall thickness accompanied by increased left ventricular cavity size. This type of remodeling is thought to be adaptive and not associated with adverse consequences. Both pathologic and physiologic forms of acquired hypertrophy can regress if the underlying stimulus is removed (e.g., by adequate treatment of high blood pressure or a period of detraining for an athlete). ## Syndromic HCM Syndromic Hypertrophic Cardiomyopathy – A Select List Characteristic facies Short stature Variable developmental delay Broad, webbed neck Unusual chest shape Conduction disease Hearing loss Slowly progressive ataxia w/onset age <25 yrs Dysarthria Muscle weakness Poor feeding Macroglossia Motor delay / muscle weakness Respiratory difficulty LVNC, DCM, restrictive cardiomyopathy Arrhythmia Myofibrillar myopathy Neurogenic scapuloperoneal syndrome Limb girdle muscular dystrophy Conduction abnormalities Joint contractures Slowly progressive muscle weakness & wasting Restrictive cardiomyopathy Myofibrillar myopathy Periodic crises of pain in extremities Angiokeratomas Hypohidrosis Ocular abnormalities Proteinuria & deterioration of kidney function Skeletal myopathy Retinal dystrophy Electrophysiologic abnormalities Neonatal hypoglycemia Vacuolar myopathy Mild facial dysmorphia &/or macroglossia Slowly progressive peripheral sensorimotor neuropathy & autonomic neuropathy Vitreous opacities CNS amyloidosis AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system; DCM = dilated cardiomyopathy; HCM = hypertrophic cardiomyopathy; LVNC = left ventricular noncompaction; MOI = mode of inheritance; XL = X-linked The RASopathies are a group of syndromes that have overlapping clinical features resulting from a common pathogenetic mechanism [ Noonan syndrome is most often inherited in an autosomal dominant manner. Noonan syndrome caused by pathogenic variants in • Characteristic facies • Short stature • Variable developmental delay • Broad, webbed neck • Unusual chest shape • Conduction disease • Hearing loss • Slowly progressive ataxia w/onset age <25 yrs • Dysarthria • Muscle weakness • Poor feeding • Macroglossia • Motor delay / muscle weakness • Respiratory difficulty • LVNC, DCM, restrictive cardiomyopathy • Arrhythmia • Myofibrillar myopathy • Neurogenic scapuloperoneal syndrome • Limb girdle muscular dystrophy • Conduction abnormalities • Joint contractures • Slowly progressive muscle weakness & wasting • Restrictive cardiomyopathy • Myofibrillar myopathy • Periodic crises of pain in extremities • Angiokeratomas • Hypohidrosis • Ocular abnormalities • Proteinuria & deterioration of kidney function • Skeletal myopathy • Retinal dystrophy • Electrophysiologic abnormalities • Neonatal hypoglycemia • Vacuolar myopathy • Mild facial dysmorphia &/or macroglossia • Slowly progressive peripheral sensorimotor neuropathy & autonomic neuropathy • Vitreous opacities • CNS amyloidosis ## Evaluation Strategy to Identify (when Possible) the Genetic Cause of Hypertrophic Cardiomyopathy Establishing a specific genetic cause of nonsyndromic hypertrophic cardiomyopathy (HCM): Can aid in discussions of prognosis (which are beyond the scope of this Usually involves a family history and genomic/genetic testing. The majority of causal pathogenic variants in nonsyndromic HCM are missense variants, except those 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 For an introduction to comprehensive genomic testing click • Can aid in discussions of prognosis (which are beyond the scope of this • Usually involves a family history and genomic/genetic testing. • The majority of causal pathogenic variants in nonsyndromic HCM are missense variants, except those 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 • For an introduction to comprehensive genomic testing click ## Management of Hypertrophic Cardiomyopathy Clinical practice guidelines for hypertrophic cardiomyopathy (HCM) have been published [ To establish the extent of disease and needs in an individual diagnosed with HCM, the evaluations summarized in Nonsyndromic Hypertrophic Cardiomyopathy: Recommended Evaluations Following Initial Diagnosis Cardiology eval EKG Echocardiogram HCM = hypertrophic cardiomyopathy; MOI = mode of inheritance Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Supportive care to improve quality of life, maximize function, and reduce complications is recommended [ Nonsyndromic Hypertrophic Cardiomyopathy: Treatment of Manifestations Pharmacologic therapy to alleviate symptoms, incl beta-blockers as first-line therapy & consideration of calcium channel blockers, disopyramide, & myosin inhibitors (adults only), as appropriate Septal reduction therapy (alcohol septal ablation or myectomy) can be considered when symptoms persist despite pharmacologic therapy. Assessment of risk for sudden cardiac death & appropriate use of primary prevention ICDs Antiarrhythmic drug therapy for refractory or symptomatic arrhythmias Consideration of electrophysiologic studies & ablation therapy for refractory or symptomatic arrhythmias Standard treatment, incl careful fluid & volume mgmt Assessment & mgmt of other causes of systolic dysfunction Timely consideration of cardiac transplantation or mechanical circulatory support in those w/progressive symptoms Guideline-based medical therapy for heart failure w/reduced ejection fraction & consideration of ICD placement for persistent LVEF <50% ICD = implantable cardioverter-defibrillator; LVEF = left ventricular ejection fraction; LVOTO = left ventricular outflow tract obstruction To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Nonsyndromic Hypertrophic Cardiomyopathy: Recommended Surveillance In those w/no change in clinical status & no new cardiac events beginning at diagnosis (regardless of age): repeat every 1-2 yrs In those w/new symptoms or cardiac events: repeat echocardiogram 12-lead EKG 48-hr ambulatory monitoring Should be used to assess latent LVOTO for all persons w/o resting obstruction, particularly if symptoms are present As needed to assess functional decline, or every 2-3 yrs w/o evidence of functional decline in adults & older children (age >~7-8 yrs) AF = atrial fibrillation; LVOTO = left ventricular outflow tract obstruction; SCD = sudden cardiac death Screening interval may be modified based on symptom development and/or family history. Avoid dehydration; in general use caution to stay adequately hydrated, particularly when exercising or when insensible losses are increased. Comorbidities such as hypertension, obesity, and sleep apnea may exacerbate clinical manifestations and, therefore, should be optimally managed. 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 cardiac Molecular genetic testing if the HCM-related pathogenic variant(s) in the family are known Those identified as having a familial HCM-related pathogenic variant(s) are at increased risk for HCM and should undergo cardiac evaluation with echocardiography and EKG every one to two years. In general, family members in whom the familial HCM-related pathogenic variant(s) are not detected are no longer considered to be at increased risk for HCM and thus may be discharged from high-risk cardiac surveillance. However, because families may segregate pathogenic variants in more than one HCM-related gene [ If the HCM-related pathogenic variant in the family is not known or the relative has not undergone genetic testing, physical examination, EKG, and echocardiography every two to three years for children and adolescents (starting before puberty) and every three to five years for adults is recommended [ See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. Pregnancy is generally well tolerated in individuals with nonsyndromic HCM, and maternal mortality is low (0.2%) [ There are currently many novel therapies for nonsyndromic HCM under investigation. The cardiac myosin inhibitor (CMI) mavacamten received FDA approval for use in symptomatic obstructive HCM in April 2022. CMI use for nonobstructive HCM ( Other therapeutic agents are also under investigation in those with obstructive and nonobstructive HCM. These include both novel agents ( A gene therapy trial is currently under way for symptomatic adults with Search • Cardiology eval • EKG • Echocardiogram • Pharmacologic therapy to alleviate symptoms, incl beta-blockers as first-line therapy & consideration of calcium channel blockers, disopyramide, & myosin inhibitors (adults only), as appropriate • Septal reduction therapy (alcohol septal ablation or myectomy) can be considered when symptoms persist despite pharmacologic therapy. • Assessment of risk for sudden cardiac death & appropriate use of primary prevention ICDs • Antiarrhythmic drug therapy for refractory or symptomatic arrhythmias • Consideration of electrophysiologic studies & ablation therapy for refractory or symptomatic arrhythmias • Standard treatment, incl careful fluid & volume mgmt • Assessment & mgmt of other causes of systolic dysfunction • Timely consideration of cardiac transplantation or mechanical circulatory support in those w/progressive symptoms • Guideline-based medical therapy for heart failure w/reduced ejection fraction & consideration of ICD placement for persistent LVEF <50% • In those w/no change in clinical status & no new cardiac events beginning at diagnosis (regardless of age): repeat every 1-2 yrs • In those w/new symptoms or cardiac events: repeat echocardiogram • 12-lead EKG • 48-hr ambulatory monitoring • Should be used to assess latent LVOTO for all persons w/o resting obstruction, particularly if symptoms are present • As needed to assess functional decline, or every 2-3 yrs w/o evidence of functional decline in adults & older children (age >~7-8 yrs) • Molecular genetic testing if the HCM-related pathogenic variant(s) in the family are known • Those identified as having a familial HCM-related pathogenic variant(s) are at increased risk for HCM and should undergo cardiac evaluation with echocardiography and EKG every one to two years. • In general, family members in whom the familial HCM-related pathogenic variant(s) are not detected are no longer considered to be at increased risk for HCM and thus may be discharged from high-risk cardiac surveillance. However, because families may segregate pathogenic variants in more than one HCM-related gene [ • Those identified as having a familial HCM-related pathogenic variant(s) are at increased risk for HCM and should undergo cardiac evaluation with echocardiography and EKG every one to two years. • In general, family members in whom the familial HCM-related pathogenic variant(s) are not detected are no longer considered to be at increased risk for HCM and thus may be discharged from high-risk cardiac surveillance. However, because families may segregate pathogenic variants in more than one HCM-related gene [ • If the HCM-related pathogenic variant in the family is not known or the relative has not undergone genetic testing, physical examination, EKG, and echocardiography every two to three years for children and adolescents (starting before puberty) and every three to five years for adults is recommended [ • Those identified as having a familial HCM-related pathogenic variant(s) are at increased risk for HCM and should undergo cardiac evaluation with echocardiography and EKG every one to two years. • In general, family members in whom the familial HCM-related pathogenic variant(s) are not detected are no longer considered to be at increased risk for HCM and thus may be discharged from high-risk cardiac surveillance. However, because families may segregate pathogenic variants in more than one HCM-related gene [ ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with HCM, the evaluations summarized in Nonsyndromic Hypertrophic Cardiomyopathy: Recommended Evaluations Following Initial Diagnosis Cardiology eval EKG Echocardiogram HCM = hypertrophic cardiomyopathy; MOI = mode of inheritance Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Cardiology eval • EKG • Echocardiogram ## Treatment of Manifestations Supportive care to improve quality of life, maximize function, and reduce complications is recommended [ Nonsyndromic Hypertrophic Cardiomyopathy: Treatment of Manifestations Pharmacologic therapy to alleviate symptoms, incl beta-blockers as first-line therapy & consideration of calcium channel blockers, disopyramide, & myosin inhibitors (adults only), as appropriate Septal reduction therapy (alcohol septal ablation or myectomy) can be considered when symptoms persist despite pharmacologic therapy. Assessment of risk for sudden cardiac death & appropriate use of primary prevention ICDs Antiarrhythmic drug therapy for refractory or symptomatic arrhythmias Consideration of electrophysiologic studies & ablation therapy for refractory or symptomatic arrhythmias Standard treatment, incl careful fluid & volume mgmt Assessment & mgmt of other causes of systolic dysfunction Timely consideration of cardiac transplantation or mechanical circulatory support in those w/progressive symptoms Guideline-based medical therapy for heart failure w/reduced ejection fraction & consideration of ICD placement for persistent LVEF <50% ICD = implantable cardioverter-defibrillator; LVEF = left ventricular ejection fraction; LVOTO = left ventricular outflow tract obstruction • Pharmacologic therapy to alleviate symptoms, incl beta-blockers as first-line therapy & consideration of calcium channel blockers, disopyramide, & myosin inhibitors (adults only), as appropriate • Septal reduction therapy (alcohol septal ablation or myectomy) can be considered when symptoms persist despite pharmacologic therapy. • Assessment of risk for sudden cardiac death & appropriate use of primary prevention ICDs • Antiarrhythmic drug therapy for refractory or symptomatic arrhythmias • Consideration of electrophysiologic studies & ablation therapy for refractory or symptomatic arrhythmias • Standard treatment, incl careful fluid & volume mgmt • Assessment & mgmt of other causes of systolic dysfunction • Timely consideration of cardiac transplantation or mechanical circulatory support in those w/progressive symptoms • Guideline-based medical therapy for heart failure w/reduced ejection fraction & consideration of ICD placement for persistent LVEF <50% ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Nonsyndromic Hypertrophic Cardiomyopathy: Recommended Surveillance In those w/no change in clinical status & no new cardiac events beginning at diagnosis (regardless of age): repeat every 1-2 yrs In those w/new symptoms or cardiac events: repeat echocardiogram 12-lead EKG 48-hr ambulatory monitoring Should be used to assess latent LVOTO for all persons w/o resting obstruction, particularly if symptoms are present As needed to assess functional decline, or every 2-3 yrs w/o evidence of functional decline in adults & older children (age >~7-8 yrs) AF = atrial fibrillation; LVOTO = left ventricular outflow tract obstruction; SCD = sudden cardiac death Screening interval may be modified based on symptom development and/or family history. • In those w/no change in clinical status & no new cardiac events beginning at diagnosis (regardless of age): repeat every 1-2 yrs • In those w/new symptoms or cardiac events: repeat echocardiogram • 12-lead EKG • 48-hr ambulatory monitoring • Should be used to assess latent LVOTO for all persons w/o resting obstruction, particularly if symptoms are present • As needed to assess functional decline, or every 2-3 yrs w/o evidence of functional decline in adults & older children (age >~7-8 yrs) ## Agents/Circumstances to Avoid Avoid dehydration; in general use caution to stay adequately hydrated, particularly when exercising or when insensible losses are increased. Comorbidities such as hypertension, obesity, and sleep apnea may exacerbate clinical manifestations and, therefore, should be optimally managed. ## Evaluation and Surveillance 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 cardiac Molecular genetic testing if the HCM-related pathogenic variant(s) in the family are known Those identified as having a familial HCM-related pathogenic variant(s) are at increased risk for HCM and should undergo cardiac evaluation with echocardiography and EKG every one to two years. In general, family members in whom the familial HCM-related pathogenic variant(s) are not detected are no longer considered to be at increased risk for HCM and thus may be discharged from high-risk cardiac surveillance. However, because families may segregate pathogenic variants in more than one HCM-related gene [ If the HCM-related pathogenic variant in the family is not known or the relative has not undergone genetic testing, physical examination, EKG, and echocardiography every two to three years for children and adolescents (starting before puberty) and every three to five years for adults is recommended [ See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. • Molecular genetic testing if the HCM-related pathogenic variant(s) in the family are known • Those identified as having a familial HCM-related pathogenic variant(s) are at increased risk for HCM and should undergo cardiac evaluation with echocardiography and EKG every one to two years. • In general, family members in whom the familial HCM-related pathogenic variant(s) are not detected are no longer considered to be at increased risk for HCM and thus may be discharged from high-risk cardiac surveillance. However, because families may segregate pathogenic variants in more than one HCM-related gene [ • Those identified as having a familial HCM-related pathogenic variant(s) are at increased risk for HCM and should undergo cardiac evaluation with echocardiography and EKG every one to two years. • In general, family members in whom the familial HCM-related pathogenic variant(s) are not detected are no longer considered to be at increased risk for HCM and thus may be discharged from high-risk cardiac surveillance. However, because families may segregate pathogenic variants in more than one HCM-related gene [ • If the HCM-related pathogenic variant in the family is not known or the relative has not undergone genetic testing, physical examination, EKG, and echocardiography every two to three years for children and adolescents (starting before puberty) and every three to five years for adults is recommended [ • Those identified as having a familial HCM-related pathogenic variant(s) are at increased risk for HCM and should undergo cardiac evaluation with echocardiography and EKG every one to two years. • In general, family members in whom the familial HCM-related pathogenic variant(s) are not detected are no longer considered to be at increased risk for HCM and thus may be discharged from high-risk cardiac surveillance. However, because families may segregate pathogenic variants in more than one HCM-related gene [ ## Pregnancy Management Pregnancy is generally well tolerated in individuals with nonsyndromic HCM, and maternal mortality is low (0.2%) [ ## Therapies Under Investigation There are currently many novel therapies for nonsyndromic HCM under investigation. The cardiac myosin inhibitor (CMI) mavacamten received FDA approval for use in symptomatic obstructive HCM in April 2022. CMI use for nonobstructive HCM ( Other therapeutic agents are also under investigation in those with obstructive and nonobstructive HCM. These include both novel agents ( A gene therapy trial is currently under way for symptomatic adults with Search ## Genetic Counseling of Family Members of an Individual with Nonsyndromic Hypertrophic Cardiomyopathy Nonsyndromic hypertrophic cardiomyopathy (HCM) is typically inherited in an autosomal dominant manner; pathogenic variants in genes associated with autosomal recessive or mitochondrial inheritance have been less commonly reported (see Some individuals diagnosed with autosomal dominant nonsyndromic HCM have an affected parent. Some individuals diagnosed with autosomal dominant nonsyndromic HCM have the disorder as the result of a An individual with nonsyndromic HCM may have pathogenic variants in more than one HCM-related gene. In a study involving 1,279 individuals with nonsyndromic HCM of known genetic cause, 34 (~3%) individuals had pathogenic / likely pathogenic variants in two or more genes that encode a component of the sarcomere [ If the proband appears to be the only family member with nonsyndromic HCM (i.e., a simplex case), recommendations for the evaluation of the parents of the proband include molecular genetic testing (if the HCM-related pathogenic variant has been identified in the proband), physical examination, EKG, and echocardiogram by a cardiologist familiar with HCM. Note: Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in asymptomatic or mildly symptomatic family members, early death of the parent before the onset of symptoms, late onset of the disease in the affected parent, or reduced penetrance. Therefore, If the HCM-related 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 [ If a parent of the proband is affected and/or is known to have the autosomal dominant nonsyndromic HCM-related pathogenic variant identified in the proband, the risk to sibs of inheriting the pathogenic variant is 50%. Sibs who inherit an autosomal dominant nonsyndromic HCM-related pathogenic variant have an increased risk of developing nonsyndromic HCM. Penetrance is estimated to be 50%-62% in at-risk relatives who are heterozygous for a familial HCM-related pathogenic variant (see If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be slightly greater than that of the general population because of the possibility of parental gonadal mosaicism [ If the proband represents a simplex case and the parents are clinically unaffected (based on appropriate cardiac evaluation) but their genetic status is unknown, sibs are still presumed to be at increased risk for nonsyndromic HCM because of the possibility of reduced penetrance in a heterozygous parent or parental gonadal mosaicism. The parents of an individual with autosomal recessive nonsyndromic HCM are presumed to be heterozygous for a nonsyndromic HCM-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 nonsyndromic HCM-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, risk of disease in heterozygotes (carriers) is not increased over that of the general population; however, individuals who are heterozygous for a pathogenic variant in If both parents are known to be heterozygous for an autosomal recessive nonsyndromic HCM-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 HCM-related pathogenic variants. Typically, the risk of disease in heterozygotes (carriers) is not increased over that of the general population; however, however, individuals who are heterozygous for a pathogenic variant in See Management, • Some individuals diagnosed with autosomal dominant nonsyndromic HCM have an affected parent. • Some individuals diagnosed with autosomal dominant nonsyndromic HCM have the disorder as the result of a • An individual with nonsyndromic HCM may have pathogenic variants in more than one HCM-related gene. In a study involving 1,279 individuals with nonsyndromic HCM of known genetic cause, 34 (~3%) individuals had pathogenic / likely pathogenic variants in two or more genes that encode a component of the sarcomere [ • If the proband appears to be the only family member with nonsyndromic HCM (i.e., a simplex case), recommendations for the evaluation of the parents of the proband include molecular genetic testing (if the HCM-related pathogenic variant has been identified in the proband), physical examination, EKG, and echocardiogram by a cardiologist familiar with HCM. Note: Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in asymptomatic or mildly symptomatic family members, early death of the parent before the onset of symptoms, late onset of the disease in the affected parent, or reduced penetrance. Therefore, • If the HCM-related 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 [ • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [ • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [ • If a parent of the proband is affected and/or is known to have the autosomal dominant nonsyndromic HCM-related pathogenic variant identified in the proband, the risk to sibs of inheriting the pathogenic variant is 50%. • Sibs who inherit an autosomal dominant nonsyndromic HCM-related pathogenic variant have an increased risk of developing nonsyndromic HCM. Penetrance is estimated to be 50%-62% in at-risk relatives who are heterozygous for a familial HCM-related pathogenic variant (see • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be slightly greater than that of the general population because of the possibility of parental gonadal mosaicism [ • If the proband represents a simplex case and the parents are clinically unaffected (based on appropriate cardiac evaluation) but their genetic status is unknown, sibs are still presumed to be at increased risk for nonsyndromic HCM because of the possibility of reduced penetrance in a heterozygous parent or parental gonadal mosaicism. • The parents of an individual with autosomal recessive nonsyndromic HCM are presumed to be heterozygous for a nonsyndromic HCM-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 nonsyndromic HCM-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, risk of disease in heterozygotes (carriers) is not increased over that of the general population; however, 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 an autosomal recessive nonsyndromic HCM-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 HCM-related pathogenic variants. • Typically, the risk of disease in heterozygotes (carriers) is not increased over that of the general population; however, however, individuals who are heterozygous for a pathogenic variant in ## Mode of Inheritance Nonsyndromic hypertrophic cardiomyopathy (HCM) is typically inherited in an autosomal dominant manner; pathogenic variants in genes associated with autosomal recessive or mitochondrial inheritance have been less commonly reported (see ## Autosomal Dominant Inheritance – Risk to Family Members Some individuals diagnosed with autosomal dominant nonsyndromic HCM have an affected parent. Some individuals diagnosed with autosomal dominant nonsyndromic HCM have the disorder as the result of a An individual with nonsyndromic HCM may have pathogenic variants in more than one HCM-related gene. In a study involving 1,279 individuals with nonsyndromic HCM of known genetic cause, 34 (~3%) individuals had pathogenic / likely pathogenic variants in two or more genes that encode a component of the sarcomere [ If the proband appears to be the only family member with nonsyndromic HCM (i.e., a simplex case), recommendations for the evaluation of the parents of the proband include molecular genetic testing (if the HCM-related pathogenic variant has been identified in the proband), physical examination, EKG, and echocardiogram by a cardiologist familiar with HCM. Note: Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in asymptomatic or mildly symptomatic family members, early death of the parent before the onset of symptoms, late onset of the disease in the affected parent, or reduced penetrance. Therefore, If the HCM-related 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 [ If a parent of the proband is affected and/or is known to have the autosomal dominant nonsyndromic HCM-related pathogenic variant identified in the proband, the risk to sibs of inheriting the pathogenic variant is 50%. Sibs who inherit an autosomal dominant nonsyndromic HCM-related pathogenic variant have an increased risk of developing nonsyndromic HCM. Penetrance is estimated to be 50%-62% in at-risk relatives who are heterozygous for a familial HCM-related pathogenic variant (see If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be slightly greater than that of the general population because of the possibility of parental gonadal mosaicism [ If the proband represents a simplex case and the parents are clinically unaffected (based on appropriate cardiac evaluation) but their genetic status is unknown, sibs are still presumed to be at increased risk for nonsyndromic HCM because of the possibility of reduced penetrance in a heterozygous parent or parental gonadal mosaicism. • Some individuals diagnosed with autosomal dominant nonsyndromic HCM have an affected parent. • Some individuals diagnosed with autosomal dominant nonsyndromic HCM have the disorder as the result of a • An individual with nonsyndromic HCM may have pathogenic variants in more than one HCM-related gene. In a study involving 1,279 individuals with nonsyndromic HCM of known genetic cause, 34 (~3%) individuals had pathogenic / likely pathogenic variants in two or more genes that encode a component of the sarcomere [ • If the proband appears to be the only family member with nonsyndromic HCM (i.e., a simplex case), recommendations for the evaluation of the parents of the proband include molecular genetic testing (if the HCM-related pathogenic variant has been identified in the proband), physical examination, EKG, and echocardiogram by a cardiologist familiar with HCM. Note: Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in asymptomatic or mildly symptomatic family members, early death of the parent before the onset of symptoms, late onset of the disease in the affected parent, or reduced penetrance. Therefore, • If the HCM-related 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 [ • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [ • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [ • If a parent of the proband is affected and/or is known to have the autosomal dominant nonsyndromic HCM-related pathogenic variant identified in the proband, the risk to sibs of inheriting the pathogenic variant is 50%. • Sibs who inherit an autosomal dominant nonsyndromic HCM-related pathogenic variant have an increased risk of developing nonsyndromic HCM. Penetrance is estimated to be 50%-62% in at-risk relatives who are heterozygous for a familial HCM-related pathogenic variant (see • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be slightly greater than that of the general population because of the possibility of parental gonadal mosaicism [ • If the proband represents a simplex case and the parents are clinically unaffected (based on appropriate cardiac evaluation) but their genetic status is unknown, sibs are still presumed to be at increased risk for nonsyndromic HCM 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 an individual with autosomal recessive nonsyndromic HCM are presumed to be heterozygous for a nonsyndromic HCM-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 nonsyndromic HCM-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, risk of disease in heterozygotes (carriers) is not increased over that of the general population; however, individuals who are heterozygous for a pathogenic variant in If both parents are known to be heterozygous for an autosomal recessive nonsyndromic HCM-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 HCM-related pathogenic variants. Typically, the risk of disease in heterozygotes (carriers) is not increased over that of the general population; however, however, individuals who are heterozygous for a pathogenic variant in • The parents of an individual with autosomal recessive nonsyndromic HCM are presumed to be heterozygous for a nonsyndromic HCM-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 nonsyndromic HCM-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, risk of disease in heterozygotes (carriers) is not increased over that of the general population; however, 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 an autosomal recessive nonsyndromic HCM-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 HCM-related pathogenic variants. • Typically, the risk of disease in heterozygotes (carriers) is not increased over that of the general population; however, however, individuals who are heterozygous for a pathogenic variant in ## Related Genetic Counseling Issues See Management, ## Resources United Kingdom • • • • • • • • United Kingdom • • • ## Chapter Notes 6 March 2025 (sw) Comprehensive update posted live 6 June 2019 (ha) Comprehensive update posted live 16 January 2014 (me) Comprehensive update posted live 5 August 2008 (me) Review posted live 11 June 2007 (ac) Original submission • 6 March 2025 (sw) Comprehensive update posted live • 6 June 2019 (ha) Comprehensive update posted live • 16 January 2014 (me) Comprehensive update posted live • 5 August 2008 (me) Review posted live • 11 June 2007 (ac) Original submission ## Author Notes ## Revision History 6 March 2025 (sw) Comprehensive update posted live 6 June 2019 (ha) Comprehensive update posted live 16 January 2014 (me) Comprehensive update posted live 5 August 2008 (me) Review posted live 11 June 2007 (ac) Original submission • 6 March 2025 (sw) Comprehensive update posted live • 6 June 2019 (ha) Comprehensive update posted live • 16 January 2014 (me) Comprehensive update posted live • 5 August 2008 (me) Review posted live • 11 June 2007 (ac) Original submission ## References Colan SD, Lipshultz SE, Lowe AM, Sleeper LA, Messere J, Cox GF, Lurie PR, Orav EJ, Towbin JA. Epidemiology and case-specific outcomes in hypertrophic cardiomyopathy in children: findings from the Pediatric Cardiomyopathy Registry. Circulation. 2007;115:773-81. [ Elliott PM ,Anastasakis A, Borger MA, Borggrefe M, Cecchi F, Charron P, Hagege AA, Lafont A, Limongelli G, Mahrholdt H, McKenna WJ, Mogensen J, Nihoyannopoulos P, Nistri S, Pieper PG, Pieske B, Rapezzi C, Rutten FH, Tillmanns C, Watkins H. 2014 ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy. Eur Heart J. 2014;35:2733-79. [ Garratt CJ, Elliott P, Behr E, Camm AJ, Cowan C, Cruickshank S, Grace A, Griffith MJ, Jolly A, Lambiase P, McKeown P, O'Callagan P, Stuart G, Watkins H. Heart Rhythm UK position statement on clinical indications for implantable cardioverter defibrillators in adult patients with familial sudden cardiac death syndrome. Europace. 2010;12:1156-75. [ Ommen SR, Ho CY, Asif IM, Balaji S, Burke MA, Day SM, Dearani JA, Epps KC, Evanovich L, Ferrari VA, Joglar JA, Khan SS, Kim JJ, Kittleson MM, Krittanawong C, Martinez MW, Mital S, Naidu SS, Saberi S, Semsarian C, Times S, Waldman CB. AHA/ACC/AMSSM/HRS/PACES/SCMR guideline for the management of hypertrophic cardiomyopathy: a report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2024;83:2324-405. [ • Colan SD, Lipshultz SE, Lowe AM, Sleeper LA, Messere J, Cox GF, Lurie PR, Orav EJ, Towbin JA. Epidemiology and case-specific outcomes in hypertrophic cardiomyopathy in children: findings from the Pediatric Cardiomyopathy Registry. Circulation. 2007;115:773-81. [ • Elliott PM ,Anastasakis A, Borger MA, Borggrefe M, Cecchi F, Charron P, Hagege AA, Lafont A, Limongelli G, Mahrholdt H, McKenna WJ, Mogensen J, Nihoyannopoulos P, Nistri S, Pieper PG, Pieske B, Rapezzi C, Rutten FH, Tillmanns C, Watkins H. 2014 ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy. Eur Heart J. 2014;35:2733-79. [ • Garratt CJ, Elliott P, Behr E, Camm AJ, Cowan C, Cruickshank S, Grace A, Griffith MJ, Jolly A, Lambiase P, McKeown P, O'Callagan P, Stuart G, Watkins H. Heart Rhythm UK position statement on clinical indications for implantable cardioverter defibrillators in adult patients with familial sudden cardiac death syndrome. Europace. 2010;12:1156-75. [ • Ommen SR, Ho CY, Asif IM, Balaji S, Burke MA, Day SM, Dearani JA, Epps KC, Evanovich L, Ferrari VA, Joglar JA, Khan SS, Kim JJ, Kittleson MM, Krittanawong C, Martinez MW, Mital S, Naidu SS, Saberi S, Semsarian C, Times S, Waldman CB. AHA/ACC/AMSSM/HRS/PACES/SCMR guideline for the management of hypertrophic cardiomyopathy: a report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2024;83:2324-405. [ ## Published Guidelines / Consensus Statements Colan SD, Lipshultz SE, Lowe AM, Sleeper LA, Messere J, Cox GF, Lurie PR, Orav EJ, Towbin JA. Epidemiology and case-specific outcomes in hypertrophic cardiomyopathy in children: findings from the Pediatric Cardiomyopathy Registry. Circulation. 2007;115:773-81. [ Elliott PM ,Anastasakis A, Borger MA, Borggrefe M, Cecchi F, Charron P, Hagege AA, Lafont A, Limongelli G, Mahrholdt H, McKenna WJ, Mogensen J, Nihoyannopoulos P, Nistri S, Pieper PG, Pieske B, Rapezzi C, Rutten FH, Tillmanns C, Watkins H. 2014 ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy. Eur Heart J. 2014;35:2733-79. [ Garratt CJ, Elliott P, Behr E, Camm AJ, Cowan C, Cruickshank S, Grace A, Griffith MJ, Jolly A, Lambiase P, McKeown P, O'Callagan P, Stuart G, Watkins H. Heart Rhythm UK position statement on clinical indications for implantable cardioverter defibrillators in adult patients with familial sudden cardiac death syndrome. Europace. 2010;12:1156-75. [ Ommen SR, Ho CY, Asif IM, Balaji S, Burke MA, Day SM, Dearani JA, Epps KC, Evanovich L, Ferrari VA, Joglar JA, Khan SS, Kim JJ, Kittleson MM, Krittanawong C, Martinez MW, Mital S, Naidu SS, Saberi S, Semsarian C, Times S, Waldman CB. AHA/ACC/AMSSM/HRS/PACES/SCMR guideline for the management of hypertrophic cardiomyopathy: a report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2024;83:2324-405. [ • Colan SD, Lipshultz SE, Lowe AM, Sleeper LA, Messere J, Cox GF, Lurie PR, Orav EJ, Towbin JA. Epidemiology and case-specific outcomes in hypertrophic cardiomyopathy in children: findings from the Pediatric Cardiomyopathy Registry. Circulation. 2007;115:773-81. [ • Elliott PM ,Anastasakis A, Borger MA, Borggrefe M, Cecchi F, Charron P, Hagege AA, Lafont A, Limongelli G, Mahrholdt H, McKenna WJ, Mogensen J, Nihoyannopoulos P, Nistri S, Pieper PG, Pieske B, Rapezzi C, Rutten FH, Tillmanns C, Watkins H. 2014 ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy. Eur Heart J. 2014;35:2733-79. [ • Garratt CJ, Elliott P, Behr E, Camm AJ, Cowan C, Cruickshank S, Grace A, Griffith MJ, Jolly A, Lambiase P, McKeown P, O'Callagan P, Stuart G, Watkins H. Heart Rhythm UK position statement on clinical indications for implantable cardioverter defibrillators in adult patients with familial sudden cardiac death syndrome. Europace. 2010;12:1156-75. [ • Ommen SR, Ho CY, Asif IM, Balaji S, Burke MA, Day SM, Dearani JA, Epps KC, Evanovich L, Ferrari VA, Joglar JA, Khan SS, Kim JJ, Kittleson MM, Krittanawong C, Martinez MW, Mital S, Naidu SS, Saberi S, Semsarian C, Times S, Waldman CB. AHA/ACC/AMSSM/HRS/PACES/SCMR guideline for the management of hypertrophic cardiomyopathy: a report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2024;83:2324-405. [ ## Literature Cited	[]	5/8/2008	6/3/2025	8/7/2021	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
hyper-ftc	hyper-ftc	[ "Familial Tumoral Calcinosis/Hyperostosis-Hyperphosphatemia Syndrome (FTC/HHS)", "HFTC", "Hyperostosis-Hyperphosphatemia Syndrome", "Primary Hyperphosphatemic Tumoral Calcinosis", "Familial Tumoral Calcinosis/Hyperostosis-Hyperphosphatemia Syndrome (FTC/HHS)", "HFTC", "Hyperostosis-Hyperphosphatemia Syndrome", "Primary Hyperphosphatemic Tumoral Calcinosis", "Fibroblast growth factor 23", "Klotho", "Polypeptide N-acetylgalactosaminyltransferase 3", "FGF23", "GALNT3", "KL", "Hyperphosphatemic Familial Tumoral Calcinosis" ]	Hyperphosphatemic Familial Tumoral Calcinosis	Mary Scott Ramnitz, Rachel I Gafni, Michael T Collins	Summary Hyperphosphatemic familial tumoral calcinosis (HFTC) is characterized by: Ectopic calcifications (tumoral calcinosis) typically found in periarticular soft tissues exposed to repetitive trauma or prolonged pressure (e.g., hips, elbows, and shoulders); and Painful swellings (referred to as hyperostosis) in the areas overlying the diaphyses of the tibiae (and less often the ulna, metacarpal bones, and radius). The dental phenotype unique to HFTC includes enamel hypoplasia, short and bulbous roots, obliteration of pulp chambers and canals, and pulp stones. Less common are large and small vessel calcifications that are often asymptomatic incidental findings on radiologic studies but can also cause peripheral vascular insufficiency (e.g., pain, cold extremities, and decreased peripheral pulses). Less frequently reported findings include testicular microlithiasis and angioid streaks of the retina. HFTC results from a relative deficiency of – or resistance to – the phosphate-regulating hormone, fibroblast growth factor 23 (FGF23). The clinical diagnosis of HFTC is established by the presence of tumoral calcinosis and/or characteristic laboratory findings of hyperphosphatemia in the setting of inappropriately increased renal tubular reabsorption of phosphorus (TRP), elevated or inappropriately normal 1,25-dihydroxyvitamin D HFTC 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 Hyperphosphatemic familial tumoral calcinosis (HFTC) Hyperphosphatemia Inappropriately increased renal tubular reabsorption of phosphorus (TRP) Elevated or inappropriately normal 1,25-dihydroxyvitamin D Renal function and serum calcium levels typically normal Parathyroid hormone levels tend to be at the lower end of the normal range. Elevated plasma levels of the C-terminal portion of the phosphate-regulating hormone, fibroblast growth factor 23 (FGF23): measured (in clinical laboratories) by enzyme-linked immunosorbent assay (ELISA) utilizing antibodies that bind to the C-terminal portion of FGF23; detecting the combination of the biologically active intact hormone and the biologically inactive C-terminal fragments Note: Assays to measure intact FGF23 are currently available in research laboratories only. Intact FGF23 is low or inappropriately normal with The diagnosis of HFTC Identification of biallelic germline loss-of-function variants in Molecular testing approaches can include Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Persons with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of HFTC, molecular genetic testing approaches can include Use of a For an introduction to multigene panels click In the event that the diagnosis of HFTC has not been considered, comprehensive genomic testing (which includes exome sequencing and genome sequencing) is likely to be the diagnostic modality selected. For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Hyperphosphatemic Familial Tumoral Calcinosis See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. One large deletion has been reported [ See One individual with the typical clinical and biochemical phenotype of HFTC did not have pathogenic variants in either One individual with the typical clinical and biochemical phenotype of HFTC did not have pathogenic variants in either • Hyperphosphatemia • Inappropriately increased renal tubular reabsorption of phosphorus (TRP) • Elevated or inappropriately normal 1,25-dihydroxyvitamin D • Renal function and serum calcium levels typically normal • Parathyroid hormone levels tend to be at the lower end of the normal range. • Elevated plasma levels of the C-terminal portion of the phosphate-regulating hormone, fibroblast growth factor 23 (FGF23): measured (in clinical laboratories) by enzyme-linked immunosorbent assay (ELISA) utilizing antibodies that bind to the C-terminal portion of FGF23; detecting the combination of the biologically active intact hormone and the biologically inactive C-terminal fragments • Note: Assays to measure intact FGF23 are currently available in research laboratories only. Intact FGF23 is low or inappropriately normal with • Use of a • For an introduction to multigene panels click ## Suggestive Findings Hyperphosphatemic familial tumoral calcinosis (HFTC) Hyperphosphatemia Inappropriately increased renal tubular reabsorption of phosphorus (TRP) Elevated or inappropriately normal 1,25-dihydroxyvitamin D Renal function and serum calcium levels typically normal Parathyroid hormone levels tend to be at the lower end of the normal range. Elevated plasma levels of the C-terminal portion of the phosphate-regulating hormone, fibroblast growth factor 23 (FGF23): measured (in clinical laboratories) by enzyme-linked immunosorbent assay (ELISA) utilizing antibodies that bind to the C-terminal portion of FGF23; detecting the combination of the biologically active intact hormone and the biologically inactive C-terminal fragments Note: Assays to measure intact FGF23 are currently available in research laboratories only. Intact FGF23 is low or inappropriately normal with • Hyperphosphatemia • Inappropriately increased renal tubular reabsorption of phosphorus (TRP) • Elevated or inappropriately normal 1,25-dihydroxyvitamin D • Renal function and serum calcium levels typically normal • Parathyroid hormone levels tend to be at the lower end of the normal range. • Elevated plasma levels of the C-terminal portion of the phosphate-regulating hormone, fibroblast growth factor 23 (FGF23): measured (in clinical laboratories) by enzyme-linked immunosorbent assay (ELISA) utilizing antibodies that bind to the C-terminal portion of FGF23; detecting the combination of the biologically active intact hormone and the biologically inactive C-terminal fragments • Note: Assays to measure intact FGF23 are currently available in research laboratories only. Intact FGF23 is low or inappropriately normal with ## Clinical Findings ## Laboratory Findings Hyperphosphatemia Inappropriately increased renal tubular reabsorption of phosphorus (TRP) Elevated or inappropriately normal 1,25-dihydroxyvitamin D Renal function and serum calcium levels typically normal Parathyroid hormone levels tend to be at the lower end of the normal range. Elevated plasma levels of the C-terminal portion of the phosphate-regulating hormone, fibroblast growth factor 23 (FGF23): measured (in clinical laboratories) by enzyme-linked immunosorbent assay (ELISA) utilizing antibodies that bind to the C-terminal portion of FGF23; detecting the combination of the biologically active intact hormone and the biologically inactive C-terminal fragments Note: Assays to measure intact FGF23 are currently available in research laboratories only. Intact FGF23 is low or inappropriately normal with • Hyperphosphatemia • Inappropriately increased renal tubular reabsorption of phosphorus (TRP) • Elevated or inappropriately normal 1,25-dihydroxyvitamin D • Renal function and serum calcium levels typically normal • Parathyroid hormone levels tend to be at the lower end of the normal range. • Elevated plasma levels of the C-terminal portion of the phosphate-regulating hormone, fibroblast growth factor 23 (FGF23): measured (in clinical laboratories) by enzyme-linked immunosorbent assay (ELISA) utilizing antibodies that bind to the C-terminal portion of FGF23; detecting the combination of the biologically active intact hormone and the biologically inactive C-terminal fragments • Note: Assays to measure intact FGF23 are currently available in research laboratories only. Intact FGF23 is low or inappropriately normal with ## Radiographs ## Computed Tomography (CT) ## Establishing the Diagnosis The diagnosis of HFTC Identification of biallelic germline loss-of-function variants in Molecular testing approaches can include Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Persons with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of HFTC, molecular genetic testing approaches can include Use of a For an introduction to multigene panels click In the event that the diagnosis of HFTC has not been considered, comprehensive genomic testing (which includes exome sequencing and genome sequencing) is likely to be the diagnostic modality selected. For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Hyperphosphatemic Familial Tumoral Calcinosis See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. One large deletion has been reported [ See One individual with the typical clinical and biochemical phenotype of HFTC did not have pathogenic variants in either One individual with the typical clinical and biochemical phenotype of HFTC did not have pathogenic variants in either • Use of a • For an introduction to multigene panels click ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of HFTC, molecular genetic testing approaches can include Use of a For an introduction to multigene panels click • Use of a • For an introduction to multigene panels click ## Option 2 In the event that the diagnosis of HFTC has not been considered, comprehensive genomic testing (which includes exome sequencing and genome sequencing) is likely to be the diagnostic modality selected. For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Hyperphosphatemic Familial Tumoral Calcinosis See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. One large deletion has been reported [ See One individual with the typical clinical and biochemical phenotype of HFTC did not have pathogenic variants in either One individual with the typical clinical and biochemical phenotype of HFTC did not have pathogenic variants in either ## Clinical Characteristics Hyperphosphatemic familial tumoral calcinosis (HFTC) is characterized most commonly by tumoral calcinosis or ectopic calcifications (typically in periarticular soft tissues exposed to repetitive trauma or prolonged pressure) and hyperostosis (typically manifesting as painful swelling overlying the diaphyses of long bones). Onset of lesions typically occurs in the first two decades of life. The dental phenotype unique to HFTC includes enamel hypoplasia, short and bulbous roots, pulp chamber and canal obliterations, and pulp stones. Less frequently reported findings include large and small vessel calcifications, testicular microlithiasis, and angioid streaks of the retina. HFTC results from a relative deficiency of or resistance to the phosphate-regulating hormone FGF23, leading to hyperphosphatemia due to increased renal phosphate reabsorption and elevated or inappropriately normal 1,25D production, which promotes gastrointestinal absorption of phosphorus and calcium (for more details see In a review of the medical literature, Since the For unknown reasons, the manifestations of HFTC vary among family members with the same pathogenic variants and genetic background and similar biochemical profiles. One member may have profound, extensive tumoral calcinosis while others are symptom free [ These lesions can be extremely painful and debilitating; some may progress in size, perforate the skin, and drain liquid hydroxyapatite (also known as "milk of calcium"), which is often confused with purulent drainage. Such lesions often heal poorly. Depending on the size and location, tumoral calcinosis can significantly impair range of motion or lead to frozen joints. Some patients experience repeat episodes of diaphysitis (inflammation of the shaft of a long bone) involving a number of sites including the ulna, tibia, metacarpal bones, and radius [ Biopsies of hyperostosis lesions demonstrate reactive new bone surrounded by fibroblastic stroma infiltrated with plasma cells, lymphocytes, and polymorphonuclear cells; cultures are negative [ The calcifications are often incidental findings on radiologic studies, and patients are often asymptomatic. Some patients have significant symptoms of peripheral vascular insufficiency such as pain, cold extremities, and decreased peripheral pulses. Small to large vessel calcifications have been identified in variable anatomic locations including the cerebral vasculature, lower-extremity vasculature ( Dental findings, reported to be the presenting sign in some individuals [ Five individuals have had elevated markers of inflammation; i.e., C-reactive protein (CRP) and/or erythrocyte sedimentation rate (ESR) [ Vascular calcifications appear to be more frequent in persons with biallelic Deficiency of or resistance to FGF23 leads to hyperphosphatemia resulting in increased renal phosphate reabsorption and elevated or inappropriately normal 1,25D production, which promotes gastrointestinal absorption of phosphorus and calcium. Thereby increased blood calcium X phosphate product, calculated by multiplying the blood calcium (mg/dL) by the blood phosphate (mg/dL), predisposes to ectopic soft-tissue calcification in tissues exposed to trauma or inflammation. In persons with renal insufficiency (where this product is most commonly clinically utilized), the incidence of soft-tissue calcification is increased when the calcium X phosphate product exceeds 70 mg No genotype-phenotype correlations are known. Sibs with the same Treatment response does not appear to vary by genotype. In the past, hyperphosphatemic familial tumoral calcinosis (HFTC) has been referred to as the following: Lipocalcinogranulomatosis Teutschlaender's lipocalcinogranulomatosis Morbus Teutschländer No formal study has estimated the prevalence of HFTC; the disorder is rare. To date, 75 individuals with a molecularly confirmed diagnosis of HFTC have been reported in the medical literature with an increased propensity in Africa and the Middle East and in populations originating from these regions [ • Sibs with the same • Treatment response does not appear to vary by genotype. • Lipocalcinogranulomatosis • Teutschlaender's lipocalcinogranulomatosis • Morbus Teutschländer ## Clinical Description Hyperphosphatemic familial tumoral calcinosis (HFTC) is characterized most commonly by tumoral calcinosis or ectopic calcifications (typically in periarticular soft tissues exposed to repetitive trauma or prolonged pressure) and hyperostosis (typically manifesting as painful swelling overlying the diaphyses of long bones). Onset of lesions typically occurs in the first two decades of life. The dental phenotype unique to HFTC includes enamel hypoplasia, short and bulbous roots, pulp chamber and canal obliterations, and pulp stones. Less frequently reported findings include large and small vessel calcifications, testicular microlithiasis, and angioid streaks of the retina. HFTC results from a relative deficiency of or resistance to the phosphate-regulating hormone FGF23, leading to hyperphosphatemia due to increased renal phosphate reabsorption and elevated or inappropriately normal 1,25D production, which promotes gastrointestinal absorption of phosphorus and calcium (for more details see In a review of the medical literature, Since the For unknown reasons, the manifestations of HFTC vary among family members with the same pathogenic variants and genetic background and similar biochemical profiles. One member may have profound, extensive tumoral calcinosis while others are symptom free [ These lesions can be extremely painful and debilitating; some may progress in size, perforate the skin, and drain liquid hydroxyapatite (also known as "milk of calcium"), which is often confused with purulent drainage. Such lesions often heal poorly. Depending on the size and location, tumoral calcinosis can significantly impair range of motion or lead to frozen joints. Some patients experience repeat episodes of diaphysitis (inflammation of the shaft of a long bone) involving a number of sites including the ulna, tibia, metacarpal bones, and radius [ Biopsies of hyperostosis lesions demonstrate reactive new bone surrounded by fibroblastic stroma infiltrated with plasma cells, lymphocytes, and polymorphonuclear cells; cultures are negative [ The calcifications are often incidental findings on radiologic studies, and patients are often asymptomatic. Some patients have significant symptoms of peripheral vascular insufficiency such as pain, cold extremities, and decreased peripheral pulses. Small to large vessel calcifications have been identified in variable anatomic locations including the cerebral vasculature, lower-extremity vasculature ( Dental findings, reported to be the presenting sign in some individuals [ Five individuals have had elevated markers of inflammation; i.e., C-reactive protein (CRP) and/or erythrocyte sedimentation rate (ESR) [ ## Phenotype Correlations by Gene Vascular calcifications appear to be more frequent in persons with biallelic ## Pathophysiology Deficiency of or resistance to FGF23 leads to hyperphosphatemia resulting in increased renal phosphate reabsorption and elevated or inappropriately normal 1,25D production, which promotes gastrointestinal absorption of phosphorus and calcium. Thereby increased blood calcium X phosphate product, calculated by multiplying the blood calcium (mg/dL) by the blood phosphate (mg/dL), predisposes to ectopic soft-tissue calcification in tissues exposed to trauma or inflammation. In persons with renal insufficiency (where this product is most commonly clinically utilized), the incidence of soft-tissue calcification is increased when the calcium X phosphate product exceeds 70 mg ## Genotype-Phenotype Correlations No genotype-phenotype correlations are known. Sibs with the same Treatment response does not appear to vary by genotype. • Sibs with the same • Treatment response does not appear to vary by genotype. ## Nomenclature In the past, hyperphosphatemic familial tumoral calcinosis (HFTC) has been referred to as the following: Lipocalcinogranulomatosis Teutschlaender's lipocalcinogranulomatosis Morbus Teutschländer • Lipocalcinogranulomatosis • Teutschlaender's lipocalcinogranulomatosis • Morbus Teutschländer ## Prevalence No formal study has estimated the prevalence of HFTC; the disorder is rare. To date, 75 individuals with a molecularly confirmed diagnosis of HFTC have been reported in the medical literature with an increased propensity in Africa and the Middle East and in populations originating from these regions [ ## Genetically Related (Allelic) Disorders Heterozygous germline gain-of-function pathogenic variants in A balanced translocation t(9:13)(q21.13;q13.1) that results in No phenotypes other than those discussed in this ## Differential Diagnosis Genetic Disorders to Consider in the Differential Diagnosis of Hyperphosphatemic Familial Tumoral Calcinosis Dystrophic calcification in areas of pseudoscleroderma Ulcerated areas at pseudoscleroderma sites in some Blistering & skin fragility w/sun exposure Hypertrichosis/ hyperpigmentation Pseudoscleroderma Increased urinary excretion of uroporphyrin Normal blood phosphorus Normal renal & intestinal reabsorption of phosphorus Calcification often preceded by inflammatory rash Lesions found in acral locations rather than periarticular Severe conjunctivitis & gingivitis Elevated blood phosphorus Subcutaneous ossifications Elevated blood parathyroid hormone due to end-organ resistance Low blood calcium, obesity Resistance to other hormones incl TSH, LH/FSH, GHRH Infantile onset of subcutaneous ossifications Congenital papular rash Gradual replacement of muscle tissue & connective tissue by bone starting w/neck & shoulders & proceeding down the body Typically, malformed big toes Extravascular periarticular calcifications May have angioid streaks of the retina Extensive medium- & large-artery calcification in infancy resulting in cardiovascular findings May have yellow papules in flexural body areas Hearing loss Congenital or early-onset punctate keratoderma of palms & soles Diffuse, irregularly shaped hypopigmented skin macules typically over arms & legs May have calcific tendinopathy Periarticular calcifications of large & small joints of lower extremities Symptomatic calcification of the large arteries of lower extremities AD = autosomal dominant; 1; AR = autosomal recessive; MOI = mode of inheritance Acquired Disorders to Consider in the Differential Diagnosis of Hyperphosphatemic Familial Tumoral Calcinosis Erythema, warmth, & diaphyseal pain of the long bones Fever Ulceration & drainage of skin Elevated inflammatory markers (ESR/CRP) Normal blood phosphorus Blood cultures may be positive Positive bacterial culture from bone biopsy obtained via sterile technique Distinct radiographic features of osteomyelitis Distinct histopathologic features following biopsy May present as septic arthritis Skin/subcutaneous calcinosis Calcinosis can occur over joints leading to functional impairment. Ulcerated areas can occur at sites of calcinosis. Elevated inflammatory markers (ESR/CRP) Other features of dermatomyositis (proximal muscle weakness, interstitial pulmonary disease, dysphagia, polyarthritis, Gottron's papules, heliotrope eruption) Other features of systemic sclerosis (arthralgia, myalgia, skin thickening/hardening, sclerodactyly, Raynaud phenomenon, esophageal dysmotility, telangiectasia, & pulmonary, renal, or cardiac disease) Other features of systemic lupus erythematosus (arthralgia, myalgia, fever, malar erythema, Raynaud phenomenon, vasculitis, & thromboembolic, pulmonary, renal, cardiac, or ophthalmologic disease) Skin/subcutaneous calcinosis Ulcerated areas can occur at sites of calcinosis. Other features of pancreatic disease in pancreatic panniculitis (pancreatitis, elevated amylase/lipase) Other features of subcutaneous fat necrosis of newborn (presents during 1st few weeks of life, typically history of trauma during delivery; may develop hypercalcemia) Other symptoms of onchocerciasis (river blindness) & travel to endemic areas (sub-Saharan Africa) Other symptoms of cysticercosis & ingestion of undercooked meat Elevated blood phosphorus Low blood 1,25D levels Skin/subcutaneous calcinosis Low blood 1,25D levels Normal or low blood phosphorus Elevated blood calcium & renal calcium excretion Elevated 25-OH vitamin D Hyperostosis is often misdiagnosed as osteomyelitis resulting in unnecessary long-term treatment with intravenous antibiotics. • Dystrophic calcification in areas of pseudoscleroderma • Ulcerated areas at pseudoscleroderma sites in some • Blistering & skin fragility w/sun exposure • Hypertrichosis/ hyperpigmentation • Pseudoscleroderma • Increased urinary excretion of uroporphyrin • Normal blood phosphorus • Normal renal & intestinal reabsorption of phosphorus • Calcification often preceded by inflammatory rash • Lesions found in acral locations rather than periarticular • Severe conjunctivitis & gingivitis • Elevated blood phosphorus • Subcutaneous ossifications • Elevated blood parathyroid hormone due to end-organ resistance • Low blood calcium, obesity • Resistance to other hormones incl TSH, LH/FSH, GHRH • Infantile onset of subcutaneous ossifications • Congenital papular rash • Gradual replacement of muscle tissue & connective tissue by bone starting w/neck & shoulders & proceeding down the body • Typically, malformed big toes • Extravascular periarticular calcifications • May have angioid streaks of the retina • Extensive medium- & large-artery calcification in infancy resulting in cardiovascular findings • May have yellow papules in flexural body areas • Hearing loss • Congenital or early-onset punctate keratoderma of palms & soles • Diffuse, irregularly shaped hypopigmented skin macules typically over arms & legs • May have calcific tendinopathy • Periarticular calcifications of large & small joints of lower extremities • Symptomatic calcification of the large arteries of lower extremities • Erythema, warmth, & diaphyseal pain of the long bones • Fever • Ulceration & drainage of skin • Elevated inflammatory markers (ESR/CRP) • Normal blood phosphorus • Blood cultures may be positive • Positive bacterial culture from bone biopsy obtained via sterile technique • Distinct radiographic features of osteomyelitis • Distinct histopathologic features following biopsy • May present as septic arthritis • Skin/subcutaneous calcinosis • Calcinosis can occur over joints leading to functional impairment. • Ulcerated areas can occur at sites of calcinosis. • Elevated inflammatory markers (ESR/CRP) • Other features of dermatomyositis (proximal muscle weakness, interstitial pulmonary disease, dysphagia, polyarthritis, Gottron's papules, heliotrope eruption) • Other features of systemic sclerosis (arthralgia, myalgia, skin thickening/hardening, sclerodactyly, Raynaud phenomenon, esophageal dysmotility, telangiectasia, & pulmonary, renal, or cardiac disease) • Other features of systemic lupus erythematosus (arthralgia, myalgia, fever, malar erythema, Raynaud phenomenon, vasculitis, & thromboembolic, pulmonary, renal, cardiac, or ophthalmologic disease) • Skin/subcutaneous calcinosis • Ulcerated areas can occur at sites of calcinosis. • Other features of pancreatic disease in pancreatic panniculitis (pancreatitis, elevated amylase/lipase) • Other features of subcutaneous fat necrosis of newborn (presents during 1st few weeks of life, typically history of trauma during delivery; may develop hypercalcemia) • Other symptoms of onchocerciasis (river blindness) & travel to endemic areas (sub-Saharan Africa) • Other symptoms of cysticercosis & ingestion of undercooked meat • Elevated blood phosphorus • Low blood 1,25D levels • Skin/subcutaneous calcinosis • Low blood 1,25D levels • Normal or low blood phosphorus • Elevated blood calcium & renal calcium excretion • Elevated 25-OH vitamin D ## Management To establish the extent of disease and needs in an individual diagnosed with hyperphosphatemic familial tumoral calcinosis (HFTC), the following evaluations are recommended if not done at the time of diagnosis: Physical examination with particular attention to: Skin and joints to assess for tumoral calcinosis; Lower extremities to assess for edema, erythema, and pain related to hyperostosis; Peripheral pulses to assess for clinically significant vascular calcification. Use ankle-brachial systolic pressure index to confirm clinical suspicion of lower-extremity arterial occlusive disease. Metabolic work up including blood phosphorus, blood creatinine, urine phosphorus, urine creatinine to evaluate renal phosphate handling by measuring the tubular reabsorption of phosphorus (TRP) and the ratio of the renal tubular maximum reabsorption rate of phosphate to the glomerular filtration rate (TmP/GFR) Duplex ultrasound examination, CT angiography, and/or magnetic resonance angiography ( Cardiac CT angiography ( Consultation with a vascular specialist and/or cardiologist for patients with symptomatic vascular calcifications Complete blood count, erythrocyte sedimentation rate, and C-reactive protein to evaluate for evidence of systemic inflammation Dental consultation including dental radiographs to assess for the HFTC dental phenotype ( Testicular ultrasound examination to assess for microlithiasis ( Renal ultrasound examination to evaluate for medullary nephrocalcinosis Ophthalmologic consultation to evaluate for eyelid calcifications and angioid streaks of the retina Consultation with a clinical geneticist and/or genetic counselor No standard treatment for HFTC exists. No randomized clinical trials have been performed, and studies of the treatment of HFTC consist of case reports or case series. Most reported therapies attempt to lower blood phosphorus; most patients with HFTC are treated with a combination of medical therapies. Clinical response to these treatments varies. No treatment regimen appears to consistently or universally decrease lesion size or prevent progression or recurrence of lesions after surgery. Low-phosphate diet. Many patients are instructed to follow a low-phosphate diet in combination with other medical therapies. Limited benefit was reported in use of low-phosphate diet alone [ Phosphate binders, such as sevelamer and aluminum hydroxide, are used to decrease absorption of dietary phosphorus. Response is mixed, including: (1) decrease or no change in blood phosphorus; (2) decrease, no change, or increase in the size of the tumoral calcinosis [ Note: (1) Aluminum-containing phosphate binders can probably be used safely in patients with HFTC as opposed to patients with renal failure, in whom the risk of aluminum toxicity is increased due to impaired renal clearance. (2) Calcium salts, used in the past, have fallen out of favor because of their potential to increase the calcium X phosphate product, as defined in Acetazolamide, a carbonic anhydrase inhibitor, increases urinary phosphate excretion. While some reports describe improvement or resolution of tumoral calcinosis following treatment with acetazolamide alone or – most often – in combination with phosphate binders, other reports describe no change in lesions. Similarly, blood phosphorus levels decreased or remained unchanged [ Probenecid (which promotes renal phosphate excretion) has been used along with other phosphate-lowering medications. Note: Because probenecid prolongs the half-life of a number of drugs, physicians should assess for drug interactions prior to starting this medication. Treatment with probenecid did not decrease blood phosphorus or improve clinical status in two individuals [ Following surgical resection of tumoral calcinosis, one individual was recurrence free after six years of probenecid and phosphate binder therapy, despite no change in blood phosphate [ In one series, treatment that included probenecid was associated with complete resolution of tumoral calcinosis in one patient but no change in the size of lesions in others [ Niacinamide/nicotinamide, shown to decrease renal phosphate reabsorption, has been evaluated as a short-term treatment in two patients: one showed decreased blood phosphorus during a 48-hour treatment [ Topical sodium thiosulfate applied to skin overlying the tumoral calcinosis lesions has been shown to decrease ectopic calcifications after at least five months of treatment in three patients [ Risedronate, a bisphosphonate with anti-osteoclast activity, was used in one patient for one year, after which no change in blood phosphorus level or obvious improvement in tumoral calcinosis burden was observed [ Synthetic salmon calcitonin, a hormone that inhibits osteoclast activity and rental tubular reabsorption of calcium and phosphorus, was administered subcutaneously to one patient in combination with a low-phosphate diet and phosphate binder. The patient had a decrease in blood phosphorus on treatment; tumoral calcinosis lesions remained stable in size while no new ectopic calcifications developed [ Surgical resection of tumoral calcinosis lesions has variable outcomes. Some patients have complete resolution of the lesions while others have required multiple surgeries due to lesion recurrence [ Nonsteroidal anti-inflammatory drugs (NSAIDs) have been used to treat the pain and edema associated with hyperostosis [ Acetaminophen in combination with NSAIDs has been shown to improve the symptoms of hyperostosis [ Steroids – prescribed for a brief course in one patient with hyperostosis – reduced edema [ No data are available on the management of vascular calcification in HFTC. Patients with vascular calcification should be evaluated by a vascular specialist and/or cardiologist for further assessment and treatment including optimizing other modifiable cardiovascular risk factors. No data are available on the management of testicular microlithiasis. Men with impaired fertility may be referred to a reproductive specialist for further evaluation. Patients should be referred to an ophthalmologist for evaluation, treatment, and monitoring of angioid streaks of the retina. Intravitrial ranibizumab injections improved visual acuity in the only individual reported to experience sudden worsening of vision due to choroidal neovascularization associated with an angioid streak [ No specific guidelines address the issue of surveillance in HFTC. The frequency of monitoring depends on clinical findings and medical treatment, as there are no data to support an appropriate monitoring interval. Blood phosphorus to help manage medication doses Blood calcium and intact parathyroid hormone because levels of 1,25D can be elevated Complete blood count, ESR, and CRP to assess for evidence of inflammation Renal function because hyperphosphatemia can contribute to development of kidney disease In patients treated with acetazolamide, blood chemistries to assess for evidence of metabolic acidosis. In patients treated with probenecid, blood uric acid levels to help manage medication doses. Probenecid should be increased until the blood uric acid level is suppressed or the maximum dose for age is reached. Radiographs of affected areas can be performed intermittently to evaluate and assess the presence or change in size of lesions of tumoral calcinosis (with the goal of minimizing radiation exposure). Because phosphorus-lowering medications are aimed at lowering the calcium X phosphate product, it is prudent to avoid the following: Use of calcium salts as phosphate binders Excessive dietary calcium intake Excessive vitamin D intake and/or supplements Foods high in phosphorus It is appropriate to evaluate apparently asymptomatic older and younger sibs of a proband in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Evaluations can include: Blood phosphorus, the most cost-effective approach Molecular genetic testing if the pathogenic variants in the family are known Evaluation of phosphorus and calcium metabolism including blood phosphorus, blood creatinine, blood calcium, parathyroid hormone, 1,25D, 25-OH vitamin D, C-terminal FGF23, urine phosphorus, and urine creatinine if initial blood phosphorus level is inconclusive or if the pathogenic variants in the family are not known See While there is a lack of information regarding pregnancies in women with HFTC, calcifications of the placenta have been noted post delivery [ Search • Physical examination with particular attention to: • Skin and joints to assess for tumoral calcinosis; • Lower extremities to assess for edema, erythema, and pain related to hyperostosis; • Peripheral pulses to assess for clinically significant vascular calcification. • Use ankle-brachial systolic pressure index to confirm clinical suspicion of lower-extremity arterial occlusive disease. • Skin and joints to assess for tumoral calcinosis; • Lower extremities to assess for edema, erythema, and pain related to hyperostosis; • Peripheral pulses to assess for clinically significant vascular calcification. • Metabolic work up including blood phosphorus, blood creatinine, urine phosphorus, urine creatinine to evaluate renal phosphate handling by measuring the tubular reabsorption of phosphorus (TRP) and the ratio of the renal tubular maximum reabsorption rate of phosphate to the glomerular filtration rate (TmP/GFR) • Duplex ultrasound examination, CT angiography, and/or magnetic resonance angiography ( • Cardiac CT angiography ( • Consultation with a vascular specialist and/or cardiologist for patients with symptomatic vascular calcifications • Complete blood count, erythrocyte sedimentation rate, and C-reactive protein to evaluate for evidence of systemic inflammation • Dental consultation including dental radiographs to assess for the HFTC dental phenotype ( • Testicular ultrasound examination to assess for microlithiasis ( • Renal ultrasound examination to evaluate for medullary nephrocalcinosis • Ophthalmologic consultation to evaluate for eyelid calcifications and angioid streaks of the retina • Consultation with a clinical geneticist and/or genetic counselor • Skin and joints to assess for tumoral calcinosis; • Lower extremities to assess for edema, erythema, and pain related to hyperostosis; • Peripheral pulses to assess for clinically significant vascular calcification. • Low-phosphate diet. Many patients are instructed to follow a low-phosphate diet in combination with other medical therapies. Limited benefit was reported in use of low-phosphate diet alone [ • Phosphate binders, such as sevelamer and aluminum hydroxide, are used to decrease absorption of dietary phosphorus. Response is mixed, including: (1) decrease or no change in blood phosphorus; (2) decrease, no change, or increase in the size of the tumoral calcinosis [ • Note: (1) Aluminum-containing phosphate binders can probably be used safely in patients with HFTC as opposed to patients with renal failure, in whom the risk of aluminum toxicity is increased due to impaired renal clearance. (2) Calcium salts, used in the past, have fallen out of favor because of their potential to increase the calcium X phosphate product, as defined in • Acetazolamide, a carbonic anhydrase inhibitor, increases urinary phosphate excretion. While some reports describe improvement or resolution of tumoral calcinosis following treatment with acetazolamide alone or – most often – in combination with phosphate binders, other reports describe no change in lesions. Similarly, blood phosphorus levels decreased or remained unchanged [ • Probenecid (which promotes renal phosphate excretion) has been used along with other phosphate-lowering medications. Note: Because probenecid prolongs the half-life of a number of drugs, physicians should assess for drug interactions prior to starting this medication. • Treatment with probenecid did not decrease blood phosphorus or improve clinical status in two individuals [ • Following surgical resection of tumoral calcinosis, one individual was recurrence free after six years of probenecid and phosphate binder therapy, despite no change in blood phosphate [ • In one series, treatment that included probenecid was associated with complete resolution of tumoral calcinosis in one patient but no change in the size of lesions in others [ • Treatment with probenecid did not decrease blood phosphorus or improve clinical status in two individuals [ • Following surgical resection of tumoral calcinosis, one individual was recurrence free after six years of probenecid and phosphate binder therapy, despite no change in blood phosphate [ • In one series, treatment that included probenecid was associated with complete resolution of tumoral calcinosis in one patient but no change in the size of lesions in others [ • Niacinamide/nicotinamide, shown to decrease renal phosphate reabsorption, has been evaluated as a short-term treatment in two patients: one showed decreased blood phosphorus during a 48-hour treatment [ • Topical sodium thiosulfate applied to skin overlying the tumoral calcinosis lesions has been shown to decrease ectopic calcifications after at least five months of treatment in three patients [ • Risedronate, a bisphosphonate with anti-osteoclast activity, was used in one patient for one year, after which no change in blood phosphorus level or obvious improvement in tumoral calcinosis burden was observed [ • Synthetic salmon calcitonin, a hormone that inhibits osteoclast activity and rental tubular reabsorption of calcium and phosphorus, was administered subcutaneously to one patient in combination with a low-phosphate diet and phosphate binder. The patient had a decrease in blood phosphorus on treatment; tumoral calcinosis lesions remained stable in size while no new ectopic calcifications developed [ • Surgical resection of tumoral calcinosis lesions has variable outcomes. Some patients have complete resolution of the lesions while others have required multiple surgeries due to lesion recurrence [ • Treatment with probenecid did not decrease blood phosphorus or improve clinical status in two individuals [ • Following surgical resection of tumoral calcinosis, one individual was recurrence free after six years of probenecid and phosphate binder therapy, despite no change in blood phosphate [ • In one series, treatment that included probenecid was associated with complete resolution of tumoral calcinosis in one patient but no change in the size of lesions in others [ • Nonsteroidal anti-inflammatory drugs (NSAIDs) have been used to treat the pain and edema associated with hyperostosis [ • Acetaminophen in combination with NSAIDs has been shown to improve the symptoms of hyperostosis [ • Steroids – prescribed for a brief course in one patient with hyperostosis – reduced edema [ • No data are available on the management of vascular calcification in HFTC. • Patients with vascular calcification should be evaluated by a vascular specialist and/or cardiologist for further assessment and treatment including optimizing other modifiable cardiovascular risk factors. • No data are available on the management of testicular microlithiasis. • Men with impaired fertility may be referred to a reproductive specialist for further evaluation. • Patients should be referred to an ophthalmologist for evaluation, treatment, and monitoring of angioid streaks of the retina. • Intravitrial ranibizumab injections improved visual acuity in the only individual reported to experience sudden worsening of vision due to choroidal neovascularization associated with an angioid streak [ • Blood phosphorus to help manage medication doses • Blood calcium and intact parathyroid hormone because levels of 1,25D can be elevated • Complete blood count, ESR, and CRP to assess for evidence of inflammation • Renal function because hyperphosphatemia can contribute to development of kidney disease • Use of calcium salts as phosphate binders • Excessive dietary calcium intake • Excessive vitamin D intake and/or supplements • Foods high in phosphorus • Blood phosphorus, the most cost-effective approach • Molecular genetic testing if the pathogenic variants in the family are known • Evaluation of phosphorus and calcium metabolism including blood phosphorus, blood creatinine, blood calcium, parathyroid hormone, 1,25D, 25-OH vitamin D, C-terminal FGF23, urine phosphorus, and urine creatinine if initial blood phosphorus level is inconclusive or 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 hyperphosphatemic familial tumoral calcinosis (HFTC), the following evaluations are recommended if not done at the time of diagnosis: Physical examination with particular attention to: Skin and joints to assess for tumoral calcinosis; Lower extremities to assess for edema, erythema, and pain related to hyperostosis; Peripheral pulses to assess for clinically significant vascular calcification. Use ankle-brachial systolic pressure index to confirm clinical suspicion of lower-extremity arterial occlusive disease. Metabolic work up including blood phosphorus, blood creatinine, urine phosphorus, urine creatinine to evaluate renal phosphate handling by measuring the tubular reabsorption of phosphorus (TRP) and the ratio of the renal tubular maximum reabsorption rate of phosphate to the glomerular filtration rate (TmP/GFR) Duplex ultrasound examination, CT angiography, and/or magnetic resonance angiography ( Cardiac CT angiography ( Consultation with a vascular specialist and/or cardiologist for patients with symptomatic vascular calcifications Complete blood count, erythrocyte sedimentation rate, and C-reactive protein to evaluate for evidence of systemic inflammation Dental consultation including dental radiographs to assess for the HFTC dental phenotype ( Testicular ultrasound examination to assess for microlithiasis ( Renal ultrasound examination to evaluate for medullary nephrocalcinosis Ophthalmologic consultation to evaluate for eyelid calcifications and angioid streaks of the retina Consultation with a clinical geneticist and/or genetic counselor • Physical examination with particular attention to: • Skin and joints to assess for tumoral calcinosis; • Lower extremities to assess for edema, erythema, and pain related to hyperostosis; • Peripheral pulses to assess for clinically significant vascular calcification. • Use ankle-brachial systolic pressure index to confirm clinical suspicion of lower-extremity arterial occlusive disease. • Skin and joints to assess for tumoral calcinosis; • Lower extremities to assess for edema, erythema, and pain related to hyperostosis; • Peripheral pulses to assess for clinically significant vascular calcification. • Metabolic work up including blood phosphorus, blood creatinine, urine phosphorus, urine creatinine to evaluate renal phosphate handling by measuring the tubular reabsorption of phosphorus (TRP) and the ratio of the renal tubular maximum reabsorption rate of phosphate to the glomerular filtration rate (TmP/GFR) • Duplex ultrasound examination, CT angiography, and/or magnetic resonance angiography ( • Cardiac CT angiography ( • Consultation with a vascular specialist and/or cardiologist for patients with symptomatic vascular calcifications • Complete blood count, erythrocyte sedimentation rate, and C-reactive protein to evaluate for evidence of systemic inflammation • Dental consultation including dental radiographs to assess for the HFTC dental phenotype ( • Testicular ultrasound examination to assess for microlithiasis ( • Renal ultrasound examination to evaluate for medullary nephrocalcinosis • Ophthalmologic consultation to evaluate for eyelid calcifications and angioid streaks of the retina • Consultation with a clinical geneticist and/or genetic counselor • Skin and joints to assess for tumoral calcinosis; • Lower extremities to assess for edema, erythema, and pain related to hyperostosis; • Peripheral pulses to assess for clinically significant vascular calcification. ## Treatment of Manifestations No standard treatment for HFTC exists. No randomized clinical trials have been performed, and studies of the treatment of HFTC consist of case reports or case series. Most reported therapies attempt to lower blood phosphorus; most patients with HFTC are treated with a combination of medical therapies. Clinical response to these treatments varies. No treatment regimen appears to consistently or universally decrease lesion size or prevent progression or recurrence of lesions after surgery. Low-phosphate diet. Many patients are instructed to follow a low-phosphate diet in combination with other medical therapies. Limited benefit was reported in use of low-phosphate diet alone [ Phosphate binders, such as sevelamer and aluminum hydroxide, are used to decrease absorption of dietary phosphorus. Response is mixed, including: (1) decrease or no change in blood phosphorus; (2) decrease, no change, or increase in the size of the tumoral calcinosis [ Note: (1) Aluminum-containing phosphate binders can probably be used safely in patients with HFTC as opposed to patients with renal failure, in whom the risk of aluminum toxicity is increased due to impaired renal clearance. (2) Calcium salts, used in the past, have fallen out of favor because of their potential to increase the calcium X phosphate product, as defined in Acetazolamide, a carbonic anhydrase inhibitor, increases urinary phosphate excretion. While some reports describe improvement or resolution of tumoral calcinosis following treatment with acetazolamide alone or – most often – in combination with phosphate binders, other reports describe no change in lesions. Similarly, blood phosphorus levels decreased or remained unchanged [ Probenecid (which promotes renal phosphate excretion) has been used along with other phosphate-lowering medications. Note: Because probenecid prolongs the half-life of a number of drugs, physicians should assess for drug interactions prior to starting this medication. Treatment with probenecid did not decrease blood phosphorus or improve clinical status in two individuals [ Following surgical resection of tumoral calcinosis, one individual was recurrence free after six years of probenecid and phosphate binder therapy, despite no change in blood phosphate [ In one series, treatment that included probenecid was associated with complete resolution of tumoral calcinosis in one patient but no change in the size of lesions in others [ Niacinamide/nicotinamide, shown to decrease renal phosphate reabsorption, has been evaluated as a short-term treatment in two patients: one showed decreased blood phosphorus during a 48-hour treatment [ Topical sodium thiosulfate applied to skin overlying the tumoral calcinosis lesions has been shown to decrease ectopic calcifications after at least five months of treatment in three patients [ Risedronate, a bisphosphonate with anti-osteoclast activity, was used in one patient for one year, after which no change in blood phosphorus level or obvious improvement in tumoral calcinosis burden was observed [ Synthetic salmon calcitonin, a hormone that inhibits osteoclast activity and rental tubular reabsorption of calcium and phosphorus, was administered subcutaneously to one patient in combination with a low-phosphate diet and phosphate binder. The patient had a decrease in blood phosphorus on treatment; tumoral calcinosis lesions remained stable in size while no new ectopic calcifications developed [ Surgical resection of tumoral calcinosis lesions has variable outcomes. Some patients have complete resolution of the lesions while others have required multiple surgeries due to lesion recurrence [ Nonsteroidal anti-inflammatory drugs (NSAIDs) have been used to treat the pain and edema associated with hyperostosis [ Acetaminophen in combination with NSAIDs has been shown to improve the symptoms of hyperostosis [ Steroids – prescribed for a brief course in one patient with hyperostosis – reduced edema [ No data are available on the management of vascular calcification in HFTC. Patients with vascular calcification should be evaluated by a vascular specialist and/or cardiologist for further assessment and treatment including optimizing other modifiable cardiovascular risk factors. No data are available on the management of testicular microlithiasis. Men with impaired fertility may be referred to a reproductive specialist for further evaluation. Patients should be referred to an ophthalmologist for evaluation, treatment, and monitoring of angioid streaks of the retina. Intravitrial ranibizumab injections improved visual acuity in the only individual reported to experience sudden worsening of vision due to choroidal neovascularization associated with an angioid streak [ • Low-phosphate diet. Many patients are instructed to follow a low-phosphate diet in combination with other medical therapies. Limited benefit was reported in use of low-phosphate diet alone [ • Phosphate binders, such as sevelamer and aluminum hydroxide, are used to decrease absorption of dietary phosphorus. Response is mixed, including: (1) decrease or no change in blood phosphorus; (2) decrease, no change, or increase in the size of the tumoral calcinosis [ • Note: (1) Aluminum-containing phosphate binders can probably be used safely in patients with HFTC as opposed to patients with renal failure, in whom the risk of aluminum toxicity is increased due to impaired renal clearance. (2) Calcium salts, used in the past, have fallen out of favor because of their potential to increase the calcium X phosphate product, as defined in • Acetazolamide, a carbonic anhydrase inhibitor, increases urinary phosphate excretion. While some reports describe improvement or resolution of tumoral calcinosis following treatment with acetazolamide alone or – most often – in combination with phosphate binders, other reports describe no change in lesions. Similarly, blood phosphorus levels decreased or remained unchanged [ • Probenecid (which promotes renal phosphate excretion) has been used along with other phosphate-lowering medications. Note: Because probenecid prolongs the half-life of a number of drugs, physicians should assess for drug interactions prior to starting this medication. • Treatment with probenecid did not decrease blood phosphorus or improve clinical status in two individuals [ • Following surgical resection of tumoral calcinosis, one individual was recurrence free after six years of probenecid and phosphate binder therapy, despite no change in blood phosphate [ • In one series, treatment that included probenecid was associated with complete resolution of tumoral calcinosis in one patient but no change in the size of lesions in others [ • Treatment with probenecid did not decrease blood phosphorus or improve clinical status in two individuals [ • Following surgical resection of tumoral calcinosis, one individual was recurrence free after six years of probenecid and phosphate binder therapy, despite no change in blood phosphate [ • In one series, treatment that included probenecid was associated with complete resolution of tumoral calcinosis in one patient but no change in the size of lesions in others [ • Niacinamide/nicotinamide, shown to decrease renal phosphate reabsorption, has been evaluated as a short-term treatment in two patients: one showed decreased blood phosphorus during a 48-hour treatment [ • Topical sodium thiosulfate applied to skin overlying the tumoral calcinosis lesions has been shown to decrease ectopic calcifications after at least five months of treatment in three patients [ • Risedronate, a bisphosphonate with anti-osteoclast activity, was used in one patient for one year, after which no change in blood phosphorus level or obvious improvement in tumoral calcinosis burden was observed [ • Synthetic salmon calcitonin, a hormone that inhibits osteoclast activity and rental tubular reabsorption of calcium and phosphorus, was administered subcutaneously to one patient in combination with a low-phosphate diet and phosphate binder. The patient had a decrease in blood phosphorus on treatment; tumoral calcinosis lesions remained stable in size while no new ectopic calcifications developed [ • Surgical resection of tumoral calcinosis lesions has variable outcomes. Some patients have complete resolution of the lesions while others have required multiple surgeries due to lesion recurrence [ • Treatment with probenecid did not decrease blood phosphorus or improve clinical status in two individuals [ • Following surgical resection of tumoral calcinosis, one individual was recurrence free after six years of probenecid and phosphate binder therapy, despite no change in blood phosphate [ • In one series, treatment that included probenecid was associated with complete resolution of tumoral calcinosis in one patient but no change in the size of lesions in others [ • Nonsteroidal anti-inflammatory drugs (NSAIDs) have been used to treat the pain and edema associated with hyperostosis [ • Acetaminophen in combination with NSAIDs has been shown to improve the symptoms of hyperostosis [ • Steroids – prescribed for a brief course in one patient with hyperostosis – reduced edema [ • No data are available on the management of vascular calcification in HFTC. • Patients with vascular calcification should be evaluated by a vascular specialist and/or cardiologist for further assessment and treatment including optimizing other modifiable cardiovascular risk factors. • No data are available on the management of testicular microlithiasis. • Men with impaired fertility may be referred to a reproductive specialist for further evaluation. • Patients should be referred to an ophthalmologist for evaluation, treatment, and monitoring of angioid streaks of the retina. • Intravitrial ranibizumab injections improved visual acuity in the only individual reported to experience sudden worsening of vision due to choroidal neovascularization associated with an angioid streak [ ## Surveillance No specific guidelines address the issue of surveillance in HFTC. The frequency of monitoring depends on clinical findings and medical treatment, as there are no data to support an appropriate monitoring interval. Blood phosphorus to help manage medication doses Blood calcium and intact parathyroid hormone because levels of 1,25D can be elevated Complete blood count, ESR, and CRP to assess for evidence of inflammation Renal function because hyperphosphatemia can contribute to development of kidney disease In patients treated with acetazolamide, blood chemistries to assess for evidence of metabolic acidosis. In patients treated with probenecid, blood uric acid levels to help manage medication doses. Probenecid should be increased until the blood uric acid level is suppressed or the maximum dose for age is reached. Radiographs of affected areas can be performed intermittently to evaluate and assess the presence or change in size of lesions of tumoral calcinosis (with the goal of minimizing radiation exposure). • Blood phosphorus to help manage medication doses • Blood calcium and intact parathyroid hormone because levels of 1,25D can be elevated • Complete blood count, ESR, and CRP to assess for evidence of inflammation • Renal function because hyperphosphatemia can contribute to development of kidney disease ## Agents/Circumstances to Avoid Because phosphorus-lowering medications are aimed at lowering the calcium X phosphate product, it is prudent to avoid the following: Use of calcium salts as phosphate binders Excessive dietary calcium intake Excessive vitamin D intake and/or supplements Foods high in phosphorus • Use of calcium salts as phosphate binders • Excessive dietary calcium intake • Excessive vitamin D intake and/or supplements • Foods high in phosphorus ## Evaluation of Relatives at Risk It is appropriate to evaluate apparently asymptomatic older and younger sibs of a proband in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Evaluations can include: Blood phosphorus, the most cost-effective approach Molecular genetic testing if the pathogenic variants in the family are known Evaluation of phosphorus and calcium metabolism including blood phosphorus, blood creatinine, blood calcium, parathyroid hormone, 1,25D, 25-OH vitamin D, C-terminal FGF23, urine phosphorus, and urine creatinine if initial blood phosphorus level is inconclusive or if the pathogenic variants in the family are not known See • Blood phosphorus, the most cost-effective approach • Molecular genetic testing if the pathogenic variants in the family are known • Evaluation of phosphorus and calcium metabolism including blood phosphorus, blood creatinine, blood calcium, parathyroid hormone, 1,25D, 25-OH vitamin D, C-terminal FGF23, urine phosphorus, and urine creatinine if initial blood phosphorus level is inconclusive or if the pathogenic variants in the family are not known ## Pregnancy Management While there is a lack of information regarding pregnancies in women with HFTC, calcifications of the placenta have been noted post delivery [ ## Therapies Under Investigation Search ## Genetic Counseling Hyperphosphatemic familial tumoral calcinosis (HFTC) is inherited in an autosomal recessive manner. The normophosphatemic 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; however, one heterozygote from a large kindred with HFTC was reported to have hyperphosphatemia and elevated 1,25D without calcinosis lesions [ Rarely, when there is consanguinity this autosomal recessive condition can be reported in consecutive generations. 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. Because of intrafamilial clinical variability, it is not possible to predict the phenotype in sibs who have inherited biallelic pathogenic variants (see Although heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder, one heterozygote from a large kindred with HFTC was reported to have hyperphosphatemia and elevated 1,25D without calcinosis lesions [ Unless an individual with HFTC has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for an HFTC has been reported in many families with multigenerational consanguinity. Consanguinity increases the likelihood that an affected individual may have a reproductive partner who is heterozygous or homozygous for pathogenic variants in the same HFTC-related gene. The offspring of a proband and an individual heterozygous for a pathogenic variant in the same HFTC-related gene have a 50% chance of being affected and 50% chance of being heterozygotes. 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. Carrier testing for reproductive partners of known carriers is appropriate, particularly if consanguinity is likely. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The normophosphatemic 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; however, one heterozygote from a large kindred with HFTC was reported to have hyperphosphatemia and elevated 1,25D without calcinosis lesions [ • Rarely, when there is consanguinity this autosomal recessive condition can be reported in consecutive generations. • 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. • Because of intrafamilial clinical variability, it is not possible to predict the phenotype in sibs who have inherited biallelic pathogenic variants (see • Although heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder, one heterozygote from a large kindred with HFTC was reported to have hyperphosphatemia and elevated 1,25D without calcinosis lesions [ • Unless an individual with HFTC has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for an • HFTC has been reported in many families with multigenerational consanguinity. Consanguinity increases the likelihood that an affected individual may have a reproductive partner who is heterozygous or homozygous for pathogenic variants in the same HFTC-related gene. • The offspring of a proband and an individual heterozygous for a pathogenic variant in the same HFTC-related gene have a 50% chance of being affected and 50% chance 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 carriers, or are at risk of being carriers. • Carrier testing for reproductive partners of known carriers is appropriate, particularly if consanguinity is likely. ## Mode of Inheritance Hyperphosphatemic familial tumoral calcinosis (HFTC) is inherited in an autosomal recessive manner. ## Risk to Family Members The normophosphatemic 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; however, one heterozygote from a large kindred with HFTC was reported to have hyperphosphatemia and elevated 1,25D without calcinosis lesions [ Rarely, when there is consanguinity this autosomal recessive condition can be reported in consecutive generations. 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. Because of intrafamilial clinical variability, it is not possible to predict the phenotype in sibs who have inherited biallelic pathogenic variants (see Although heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder, one heterozygote from a large kindred with HFTC was reported to have hyperphosphatemia and elevated 1,25D without calcinosis lesions [ Unless an individual with HFTC has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for an HFTC has been reported in many families with multigenerational consanguinity. Consanguinity increases the likelihood that an affected individual may have a reproductive partner who is heterozygous or homozygous for pathogenic variants in the same HFTC-related gene. The offspring of a proband and an individual heterozygous for a pathogenic variant in the same HFTC-related gene have a 50% chance of being affected and 50% chance of being heterozygotes. • The normophosphatemic 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; however, one heterozygote from a large kindred with HFTC was reported to have hyperphosphatemia and elevated 1,25D without calcinosis lesions [ • Rarely, when there is consanguinity this autosomal recessive condition can be reported in consecutive generations. • 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. • Because of intrafamilial clinical variability, it is not possible to predict the phenotype in sibs who have inherited biallelic pathogenic variants (see • Although heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder, one heterozygote from a large kindred with HFTC was reported to have hyperphosphatemia and elevated 1,25D without calcinosis lesions [ • Unless an individual with HFTC has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for an • HFTC has been reported in many families with multigenerational consanguinity. Consanguinity increases the likelihood that an affected individual may have a reproductive partner who is heterozygous or homozygous for pathogenic variants in the same HFTC-related gene. • The offspring of a proband and an individual heterozygous for a pathogenic variant in the same HFTC-related gene have a 50% chance of being affected and 50% chance of being heterozygotes. ## Carrier (Heterozygote) Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Carrier testing for reproductive partners of known carriers is appropriate, particularly if consanguinity is likely. • 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. • Carrier testing for reproductive partners of known carriers is appropriate, particularly if consanguinity is likely. ## 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 Hyperphosphatemic Familial Tumoral Calcinosis: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Hyperphosphatemic Familial Tumoral Calcinosis ( 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 Dr Collins' Our research focuses on bone biology and mineral metabolism, which are studied through clinical and translational studies. Specific areas of interest include the role of PTH, G-proteins, and cAMP in bone cell biology, and FGF23 in mineral metabolism. The primary approach is the study and treatment of patients with rare disorders of bone and mineral metabolism as models through which to understand human bone and mineral biology and physiology. Current models of focus include fibrous dysplasia of bone, hypoparathyroidism, and disorders of FGF23 excess such as tumor-induced osteomalacia and X-linked hypophosphatemic rickets and deficiency such as hyperphosphatemic familial tumoral calcinosis. This research was supported by the Intramural Research Program of the NIH, NIDCR. 1 February 2018 (bp) Review posted live 14 November 2016 (msr) Original submission Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the • 1 February 2018 (bp) Review posted live • 14 November 2016 (msr) Original submission ## Author Notes Dr Collins' Our research focuses on bone biology and mineral metabolism, which are studied through clinical and translational studies. Specific areas of interest include the role of PTH, G-proteins, and cAMP in bone cell biology, and FGF23 in mineral metabolism. The primary approach is the study and treatment of patients with rare disorders of bone and mineral metabolism as models through which to understand human bone and mineral biology and physiology. Current models of focus include fibrous dysplasia of bone, hypoparathyroidism, and disorders of FGF23 excess such as tumor-induced osteomalacia and X-linked hypophosphatemic rickets and deficiency such as hyperphosphatemic familial tumoral calcinosis. ## Acknowledgments This research was supported by the Intramural Research Program of the NIH, NIDCR. ## Revision History 1 February 2018 (bp) Review posted live 14 November 2016 (msr) Original submission Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the • 1 February 2018 (bp) Review posted live • 14 November 2016 (msr) Original submission A. Computed tomography (CT) scan showing calcifications in an adult with HFTC including shoulder and hip soft tissue calcifications (white arrows), aortic calcification (dashed arrow), papillary muscle calcification (black arrow), and submucosal gut calcifications (asterisks) B. CT 3D reconstruction in an adult demonstrating extensive calcifications in both hips and scattered calcifications throughout the chest C. Testicular ultrasound in an adult showing several tiny foci of hyperechogenicity consistent with testicular microlithiasis D. Colonoscopy image in an adult demonstrating submucosal partially obstructing tumoral calcinosis in the sigmoid colon A&B. Radiographs in a child with hyperphosphatemic familial tumoral calcinosis showing tumoral calcinosis of the lateral proximal femur (A) and elbow (B) C. Radiograph of tibias/fibulas in a child showing hyperostosis with hypermineralization of the cortical bone (dashed arrow) and patchy sclerosis of the medullary cavities (solid arrows) D. Panoramic dental radiograph in a child showing short, bulbous roots (solid arrows) with obliteration of dental pulp chambers (asterisks) E. Periapical dental radiograph with thistle-shaped pulp chambers and a pulp stone (arrow) A. CT 3D reconstruction in an adult with HFTC demonstrating bilateral vascular calcifications in superficial femoral arteries (solid arrows) and multifocal sheet-like calcification of the subcutaneous tissues at the level of the distal tibiae and fibulae (dashed arrows) B. Magnetic resonance angiography of the bilateral proximal lower extremities in an adult showing high-grade vascular stenoses of both superficial femoral arteries (arrows) with presence of multiple collateral vessels (red arrowheads) C. Cardiac CT angiography in an adult with calcification of the left anterior descending coronary artery (arrow) D. Cardiac CT angiography in an adult with calcification of the posterior medial papillary muscle (arrow)	[ "H Annamunthodo. Calcinosis.. Am J Surg 1960;99:951-5", "A Benet-Pagès, P Orlik, TM Strom, B Lorenz-Depiereux. An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia.. Hum Mol Genet. 2005;14:385-90", "C Bergwitz, S Banerjee, H Abu-Zahra, H Kaji, A Miyauchi, T Sugimoto, H Jüppner. Defective O-glycosylation due to a novel homozygous S129P mutation is associated with lack of fibroblast growth factor 23 secretion and tumoral calcinosis.. J Clin Endocrinol Metab 2009;94:4267-74", "AL Boskey, VJ Vigorita, O Sencer, SA Stuchin, JM Lane. Chemical, microscopic, and ultrastructural characterization of the mineral deposits in tumoral calcinosis.. Clin Orthop Relat Res 1983:258-69", "EJ Burkes, KW Lyles, EA Dolan, B Giammara, J Hanker. Dental lesions in tumoral calcinosis.. J Oral Pathol Med. 1991;20:222-7", "MF Campagnoli, A Pucci, E Garelli, A Carando, C Defilippi, R Lala, G Ingrosso, I Dianzani, M Forni, U Ramenghi. Familial tumoral calcinosis and testicular microlithiasis associated with a new mutation of GALNT3 in a white family.. J Clin Pathol 2006b;59:440-2", "M Campagnoli, S Rosipal, M Debreová, R Rosipal, A Sala, A Romano, S Labò, M Galliano, L Minchiotti. Analbuminemia in a Slovak Romany (gypsy) family: case report and mutational analysis.. Clin Chim Acta 2006a;365:188-93", "R Candrina, B Cerudelli, V Braga, A Salvi. Effects of the acute subcutaneous administration of synthetic salmon calcitonin in tumoral calcinosis.. J Endocrinol Invest 1989;12:55-7", "KD Carmichael, JA Bynum, EB Evans. Familial tumoral calcinosis: a forty-year follow-up on one family.. J Bone Joint Surg Am 2009;91:664-71", "I Chefetz, R Heller, A Galli-Tsinopoulou, G Richard, B Wollnik, M Indelman, F Koerber, O Topaz, R Bergman, E Sprecher, E Schoenau. A novel homozygous missense mutation in FGF23 causes familial tumoral calcinosis associated with disseminated visceral calcification.. Hum Genet 2005;118:261-6", "E Clarke, LE Swischuk, CK Hayden. Tumoral calcinosis, diaphysitis, and hyperphosphatemia.. Radiology 1984;151:643-6", "DE Demellawy, N Chang, J de Nanassy, A Nasr. GALNT3 gene mutation-associated chronic recurrent multifocal osteomyelitis and familial hyperphosphatemic familial tumoral calcinosis.. Scand J Rheumatol 2015;44:170-2", "CE Dumitrescu, MH Kelly, A Khosravi, TC Hart, J Brahim, KE White, EG Farrow, MH Nathan, MD Murphey, MT Collins. A case of familial tumoral calcinosis/hyperostosis-hyperphosphatemia syndrome due to a compound heterozygous mutation in GALNT3 demonstrating new phenotypic features.. Osteoporos Int 2009;20:1273-8", "G Favia, MG Lacaita, L Limongelli, A Tempesta, N Laforgia, AP Cazzolla, E Maiorano. Hyperphosphatemic familial tumoral calcinosis: odontostomatologic management and pathological features.. Am J Case Rep 2014;15:569-75", "G Finer, HE Price, RM Shore, KE White, CB Langman. Hyperphosphatemic familial tumoral calcinosis: response to acetazolamide and postulated mechanisms.. Am J Med Genet A 2014;164A:1545-9", "BL Foster, MS Ramnitz, RI Gafni, AB Burke, AM Boyce, JS Lee, JT Wright, SO Akintoye, MJ Somerman, MT Collins. Rare bone diseases and their dental, oral, and craniofacial manifestations.. J Dent Res 2014;93:7S-19S", "Y Frishberg, O Topaz, R Bergman, D Behar, D Fisher, D Gordon, G Richard, E Sprecher. Identification of a recurrent mutation in GALNT3 demonstrates that hyperostosis-hyperphosphatemia syndrome and familial tumoral calcinosis are allelic disorders.. J Mol Med (Berl) 2005;83:33-8", "HJ Garringer, C Fisher, TE Larsson, SI Davis, DL Koller, MJ Cullen, MS Draman, N Conlon, A Jain, NS Fedarko, B Dasgupta, KE White. The role of mutant UDP-N-acetyl-alpha-D-galactosamine-polypeptide N-acetylgalactosaminyltransferase 3 in regulating serum intact fibroblast growth factor 23 and matrix extracellular phosphoglycoprotein in heritable tumoral calcinosis.. J Clin Endocrinol Metab 2006;91:4037-42", "HJ Garringer, SM Mortazavi, F Esteghamat, M Malekpour, H Boztepe, R Tanakol, SI Davis, KE White. Two novel GALNT3 mutations in familial tumoral calcinosis.. Am J Med Genet A 2007;143A:2390-6", "F Gok, I Chefetz, M Indelman, M Kocaoglu, E Sprecher. Newly discovered mutations in the GALNT3 gene causing autosomal recessive hyperostosis-hyperphosphatemia syndrome.. Acta Orthop 2009;80:131-4", "S Ichikawa, G Baujat, A Seyahi, AG Garoufali, EA Imel, LR Padgett, AM Austin, AH Sorenson, Z Pejin, V Topouchian, P Quartier, V Cormier-Daire, M Dechaux, FCh Malandrinou, PN Singhellakis, M Le Merrer, MJ Econs. Clinical variability of familial tumoral calcinosis caused by novel GALNT3 mutations.. Am J Med Genet A 2010;152A:896-903", "S Ichikawa, V Guigonis, EA Imel, M Courouble, S Heissat, JD Henley, AH Sorenson, B Petit, A Lienhardt, MJ Econs. Novel GALNT3 mutations causing hyperostosis-hyperphosphatemia syndrome result in low intact fibroblast growth factor 23 concentrations.. J Clin Endocrinol Metab 2007a;92:1943-7", "S Ichikawa, EA Imel, ML Kreiter, X Yu, DS Mackenzie, AH Sorenson, R Goetz, M Mohammadi, KE White, MJ Econs. A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis.. J Musculoskelet Neuronal Interact 2007b;7:318-9", "S Ichikawa, EA Imel, ML Kreiter, X Yu, DS Mackenzie, AH Sorenson, R Goetz, M Mohammadi, KE White, MJ Econs. A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis.. J Clin Invest 2007c;117:2684-91", "S Ichikawa, EA Imel, AH Sorenson, R Severe, P Knudson, GJ Harris, JL Shaker, MJ Econs. Tumoral calcinosis presenting with eyelid calcifications due to novel missense mutations in the glycosyl transferase domain of the GALNT3 gene.. J Clin Endocrinol Metab 2006;91:4472-5", "S Ichikawa, KW Lyles, MJ Econs. A novel GALNT3 mutation in a pseudoautosomal dominant form of tumoral calcinosis: evidence that the disorder is autosomal recessive.. J Clin Endocrinol Metab. 2005;90:2420-3", "L Joseph, SN Hing, N Presneau, P O'Donnell, T Diss, BD Idowu, S Joseph, AM Flanagan, D Delaney. Familial tumoral calcinosis and hyperostosis-hyperphosphataemia syndrome are different manifestations of the same disease: novel missense mutations in GALNT3.. Skeletal Radiol 2010;39:63-8", "J Jost, C Bahans, M Courbebaisse, TA Tran, A Linglart, K Benistan, A Lienhardt, H Mutar, E Pfender, V Ratsimbazafy, V Guigonis. Topical sodium thiosulfate: a treatment for calcifications in hyperphosphatemic familial tumoral calcinosis?. J Clin Endocrinol Metab 2016;101:2810-5", "VS Keskar, EA Imel, M Kulkarni, S Mane, TE Jamale, MJ Econs, NK Hase. The case: ectopic calcifications in a child.. Kidney Int 2015;87:1079-81", "A Krstevska, S Gale, F. Blair. Tumoral calcinosis: a dental literature review and case report.. Dent Update. 2012;39:416-8, 421", "A Laleye, MJ Alao, G Gbessi, M Adjagba, M Marche, I Coupry, I Redonnet-Vernhet, S Lepreux, B Ayivi, RB Darboux, D Lacombe, B Arveiler. Tumoral calcinosis due to GALNT3 C.516-2A >T mutation in a black African family.. Genet Couns. 2008;19:183-92", "JJ Lammoglia, V Mericq. Familial tumoral calcinosis caused by a novel FGF23 mutation: response to induction of tubular renal acidosis with acetazolamide and the non-calcium phosphate binder sevelamer.. Horm Res 2009;71:178-84", "SW Li Voon Chong, S Ah Kion, MJ Cullen. A report of familial hyperphosphataemia in an Irish family.. Ir J Med Sci 1999;168:262-4", "KW Lyles, EJ Burkes, GJ Ellis, KJ Lucas, EA Dolan, MK Drezner. Genetic transmission of tumoral calcinosis: autosomal dominant with variable clinical expressivity.. J Clin Endocrinol Metab. 1985;60:1093-6", "S Martinez, JB Vogler, JM Harrelson, KW Lyles. Imaging of tumoral calcinosis: new observations.. Radiology 1990;174:215-22", "L Masi, G Beltrami, S Ottanelli, F Franceschelli, A Gozzini, R Zonefrati, G Galli, S Ciuffi, C Mavilia, F Giusti, G Marcucci, F Cioppi, E Colli, C Fossi, A Franchi, C Casentini, R Capanna, ML Brandi. Human preosteoblastic cell culture from a patient with severe tumoral calcinosis-hyperphosphatemia due to a new GALNT3 gene mutation: study of in vitro mineralization.. Calcif Tissue Int 2015;96:438-52", "L Masi, A Gozzini, A Franchi, D Campanacci, A Amedei, A Falchetti, F Franceschelli, G Marcucci, A Tanini, R Capanna, ML Brandi. A novel recessive mutation of fibroblast growth factor-23 in tumoral calcinosis.. J Bone Joint Surg Am 2009;91:1190-8", "E McGrath, F Harney, F Kinsella. An ocular presentation of familial tumoral calcinosis.. BMJ Case Rep 2010;2010", "JJ McPhaul, FL Engel. Heterotopic calcification, hyperphosphatemia and angioid streaks of the retina.. Am J Med 1961;31:488-92", "H Olauson, T Krajisnik, C Larsson, B Lindberg, TE Larsson. A novel missense mutation in GALNT3 causing hyperostosis-hyperphosphataemia syndrome.. Eur J Endocrinol 2008;158:929-34", "S Rafaelsen, S Johansson, H Ræder, R Bjerknes. Long-term clinical outcome and phenotypic variability in hyperphosphatemic familial tumoral calcinosis and hyperphosphatemic hyperostosis syndrome caused by a novel GALNT3 mutation; case report and review of the literature.. BMC Genet 2014;15:98", "MS Ramnitz, P Gourh, R Goldbach-Mansky, F Wodajo, S Ichikawa, MJ Econs, KE White, A Molinolo, MY Chen, T Heller, J Del Rivero, P Seo-Mayer, B Arabshahi, MB Jackson, S Hatab, E McCarthy, LC Guthrie, BA Brillante, RI Gafni, MT Collins. Phenotypic and genotypic characterization and treatment of a cohort with familial tumoral calcinosis/hyperostosis-hyperphosphatemia syndrome.. J Bone Miner Res 2016;31:1845-54", "A Shah, CJ Miller, CC Nast, MD Adams, B Truitt, JA Tayek, L Tong, P Mehtani, F Monteon, JR Sedor, EL Clinkenbeard, K White, R Mehrotra, J LaPage, P Dickson, SG Adler, SK Iyengar. Severe vascular calcification and tumoral calcinosis in a family with hyperphosphatemia: a fibroblast growth factor 23 mutation identified by exome sequencing.. Nephrol Dial Transplant 2014;29:2235-43", "RE Slavin, J Wen, D Kumar, EB Evans. Familial tumoral calcinosis. A clinical, histopathologic, and ultrastructural study with an analysis of its calcifying process and pathogenesis.. Am J Surg Pathol 1993;17:788-802", "E Sprecher. Familial tumoral calcinosis: from characterization of a rare phenotype to the pathogenesis of ectopic calcification.. J Invest Dermatol 2010;130:652-60", "R Steinherz, RW Chesney, B Eisenstein, A Metzker, HF DeLuca, M Phelps. Elevated serum calcitriol concentrations do not fall in response to hyperphosphatemia in familial tumoral calcinosis.. Am J Dis Child 1985;139:816-9", "AR Vieira, M Lee, F Vairo, JC Loguercio Leite, MC Munerato, F Visioli, SR D'Ávila, SK Wang, M Choi, JP Simmer, JC Hu. Root anomalies and dentin dysplasia in autosomal recessive hyperphosphatemic familial tumoral calcinosis (HFTC).. Oral Surg Oral Med Oral Pathol Oral Radiol. 2015;120:e235-9", "T Yamaguchi, T Sugimoto, Y Imai, M Fukase, T Fujita, K Chihara. Successful treatment of hyperphosphatemic tumoral calcinosis with long-term acetazolamide.. Bone 1995;16:247S-250S", "A Yancovitch, D Hershkovitz, M Indelman, P Galloway, M Whiteford, E Sprecher, E Kılıç. Novel mutations in GALNT3 causing hyperphosphatemic familial tumoral calcinosis.. J Bone Miner Metab 2011;29:621-5" ]	1/2/2018			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
hyper-nfj2	hyper-nfj2	[ "ADTKD-REN", "Familial Juvenile Hyperuricemic Nephropathy Type 2 (FJHN2)", "ADTKD-REN", "Familial Juvenile Hyperuricemic Nephropathy Type 2 (FJHN2)", "Renin", "REN", "Autosomal Dominant Tubulointerstitial Kidney Disease – REN" ]	Autosomal Dominant Tubulointerstitial Kidney Disease –	Martina Živná, Kendrah Kidd, Stanislav Kmoch, Anthony J Bleyer	Summary The two clinical presentations observed in autosomal dominant tubulointerstitial kidney disease – Childhood/adolescent onset, the more common presentation (caused by Adult onset, the less common presentation (caused by The diagnosis of ADTKD- In all persons with ADTKD- ADTKD-	## Diagnosis Consensus clinical diagnostic criteria for autosomal dominant tubulointerstitial kidney disease due to ADTKD- Blood pressure that is often borderline low, but usually asymptomatic Hyperkalemia (serum potassium levels >5 mEq/L, sometimes as high as 6.5 mEq/L) in about 50% of individuals, often present from birth Acidosis (serum bicarbonate levels between 15 and 24 mEq/L), often present from birth Low erythropoietin concentration Low hemoglobin concentrations (usually 9-11 g/dL) Low reticulocyte count relative to the hemoglobin concentration Otherwise normal hematologic findings Hyperuricemia (serum uric acid concentration >6 mg/dL) is present in 80% of affected individuals beginning in childhood. Usually, hyperuricemia in an individual with normal kidney function corresponds to a serum concentration of uric acid >1 SD above the normal value for age and sex. It is important to use age-related norms for serum urate [ Decreased fractional excretion of urinary uric acid in the vast majority of individuals with ADTKD- The fractional excretion of uric acid is usually <5% in adult men and <6% in adult women. The reduction of urate excretion can be detected in affected children with preserved renal function [ Note: (1) The fractional excretion of urinary uric acid can be measured from a spot urine sample; however, a 24-hour urine collection is preferable. (2) Aspirin, diuretics, and nonsteroidal agents should be avoided during the collection. (3) Because the fractional excretion of uric acid rises above 5% as renal function worsens, this test is not sensitive in individuals who have an eGFR <70 mL/min. Serum Uric Acid Concentration in Individuals with Normal Renal Function Fractional Excretion of Urinary Uric Acid in Individuals with Normal Renal Function The fractional excretion of urinary uric acid can be calculated as follows: urine uric acid concentration x serum creatinine concentration ÷ serum uric acid concentration x urine creatinine concentration A fractional excretion of urate >1 SD below the mean suggests reduced urate excretion. Estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m Bland urinary sediment (i.e., little blood or protein). Hematuria is generally not present, and excretion of protein is <1 g per 24 hours except when CKD is advanced. Kidney ultrasound examination shows normal-to-small kidney size without cysts. Predisposition to acute, but reversible, kidney injury in the setting of dehydration or viral illness, especially if there has been concomitant treatment with a nonsteroidal anti-inflammatory drug [ Family history consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis. The diagnosis of ADTKD- 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 ADTKD- See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and 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. • Blood pressure that is often borderline low, but usually asymptomatic • Hyperkalemia (serum potassium levels >5 mEq/L, sometimes as high as 6.5 mEq/L) in about 50% of individuals, often present from birth • Acidosis (serum bicarbonate levels between 15 and 24 mEq/L), often present from birth • Low erythropoietin concentration • Low hemoglobin concentrations (usually 9-11 g/dL) • Low reticulocyte count relative to the hemoglobin concentration • Otherwise normal hematologic findings • Hyperuricemia (serum uric acid concentration >6 mg/dL) is present in 80% of affected individuals beginning in childhood. • Usually, hyperuricemia in an individual with normal kidney function corresponds to a serum concentration of uric acid >1 SD above the normal value for age and sex. It is important to use age-related norms for serum urate [ • Decreased fractional excretion of urinary uric acid in the vast majority of individuals with ADTKD- • The fractional excretion of uric acid is usually <5% in adult men and <6% in adult women. The reduction of urate excretion can be detected in affected children with preserved renal function [ • Note: (1) The fractional excretion of urinary uric acid can be measured from a spot urine sample; however, a 24-hour urine collection is preferable. (2) Aspirin, diuretics, and nonsteroidal agents should be avoided during the collection. (3) Because the fractional excretion of uric acid rises above 5% as renal function worsens, this test is not sensitive in individuals who have an eGFR <70 mL/min. • Estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m • Bland urinary sediment (i.e., little blood or protein). Hematuria is generally not present, and excretion of protein is <1 g per 24 hours except when CKD is advanced. • Kidney ultrasound examination shows normal-to-small kidney size without cysts. • Bland urinary sediment (i.e., little blood or protein). Hematuria is generally not present, and excretion of protein is <1 g per 24 hours except when CKD is advanced. • Kidney ultrasound examination shows normal-to-small kidney size without cysts. • Predisposition to acute, but reversible, kidney injury in the setting of dehydration or viral illness, especially if there has been concomitant treatment with a nonsteroidal anti-inflammatory drug [ • Bland urinary sediment (i.e., little blood or protein). Hematuria is generally not present, and excretion of protein is <1 g per 24 hours except when CKD is advanced. • Kidney ultrasound examination shows normal-to-small kidney size without cysts. ## Suggestive Findings ADTKD- Blood pressure that is often borderline low, but usually asymptomatic Hyperkalemia (serum potassium levels >5 mEq/L, sometimes as high as 6.5 mEq/L) in about 50% of individuals, often present from birth Acidosis (serum bicarbonate levels between 15 and 24 mEq/L), often present from birth Low erythropoietin concentration Low hemoglobin concentrations (usually 9-11 g/dL) Low reticulocyte count relative to the hemoglobin concentration Otherwise normal hematologic findings Hyperuricemia (serum uric acid concentration >6 mg/dL) is present in 80% of affected individuals beginning in childhood. Usually, hyperuricemia in an individual with normal kidney function corresponds to a serum concentration of uric acid >1 SD above the normal value for age and sex. It is important to use age-related norms for serum urate [ Decreased fractional excretion of urinary uric acid in the vast majority of individuals with ADTKD- The fractional excretion of uric acid is usually <5% in adult men and <6% in adult women. The reduction of urate excretion can be detected in affected children with preserved renal function [ Note: (1) The fractional excretion of urinary uric acid can be measured from a spot urine sample; however, a 24-hour urine collection is preferable. (2) Aspirin, diuretics, and nonsteroidal agents should be avoided during the collection. (3) Because the fractional excretion of uric acid rises above 5% as renal function worsens, this test is not sensitive in individuals who have an eGFR <70 mL/min. Serum Uric Acid Concentration in Individuals with Normal Renal Function Fractional Excretion of Urinary Uric Acid in Individuals with Normal Renal Function The fractional excretion of urinary uric acid can be calculated as follows: urine uric acid concentration x serum creatinine concentration ÷ serum uric acid concentration x urine creatinine concentration A fractional excretion of urate >1 SD below the mean suggests reduced urate excretion. Estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m Bland urinary sediment (i.e., little blood or protein). Hematuria is generally not present, and excretion of protein is <1 g per 24 hours except when CKD is advanced. Kidney ultrasound examination shows normal-to-small kidney size without cysts. Predisposition to acute, but reversible, kidney injury in the setting of dehydration or viral illness, especially if there has been concomitant treatment with a nonsteroidal anti-inflammatory drug [ 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. • Blood pressure that is often borderline low, but usually asymptomatic • Hyperkalemia (serum potassium levels >5 mEq/L, sometimes as high as 6.5 mEq/L) in about 50% of individuals, often present from birth • Acidosis (serum bicarbonate levels between 15 and 24 mEq/L), often present from birth • Low erythropoietin concentration • Low hemoglobin concentrations (usually 9-11 g/dL) • Low reticulocyte count relative to the hemoglobin concentration • Otherwise normal hematologic findings • Hyperuricemia (serum uric acid concentration >6 mg/dL) is present in 80% of affected individuals beginning in childhood. • Usually, hyperuricemia in an individual with normal kidney function corresponds to a serum concentration of uric acid >1 SD above the normal value for age and sex. It is important to use age-related norms for serum urate [ • Decreased fractional excretion of urinary uric acid in the vast majority of individuals with ADTKD- • The fractional excretion of uric acid is usually <5% in adult men and <6% in adult women. The reduction of urate excretion can be detected in affected children with preserved renal function [ • Note: (1) The fractional excretion of urinary uric acid can be measured from a spot urine sample; however, a 24-hour urine collection is preferable. (2) Aspirin, diuretics, and nonsteroidal agents should be avoided during the collection. (3) Because the fractional excretion of uric acid rises above 5% as renal function worsens, this test is not sensitive in individuals who have an eGFR <70 mL/min. • Estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m • Bland urinary sediment (i.e., little blood or protein). Hematuria is generally not present, and excretion of protein is <1 g per 24 hours except when CKD is advanced. • Kidney ultrasound examination shows normal-to-small kidney size without cysts. • Bland urinary sediment (i.e., little blood or protein). Hematuria is generally not present, and excretion of protein is <1 g per 24 hours except when CKD is advanced. • Kidney ultrasound examination shows normal-to-small kidney size without cysts. • Predisposition to acute, but reversible, kidney injury in the setting of dehydration or viral illness, especially if there has been concomitant treatment with a nonsteroidal anti-inflammatory drug [ • Bland urinary sediment (i.e., little blood or protein). Hematuria is generally not present, and excretion of protein is <1 g per 24 hours except when CKD is advanced. • Kidney ultrasound examination shows normal-to-small kidney size without cysts. ## Clinical Findings – Childhood/Adolescent-Onset Disease Blood pressure that is often borderline low, but usually asymptomatic Hyperkalemia (serum potassium levels >5 mEq/L, sometimes as high as 6.5 mEq/L) in about 50% of individuals, often present from birth Acidosis (serum bicarbonate levels between 15 and 24 mEq/L), often present from birth Low erythropoietin concentration Low hemoglobin concentrations (usually 9-11 g/dL) Low reticulocyte count relative to the hemoglobin concentration Otherwise normal hematologic findings Hyperuricemia (serum uric acid concentration >6 mg/dL) is present in 80% of affected individuals beginning in childhood. Usually, hyperuricemia in an individual with normal kidney function corresponds to a serum concentration of uric acid >1 SD above the normal value for age and sex. It is important to use age-related norms for serum urate [ Decreased fractional excretion of urinary uric acid in the vast majority of individuals with ADTKD- The fractional excretion of uric acid is usually <5% in adult men and <6% in adult women. The reduction of urate excretion can be detected in affected children with preserved renal function [ Note: (1) The fractional excretion of urinary uric acid can be measured from a spot urine sample; however, a 24-hour urine collection is preferable. (2) Aspirin, diuretics, and nonsteroidal agents should be avoided during the collection. (3) Because the fractional excretion of uric acid rises above 5% as renal function worsens, this test is not sensitive in individuals who have an eGFR <70 mL/min. Serum Uric Acid Concentration in Individuals with Normal Renal Function Fractional Excretion of Urinary Uric Acid in Individuals with Normal Renal Function The fractional excretion of urinary uric acid can be calculated as follows: urine uric acid concentration x serum creatinine concentration ÷ serum uric acid concentration x urine creatinine concentration A fractional excretion of urate >1 SD below the mean suggests reduced urate excretion. Estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m Bland urinary sediment (i.e., little blood or protein). Hematuria is generally not present, and excretion of protein is <1 g per 24 hours except when CKD is advanced. Kidney ultrasound examination shows normal-to-small kidney size without cysts. Predisposition to acute, but reversible, kidney injury in the setting of dehydration or viral illness, especially if there has been concomitant treatment with a nonsteroidal anti-inflammatory drug [ • Blood pressure that is often borderline low, but usually asymptomatic • Hyperkalemia (serum potassium levels >5 mEq/L, sometimes as high as 6.5 mEq/L) in about 50% of individuals, often present from birth • Acidosis (serum bicarbonate levels between 15 and 24 mEq/L), often present from birth • Low erythropoietin concentration • Low hemoglobin concentrations (usually 9-11 g/dL) • Low reticulocyte count relative to the hemoglobin concentration • Otherwise normal hematologic findings • Hyperuricemia (serum uric acid concentration >6 mg/dL) is present in 80% of affected individuals beginning in childhood. • Usually, hyperuricemia in an individual with normal kidney function corresponds to a serum concentration of uric acid >1 SD above the normal value for age and sex. It is important to use age-related norms for serum urate [ • Decreased fractional excretion of urinary uric acid in the vast majority of individuals with ADTKD- • The fractional excretion of uric acid is usually <5% in adult men and <6% in adult women. The reduction of urate excretion can be detected in affected children with preserved renal function [ • Note: (1) The fractional excretion of urinary uric acid can be measured from a spot urine sample; however, a 24-hour urine collection is preferable. (2) Aspirin, diuretics, and nonsteroidal agents should be avoided during the collection. (3) Because the fractional excretion of uric acid rises above 5% as renal function worsens, this test is not sensitive in individuals who have an eGFR <70 mL/min. • Estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m • Bland urinary sediment (i.e., little blood or protein). Hematuria is generally not present, and excretion of protein is <1 g per 24 hours except when CKD is advanced. • Kidney ultrasound examination shows normal-to-small kidney size without cysts. • Bland urinary sediment (i.e., little blood or protein). Hematuria is generally not present, and excretion of protein is <1 g per 24 hours except when CKD is advanced. • Kidney ultrasound examination shows normal-to-small kidney size without cysts. • Predisposition to acute, but reversible, kidney injury in the setting of dehydration or viral illness, especially if there has been concomitant treatment with a nonsteroidal anti-inflammatory drug [ • Bland urinary sediment (i.e., little blood or protein). Hematuria is generally not present, and excretion of protein is <1 g per 24 hours except when CKD is advanced. • Kidney ultrasound examination shows normal-to-small kidney size without cysts. ## Clinical Findings – Adult-Onset Disease (from 3rd decade) ## Family History Family history consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis. ## Establishing the Diagnosis The diagnosis of ADTKD- 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 ADTKD- See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Option 1 For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in ADTKD- See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and 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 In the most comprehensive report of autosomal dominant tubulointerstitial kidney disease due to Childhood/adolescent onset, the more common presentation, is caused by Adult onset, the less common presentation, is caused by ADTKD- Adapted from AKI = acute kidney injury; CKD = chronic kidney disease; ESKD = end-stage kidney disease; SD = standard deviation(s) Correlated with Correlated with Individuals often present between birth and age ten years with manifestations related to renin deficiency. As renin is important in prenatal kidney development, the eGFR is low (usually <60 mL/min/1.73 m Chronic kidney disease may slowly worsen in the second decade; acidemia and hyperkalemia persist. Gout may develop at this time due to decreased renal excretion of uric acid. Despite low eGFR at presentation, only one child required renal replacement therapy at age 15 years; others did not reach end-stage kidney disease (ESKD) until after age 30 years (mean age ~52 years). For these individuals, kidney function continues to worsen very slowly over time, with a mean age of ESKD of 53 in the signal peptide group and 51 in the prosegment group (see Individuals present in their twenties with gout and chronic kidney disease. Gout is easily controlled with allopurinol. The serum creatinine slowly rises with slow progression to ESKD at a mean age of 64 years [ The following information is provided in the event that some affected individuals (or their relatives) may have undergone kidney biopsy prior to consideration of ADTKD- Histologic examination reveals focal tubular atrophy, secondary glomerular scarring, and interstitial fibrosis [ The following phenotype-genotype correlations have been identified based on the Penetrance is age related. Thus, in individuals with childhood-onset disease, manifestations of ADTKD- According to the 2015 nomenclature [ Autosomal dominant inheritance Slowly progressive chronic tubulointerstitial kidney disease resulting in ESKD in the third through seventh decade of life Urinalysis revealing a bland urinary sediment (i.e., little blood or protein) Renal ultrasound examination that is normal early in the disease course [ ADTKD- The prevalence of disease is expected to be similar in all populations. • Autosomal dominant inheritance • Slowly progressive chronic tubulointerstitial kidney disease resulting in ESKD in the third through seventh decade of life • Urinalysis revealing a bland urinary sediment (i.e., little blood or protein) • Renal ultrasound examination that is normal early in the disease course [ ## Clinical Description In the most comprehensive report of autosomal dominant tubulointerstitial kidney disease due to Childhood/adolescent onset, the more common presentation, is caused by Adult onset, the less common presentation, is caused by ADTKD- Adapted from AKI = acute kidney injury; CKD = chronic kidney disease; ESKD = end-stage kidney disease; SD = standard deviation(s) Correlated with Correlated with Individuals often present between birth and age ten years with manifestations related to renin deficiency. As renin is important in prenatal kidney development, the eGFR is low (usually <60 mL/min/1.73 m Chronic kidney disease may slowly worsen in the second decade; acidemia and hyperkalemia persist. Gout may develop at this time due to decreased renal excretion of uric acid. Despite low eGFR at presentation, only one child required renal replacement therapy at age 15 years; others did not reach end-stage kidney disease (ESKD) until after age 30 years (mean age ~52 years). For these individuals, kidney function continues to worsen very slowly over time, with a mean age of ESKD of 53 in the signal peptide group and 51 in the prosegment group (see Individuals present in their twenties with gout and chronic kidney disease. Gout is easily controlled with allopurinol. The serum creatinine slowly rises with slow progression to ESKD at a mean age of 64 years [ The following information is provided in the event that some affected individuals (or their relatives) may have undergone kidney biopsy prior to consideration of ADTKD- Histologic examination reveals focal tubular atrophy, secondary glomerular scarring, and interstitial fibrosis [ ## Childhood/Adolescent Onset Individuals often present between birth and age ten years with manifestations related to renin deficiency. As renin is important in prenatal kidney development, the eGFR is low (usually <60 mL/min/1.73 m Chronic kidney disease may slowly worsen in the second decade; acidemia and hyperkalemia persist. Gout may develop at this time due to decreased renal excretion of uric acid. Despite low eGFR at presentation, only one child required renal replacement therapy at age 15 years; others did not reach end-stage kidney disease (ESKD) until after age 30 years (mean age ~52 years). For these individuals, kidney function continues to worsen very slowly over time, with a mean age of ESKD of 53 in the signal peptide group and 51 in the prosegment group (see ## Adult Onset Individuals present in their twenties with gout and chronic kidney disease. Gout is easily controlled with allopurinol. The serum creatinine slowly rises with slow progression to ESKD at a mean age of 64 years [ ## Kidney Biopsy The following information is provided in the event that some affected individuals (or their relatives) may have undergone kidney biopsy prior to consideration of ADTKD- Histologic examination reveals focal tubular atrophy, secondary glomerular scarring, and interstitial fibrosis [ ## Genotype-Phenotype Correlations The following phenotype-genotype correlations have been identified based on the ## Penetrance Penetrance is age related. Thus, in individuals with childhood-onset disease, manifestations of ADTKD- ## Nomenclature According to the 2015 nomenclature [ Autosomal dominant inheritance Slowly progressive chronic tubulointerstitial kidney disease resulting in ESKD in the third through seventh decade of life Urinalysis revealing a bland urinary sediment (i.e., little blood or protein) Renal ultrasound examination that is normal early in the disease course [ • Autosomal dominant inheritance • Slowly progressive chronic tubulointerstitial kidney disease resulting in ESKD in the third through seventh decade of life • Urinalysis revealing a bland urinary sediment (i.e., little blood or protein) • Renal ultrasound examination that is normal early in the disease course [ ## Prevalence ADTKD- The prevalence of disease is expected to be similar in all populations. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this Homozygosity or compound heterozygosity for loss-of-function (null) ## Differential Diagnosis See Monogenic Kidney Diseases in the Differential Diagnosis of ADTKD- Absence of affected family members in multiple generations Anemia usually correlates w/level of kidney function (i.e., may not be present in childhood). Severity of kidney failure is usually much greater (usually requiring dialysis in teens & early 20s). Hyperkalemia & acidemia are not as pronounced. Frequent cochlear & ocular manifestations Hematuria is present. Much more severe in males than in females Not assoc w/anemia in childhood or acidemia & hyperkalemia often seen in ADTKD- Phenotype is indistinguishable from adult-onset ADTKD- α-Gal A = alpha-galactosidase A; AD = autosomal dominant; AR = autosomal recessive; CAKUT = congenital anomalies of the kidneys and urinary tract; CKD = chronic kidney disease; ESKD = end-stage kidney disease; Mat = maternal; MOI = mode of inheritance; XL = X-linked Listed genes represent the most common genetic causes of isolated nephronophthisis. Other genes known to be associated with nephronophthisis are "Bland" refers to urinary sediment with little blood or protein. Males with >1% alpha-galactosidase A activity have a cardiac or renal variant phenotype. Rarely, heterozygous carrier females may have symptoms as severe as those observed in males with the classic phenotype. • Absence of affected family members in multiple generations • Anemia usually correlates w/level of kidney function (i.e., may not be present in childhood). • Severity of kidney failure is usually much greater (usually requiring dialysis in teens & early 20s). • Hyperkalemia & acidemia are not as pronounced. • Frequent cochlear & ocular manifestations • Hematuria is present. • Much more severe in males than in females • Not assoc w/anemia in childhood or acidemia & hyperkalemia often seen in ADTKD- • Phenotype is indistinguishable from adult-onset ADTKD- ## Management Consensus management guidelines for autosomal dominant tubulointerstitial kidney disease due to pathogenic variants in To establish the extent of disease and needs in an individual diagnosed with ADTKD- Recommended Evaluations Following Initial Diagnosis in Individuals with ADTKD- Hemoglobin level In childhood/adolescent-onset ADTKD- Obtain history for enuresis & excessive thirst or urination. 24-hr urine collection to quantify urine output MOI = mode of inheritance Applies to both presentations of ADTKD- Medical geneticist, certified genetic counselor, or certified advanced genetic nurse Care by a nephrologist is recommended. Many children have relatively mild anemia with hemoglobin levels of 10-11 g/dL, and can be safely followed off erythropoietin. Note: The dose of erythropoietin will need to be reduced as hemoglobin concentration increases during adolescence. Iron stores should be replenished as needed to treat iron deficiency (an unrelated condition) if it is present. In a retrospective cohort study [ Because fludrocortisone increases estimated glomerular filtration rate (eGFR), fludrocortisone treatment should be started prior to chronic kidney disease (CKD) Stage 3 (eGFR >60 mL/min/1.73 m Acute gout typically responds well to prednisone or colchicine. Prednisone is preferred to nonsteroidal anti-inflammatory drugs because the combination of NSAIDs and the low renin state in individuals with ADTKD- For individuals with allergies or intolerance to allopurinol, febuxostat may be considered. Renal replacement therapies such as hemodialysis and peritoneal dialysis replace renal function but are associated with potential complications. Kidney transplantation cures ADTKD- Avoid use of the following: NSAIDs, especially in a person who is dehydrated or in a febrile child, as they can precipitate acute renal failure [ Angiotensin-converting enzyme inhibitors, which may not be beneficial in the treatment of CKD and could aggravate the underlying relative renin deficit Drugs known to be nephrotoxic The low-sodium diet typically prescribed in the treatment of CKD Avoid the following, which may worsen hyperuricemia, leading to more frequent attacks of gout: Volume depletion, dehydration, and physical exertion under extreme conditions (e.g., when it is hot) High meat and seafood intake * Chronic kidney disease, one of the primary manifestations of this disorder, is often asymptomatic. See Successful pregnancies have been documented in women with ADTKD- In the authors' experience, in ADTKD- See Search • Hemoglobin level • In childhood/adolescent-onset ADTKD- • Obtain history for enuresis & excessive thirst or urination. • 24-hr urine collection to quantify urine output • NSAIDs, especially in a person who is dehydrated or in a febrile child, as they can precipitate acute renal failure [ • Angiotensin-converting enzyme inhibitors, which may not be beneficial in the treatment of CKD and could aggravate the underlying relative renin deficit • Drugs known to be nephrotoxic • The low-sodium diet typically prescribed in the treatment of CKD • Volume depletion, dehydration, and physical exertion under extreme conditions (e.g., when it is hot) • High meat and seafood intake ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with ADTKD- Recommended Evaluations Following Initial Diagnosis in Individuals with ADTKD- Hemoglobin level In childhood/adolescent-onset ADTKD- Obtain history for enuresis & excessive thirst or urination. 24-hr urine collection to quantify urine output MOI = mode of inheritance Applies to both presentations of ADTKD- Medical geneticist, certified genetic counselor, or certified advanced genetic nurse • Hemoglobin level • In childhood/adolescent-onset ADTKD- • Obtain history for enuresis & excessive thirst or urination. • 24-hr urine collection to quantify urine output ## Treatment of Manifestations Care by a nephrologist is recommended. Many children have relatively mild anemia with hemoglobin levels of 10-11 g/dL, and can be safely followed off erythropoietin. Note: The dose of erythropoietin will need to be reduced as hemoglobin concentration increases during adolescence. Iron stores should be replenished as needed to treat iron deficiency (an unrelated condition) if it is present. In a retrospective cohort study [ Because fludrocortisone increases estimated glomerular filtration rate (eGFR), fludrocortisone treatment should be started prior to chronic kidney disease (CKD) Stage 3 (eGFR >60 mL/min/1.73 m Acute gout typically responds well to prednisone or colchicine. Prednisone is preferred to nonsteroidal anti-inflammatory drugs because the combination of NSAIDs and the low renin state in individuals with ADTKD- For individuals with allergies or intolerance to allopurinol, febuxostat may be considered. Renal replacement therapies such as hemodialysis and peritoneal dialysis replace renal function but are associated with potential complications. Kidney transplantation cures ADTKD- ## Childhood/Adolescent-Onset Disease Only Many children have relatively mild anemia with hemoglobin levels of 10-11 g/dL, and can be safely followed off erythropoietin. Note: The dose of erythropoietin will need to be reduced as hemoglobin concentration increases during adolescence. Iron stores should be replenished as needed to treat iron deficiency (an unrelated condition) if it is present. In a retrospective cohort study [ Because fludrocortisone increases estimated glomerular filtration rate (eGFR), fludrocortisone treatment should be started prior to chronic kidney disease (CKD) Stage 3 (eGFR >60 mL/min/1.73 m ## Both Childhood/Adolescent-Onset and Adult-Onset Disease Acute gout typically responds well to prednisone or colchicine. Prednisone is preferred to nonsteroidal anti-inflammatory drugs because the combination of NSAIDs and the low renin state in individuals with ADTKD- For individuals with allergies or intolerance to allopurinol, febuxostat may be considered. Renal replacement therapies such as hemodialysis and peritoneal dialysis replace renal function but are associated with potential complications. Kidney transplantation cures ADTKD- ## Surveillance ## Agents/Circumstances to Avoid Avoid use of the following: NSAIDs, especially in a person who is dehydrated or in a febrile child, as they can precipitate acute renal failure [ Angiotensin-converting enzyme inhibitors, which may not be beneficial in the treatment of CKD and could aggravate the underlying relative renin deficit Drugs known to be nephrotoxic The low-sodium diet typically prescribed in the treatment of CKD Avoid the following, which may worsen hyperuricemia, leading to more frequent attacks of gout: Volume depletion, dehydration, and physical exertion under extreme conditions (e.g., when it is hot) High meat and seafood intake • NSAIDs, especially in a person who is dehydrated or in a febrile child, as they can precipitate acute renal failure [ • Angiotensin-converting enzyme inhibitors, which may not be beneficial in the treatment of CKD and could aggravate the underlying relative renin deficit • Drugs known to be nephrotoxic • The low-sodium diet typically prescribed in the treatment of CKD • Volume depletion, dehydration, and physical exertion under extreme conditions (e.g., when it is hot) • High meat and seafood intake ## Evaluation of Relatives at Risk * Chronic kidney disease, one of the primary manifestations of this disorder, is often asymptomatic. See ## Pregnancy Management Successful pregnancies have been documented in women with ADTKD- In the authors' experience, in ADTKD- See ## Therapies Under Investigation Search ## Genetic Counseling By definition, autosomal dominant tubulointerstitial kidney disease due to pathogenic variants in Most individuals diagnosed with ADTKD- A proband with ADTKD- 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 (although no instances of germline mosaicism have been reported, it remains a possibility). Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. An apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the 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 and/or a milder phenotypic presentation. Parents will usually have had anemia in childhood, but they may not recall this from their childhood, or the diagnosis of anemia may have been missed at that time. If a parent of the proband has the 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 a personal decision, discussion of these issues may be helpful. • Most individuals diagnosed with ADTKD- • A proband with ADTKD- • 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 (although no instances of germline mosaicism have been reported, it remains a possibility). Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism (although no instances of germline mosaicism have been reported, it remains a possibility). Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. • An apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the • 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 and/or a milder phenotypic presentation. • Parents will usually have had anemia in childhood, but they may not recall this from their childhood, or the diagnosis of anemia may have been missed at that time. • 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 and/or a milder phenotypic presentation. • Parents will usually have had anemia in childhood, but they may not recall this from their childhood, or the diagnosis of anemia may have been missed at that time. • 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). Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. • 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 and/or a milder phenotypic presentation. • Parents will usually have had anemia in childhood, but they may not recall this from their childhood, or the diagnosis of anemia may have been missed at that time. • If a parent of the proband has the • 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 By definition, autosomal dominant tubulointerstitial kidney disease due to pathogenic variants in ## Risk to Family Members Most individuals diagnosed with ADTKD- A proband with ADTKD- 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 (although no instances of germline mosaicism have been reported, it remains a possibility). Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. An apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the 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 and/or a milder phenotypic presentation. Parents will usually have had anemia in childhood, but they may not recall this from their childhood, or the diagnosis of anemia may have been missed at that time. If a parent of the proband has the If the proband has a known If the parents have not been tested for the • Most individuals diagnosed with ADTKD- • A proband with ADTKD- • 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 (although no instances of germline mosaicism have been reported, it remains a possibility). Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism (although no instances of germline mosaicism have been reported, it remains a possibility). Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. • An apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the • 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 and/or a milder phenotypic presentation. • Parents will usually have had anemia in childhood, but they may not recall this from their childhood, or the diagnosis of anemia may have been missed at that time. • 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 and/or a milder phenotypic presentation. • Parents will usually have had anemia in childhood, but they may not recall this from their childhood, or the diagnosis of anemia may have been missed at that time. • 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). Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. • 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 and/or a milder phenotypic presentation. • Parents will usually have had anemia in childhood, but they may not recall this from their childhood, or the diagnosis of anemia may have been missed at that time. • If a parent of the proband has the • 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 a personal decision, discussion of these issues may be helpful. ## Resources • • • • ## Molecular Genetics Autosomal Dominant Tubulointerstitial Kidney Disease -- REN: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Autosomal Dominant Tubulointerstitial Kidney Disease -- REN ( Renin is an aspartyl protease synthesized as preprorenin, which contains a signal sequence that directs endoplasmic reticulum (ER) targeting, glycosylation, and proteolytic processing [ In vitro studies have shown that the presence of the mutated signal peptide affects renin targeting and cotranslational translocation of preprorenin into the ER, and thus proper biosynthesis and intracellular trafficking of prorenin. This results in ER stress, cytosolic accumulation of abnormal non-glycosylated preprorenin, accelerated autophagocytosis, and reduced growth rate. In vivo this gradually reduces viability of renin-producing juxtaglomerular cells, and results – by as-yet undefined mechanism(s) – in tubular atrophy, nephron loss, and chronic kidney failure, similar to that observed in mice with ablated juxtaglomerular cells [ Mutated signal peptide cannot enter the ER for transcription. Mutated prosegment prevents proper folding of the renin peptide. In both instances, mutated renin is deposited within the cell, leading to cell stress, premature cell death, and subsequent tubular cell dropout, interstitial scarring, and chronic kidney disease. Individuals with childhood/adolescent-onset disease, caused by Mutated mature renin peptide is deposited in the endoplasmic reticulum. Individuals with adult-onset disease, caused by 62% occur in exon 1 encoding the signal peptide of preprorenin, and 27% in the part encoding the prosegment of prorenin. 15% occur in exons 2, 8, 9, and 10 encoding the mature renin peptide. Notable Variants listed in the table have been provided by the authors. • Mutated signal peptide cannot enter the ER for transcription. Mutated prosegment prevents proper folding of the renin peptide. In both instances, mutated renin is deposited within the cell, leading to cell stress, premature cell death, and subsequent tubular cell dropout, interstitial scarring, and chronic kidney disease. Individuals with childhood/adolescent-onset disease, caused by • Mutated mature renin peptide is deposited in the endoplasmic reticulum. Individuals with adult-onset disease, caused by • 62% occur in exon 1 encoding the signal peptide of preprorenin, and 27% in the part encoding the prosegment of prorenin. • 15% occur in exons 2, 8, 9, and 10 encoding the mature renin peptide. ## Molecular Pathogenesis Renin is an aspartyl protease synthesized as preprorenin, which contains a signal sequence that directs endoplasmic reticulum (ER) targeting, glycosylation, and proteolytic processing [ In vitro studies have shown that the presence of the mutated signal peptide affects renin targeting and cotranslational translocation of preprorenin into the ER, and thus proper biosynthesis and intracellular trafficking of prorenin. This results in ER stress, cytosolic accumulation of abnormal non-glycosylated preprorenin, accelerated autophagocytosis, and reduced growth rate. In vivo this gradually reduces viability of renin-producing juxtaglomerular cells, and results – by as-yet undefined mechanism(s) – in tubular atrophy, nephron loss, and chronic kidney failure, similar to that observed in mice with ablated juxtaglomerular cells [ Mutated signal peptide cannot enter the ER for transcription. Mutated prosegment prevents proper folding of the renin peptide. In both instances, mutated renin is deposited within the cell, leading to cell stress, premature cell death, and subsequent tubular cell dropout, interstitial scarring, and chronic kidney disease. Individuals with childhood/adolescent-onset disease, caused by Mutated mature renin peptide is deposited in the endoplasmic reticulum. Individuals with adult-onset disease, caused by 62% occur in exon 1 encoding the signal peptide of preprorenin, and 27% in the part encoding the prosegment of prorenin. 15% occur in exons 2, 8, 9, and 10 encoding the mature renin peptide. Notable Variants listed in the table have been provided by the authors. • Mutated signal peptide cannot enter the ER for transcription. Mutated prosegment prevents proper folding of the renin peptide. In both instances, mutated renin is deposited within the cell, leading to cell stress, premature cell death, and subsequent tubular cell dropout, interstitial scarring, and chronic kidney disease. Individuals with childhood/adolescent-onset disease, caused by • Mutated mature renin peptide is deposited in the endoplasmic reticulum. Individuals with adult-onset disease, caused by • 62% occur in exon 1 encoding the signal peptide of preprorenin, and 27% in the part encoding the prosegment of prorenin. • 15% occur in exons 2, 8, 9, and 10 encoding the mature renin peptide. ## Chapter Notes Martina Živná, PhD ( Related website: The authors would like to acknowledge the many patients and their physicians who shared clinical and genetic information that formed the basis of our clinical and genetic characterization of ADTKD- 10 December 2020 (bp) Comprehensive update posted live 29 December 2015 (me) Comprehensive update posted live 5 April 2011 (me) Review posted live 21 December 2010 (ab) Original submission • 10 December 2020 (bp) Comprehensive update posted live • 29 December 2015 (me) Comprehensive update posted live • 5 April 2011 (me) Review posted live • 21 December 2010 (ab) Original submission ## Author Notes Martina Živná, PhD ( Related website: ## Acknowledgements The authors would like to acknowledge the many patients and their physicians who shared clinical and genetic information that formed the basis of our clinical and genetic characterization of ADTKD- ## Revision History 10 December 2020 (bp) Comprehensive update posted live 29 December 2015 (me) Comprehensive update posted live 5 April 2011 (me) Review posted live 21 December 2010 (ab) Original submission • 10 December 2020 (bp) Comprehensive update posted live • 29 December 2015 (me) Comprehensive update posted live • 5 April 2011 (me) Review posted live • 21 December 2010 (ab) Original submission ## References ## Literature Cited Testing strategy for inherited kidney disease	[ "M Abdelwahed, Y Chaabouni, L Michel-Calemard, K Chaabouni, Y Morel, J Hachicha, FA Makni, H Kamoun, L Ammar-Keskes, N Belghith. A novel disease-causing mutation in the Renin gene in a Tunisian family with autosomal dominant tubulointerstitial kidney disease.. Int J Biochem Cell Biol. 2019;117", "BB Beck, H Trachtman, M Gitman, I Miller, JA Sayer, A Pannes, A Baasner, F Hildebrandt, MT Wolf. Autosomal dominant mutation in the signal peptide of renin in a kindred with anemia, hyperuricemia, and CKD.. Am J Kidney Dis. 2011;58:821-5", "M Berkenstadt, B Weisz, H Cuckle, M Di-Castro, E Guetta, G Barkai. Chromosomal abnormalities and birth defects among couples with colchicine treated familial Mediterranean fever.. Am J Obstet Gynecol. 2005;193:1513-6", "AJ Bleyer, PS Hart, S Kmoch. Hereditary interstitial kidney disease.. Semin Nephrol 2010a;30:366-73", "AJ Bleyer, M Zivná, H Hulková, K Hodanová, P Vyletal, J Sikora, J Zivny, J Sovová, TC Hart, JN Adams, M Elleder, K Kapp, R Haws, LD Cornell, S Kmoch, PS Hart. Clinical and molecular characterization of a family with a dominant renin gene mutation and response to treatment with fludrocortisone.. Clin Nephrol 2010b;74:411-22", "SL Carmichael, GM Shaw, C Ma, MM Werler, SA Rasmussen, EJ Lammer. Maternal corticosteroid use and orofacial clefts.. Am J Obstet Gynecol. 2007;197:585.e1-7", "RL Clissold, HC Clarke, O Spasic-Boskovic, K Brugger, S Abbs, C Bingham, C Shaw-Smith. Discovery of a novel dominant mutation in the REN gene after forty years of renal disease: a case report.. BMC Nephrol. 2017;18:234", "TM Connor, S Hoer, A Mallett, DP Gale, A Gomez-Duran, V Posse, R Antrobus, P Moreno, M Sciacovelli, C Frezza, J Duff, NS Sheerin, JA Sayer, M Ashcroft, MS Wiesener, G Hudson, CM Gustafsson, PF Chinnery, PH Maxwell. Mutations in mitochondrial DNA causing tubulointerstitial kidney disease.. PLoS Genet. 2017;13", "A Cyganek, B Pietrzak, B Kociszewska-Najman, J Sanko-Resmer, L Paczek, M Wielgos. Anemia treatment with erythropoietin in pregnant renal recipients.. Transplant Proc. 2011;43:2970-2", "KU Eckardt, SL Alper, C Antignac, AJ Bleyer, D Chauveau, K Dahan, C Deltas, A Hosking, S Kmoch, L Rampoldi, M Wiesener, MT Wolf, O Devuyst. Autosomal dominant tubulointerstitial kidney disease: diagnosis, classification, and management--A KDIGO consensus report.. Kidney Int. 2015;88:676-83", "O Devuyst, E Olinger, S Weber, KU Eckardt, S Kmoch, L Rampoldi, AJ Bleyer. Autosomal dominant tubulointerstitial kidney disease.. Nat Rev Dis Primers. 2019;5:60", "RA Harkness, AD Nicol. Plasma uric acid levels in children.. Arch Dis Child 1969;44:773-8", "M Hoeltzenbein, K Stieler, M Panse, E Wacker, C Schaefer. Allopurinol use during pregnancy - outcome of 31 prospectively ascertained cases and a phenotype possibly indicative for teratogenicity.. PLoS One. 2013;8", "T Imai, H Miyazaki, S Hirose, H Hori, T Hayashi, R Kageyama, H Ohkubo, S Nakanishi, K Murakami. Cloning and sequence analysis of cDNA for human renin precursor.. Proc Natl Acad Sci U S A. 1983;80:7405-9", "M Kozenko, D Grynspan, T Oluyomi-Obi, D Sitar, AM Elliott, BN Chodirker. Potential teratogenic effects of allopurinol: a case report.. Am J Med Genet A. 2011;155A:2247-52", "MB McBride, S Rigden, GB Haycock, N Dalton, W Van't Hoff, L Rees, GV Raman, F Moro, CS Ogg, JS Cameron, HA Simmonds. Presymptomatic detection of familial juvenile hyperuricaemic nephropathy in children.. Pediatr Nephrol. 1998;12:357-64", "WM Mikkelsen, HJ Dodge, H Valkenburg. The distribution of serum uric acid values in a population unselected as to gout or hyperuricemia: Tecumseh, Michigan 1959-1960.. Am J Med 1965;39:242-51", "F Moro, CS Ogg, HA Simmonds, JS Cameron, C Chantler, MB McBride, JA Duley, PM Davies. Familial juvenile gouty nephropathy with renal urate hypoexcretion preceding renal disease.. Clin Nephrol. 1991;35:263-9", "M Paul, A Poyan Mehr, R Kreutz. Physiology of local renin-angiotensin systems.. Physiol Rev. 2006;86:747-803", "ES Pentz, MA Moyano, BA Thornhill, ML Sequeira Lopez, RA Gomez. Ablation of renin-expressing juxtaglomerular cells results in a distinct kidney phenotype.. Am J Physiol Regul Integr Comp Physiol. 2004;286:R474-83", "T Petrijan, M Menih. Discovery of a novel mutation in the REN gene in patient with chronic progressive kidney disease of unknown etiology presenting with acute spontaneous carotid artery dissection.. J Stroke Cerebrovasc Dis. 2019;28", "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", "C Schaeffer, C Izzi, A Vettori, E Pasqualetto, D Cittaro, D Lazarevic, G Caridi, B Gnutti, C Mazza, L Jovine, F Scolari, L Rampoldi. Autosomal dominant tubulointerstitial kidney disease with adult onset due to a novel renin mutation mapping in the mature protein.. Sci Rep 2019;9:11601", "B Stibůrková, E Pospísilová, S Kmoch, I Sebesta. Analysis of excretion fraction of uric acid.. Nucleosides Nucleotides Nucleic Acids. 2006;25:1301-4", "WD Wilcox. Abnormal serum uric acid levels in children.. J Pediatr. 1996;128:731-41", "M Zivná, H Hůlková, M Matignon, K Hodanová, P Vylet'al, M Kalbácová, V Baresová, J Sikora, H Blazková, J Zivný, R Ivánek, V Stránecký, J Sovová, K Claes, E Lerut, JP Fryns, PS Hart, TC Hart, JN Adams, A Pawtowski, M Clemessy, JM Gasc, MC Gübler, C Antignac, M Elleder, K Kapp, P Grimbert, AJ Bleyer, S Kmoch. Dominant renin gene mutations associated with early-onset hyperuricemia, anemia, and chronic kidney failure.. Am J Hum Genet. 2009;85:204-13", "M Živná, K Kidd, M Zaidan, P Vyleťal, V Barešová, K Hodaňová, J Sovová, H Hartmannová, M Votruba, H Trešlová, I Jedličková, J Sikora, H Hůlková, V Robins, A Hnízda, J Živný, G Papagregoriou, L Mesnard, BB Beck, A Wenzel, K Tory, K Häeffner, MTF Wolf, ME Bleyer, JA Sayer, ACM Ong, L Balogh, A Jakubowska, A Łaszkiewicz, R Clissold, C Shaw-Smith, R Munshi, RM Haws, C Izzi, I Capelli, M Santostefano, C Graziano, F Scolari, A Sussman, H Trachtman, S Decramer, M Matignon, P Grimbert, LR Shoemaker, C Stavrou, M Abdelwahed, N Belghith, M Sinclair, K Claes, T Kopel, S Moe, C Deltas, B Knebelmann, L Rampoldi, S Kmoch, AJ Bleyer. An international cohort study of autosomal dominant tubulointerstitial kidney disease due to REN mutations identifies distinct clinical subtypes.. Kidney Int. 2020;98:1589-604" ]	5/4/2011	10/12/2020		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
hyper-pp	hyper-pp	[ "HyperKPP", "HyperPP", "HYPP", "HyperPP", "HYPP", "HyperKPP", "Sodium channel protein type 4 subunit alpha", "SCN4A", "Hyperkalemic Periodic Paralysis" ]	Hyperkalemic Periodic Paralysis	Frank Weber	Summary Hyperkalemic periodic paralysis (hyperPP) is characterized by attacks of flaccid limb weakness (which may also include weakness of the muscles of the eyes, throat, breathing muscles, and trunk), hyperkalemia (serum potassium concentration >5 mmol/L) or an increase of serum potassium concentration of at least 1.5 mmol/L during an attack of weakness and/or provoking/worsening of an attack by oral potassium intake, normal serum potassium between attacks, and onset before age 20 years. In approximately half of affected individuals, attacks of flaccid muscle weakness begin in the first decade of life, with 25% reporting their first attack at age ten years or older. Initially infrequent, the attacks then increase in frequency and severity over time until approximately age 50 years, after which the frequency of attacks declines considerably. The major attack trigger is eating potassium-rich foods; other triggers include: cold environment; rest after exercise, stress, or fatigue; alcohol; hunger; and changes in activity level. A spontaneous attack commonly starts in the morning before breakfast, lasts for 15 minutes to one hour, and then passes. Individuals with hyperPP frequently have myotonia (muscle stiffness), especially around the time of an episode of weakness. Paramyotonia (muscle stiffness aggravated by cold and exercise) is present in about 45% of affected individuals. More than 80% of individuals with hyperPP older than age 40 years report permanent muscle weakness and about one third develop a chronic progressive myopathy. The diagnosis of hyperPP is established in a proband with suggestive findings and a heterozygous pathogenic variant in HyperPP is inherited in an autosomal dominant manner. Most individuals with hyperPP have an affected parent; the proportion of individuals with hyperPP caused by a	## Diagnosis Hyperkalemic periodic paralysis (hyperPP) History of at least two attacks of flaccid limb weakness (which may also include weakness of the muscles of the eyes, throat, breathing muscles, and trunk) Onset or worsening of an attack as a result of oral potassium intake Disease manifestations before age 20 years Absence of cardiac arrhythmia between attacks Normal psychomotor development Typically, at least one affected first-degree relative Note: Absence of a family history suggestive of hyperPP does not preclude the diagnosis. During the attack, EMG demonstrates a reduced number of motor units or may be silent (no insertional or voluntary activity). In the intervals between attacks, EMG may reveal myotonic activity (bursts of muscle fiber action potentials with amplitude and frequency modulation, firing rate generally between 20 and 150 Hz), even though myotonic stiffness may not be clinically present. In some individuals, especially in those with permanent weakness, a myopathic pattern may be visible. Note: Approximately 50% of affected individuals have no detectable electric myotonia. Hyperkalemia (serum potassium concentration >5 mmol/L) or an increase of serum potassium concentration of at least 1.5 mmol/L. Note: Serum potassium concentration seldom reaches cardiotoxic levels, but changes in the EKG (increased amplitude of T waves) may occur. Elevated serum creatine kinase (CK) concentration (sometimes 5-10x the normal range) Normal serum potassium concentration and muscle strength between attacks Note: At the end of an attack of weakness, elimination of potassium via the kidney and reuptake of potassium by the muscle can cause transient hypokalemia that may lead to the misdiagnosis of Elevated serum CK concentration with normal serum sodium concentration The diagnosis of hyperkalemic periodic paralysis (hyperPP) Note: Identification of a heterozygous Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Typically, 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; however, to date such variants have not been identified as a cause of this disorder. For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Hyperkalemic Periodic Paralysis (hyperPP) See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and 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. In a clinical setting in about one third of individuals with a typical phenotype of hyperPP, no pathogenic variant in SCN4A or in any other gene is identified on molecular genetic testing. In case of diagnostic uncertainty (i.e., in the absence of a measurement of ictal (during an attack) serum potassium concentration and normal molecular genetic studies), a provocative test may be employed to ensure the diagnosis. The availability of genetic testing and electrophysiologic studies largely obviates the need for such dangerous tests. Systemic provocative testing carries the risk of inducing a severe attack; therefore, such testing must be performed by an experienced physician and a stand-by anesthetist, with close monitoring of the EKG and serum concentration of potassium. The classic provocative test consists of the administration of 2-10 g potassium under clinical surveillance with serum potassium concentration and strength measured at 20-minute intervals. Usually, an attack is induced within an hour and lasts approximately 30 to 60 minutes, accompanied by an increase in serum potassium concentration, similar to spontaneously occurring attacks of weakness. Note: The test is contraindicated in individuals who already have hyperkalemia and in those individuals who do not have adequate renal or adrenal function. • History of at least two attacks of flaccid limb weakness (which may also include weakness of the muscles of the eyes, throat, breathing muscles, and trunk) • Onset or worsening of an attack as a result of oral potassium intake • Disease manifestations before age 20 years • Absence of cardiac arrhythmia between attacks • Normal psychomotor development • Typically, at least one affected first-degree relative • Note: Absence of a family history suggestive of hyperPP does not preclude the diagnosis. • During the attack, EMG demonstrates a reduced number of motor units or may be silent (no insertional or voluntary activity). • In the intervals between attacks, EMG may reveal myotonic activity (bursts of muscle fiber action potentials with amplitude and frequency modulation, firing rate generally between 20 and 150 Hz), even though myotonic stiffness may not be clinically present. • In some individuals, especially in those with permanent weakness, a myopathic pattern may be visible. • Note: Approximately 50% of affected individuals have no detectable electric myotonia. • Hyperkalemia (serum potassium concentration >5 mmol/L) or an increase of serum potassium concentration of at least 1.5 mmol/L. • Note: Serum potassium concentration seldom reaches cardiotoxic levels, but changes in the EKG (increased amplitude of T waves) may occur. • Elevated serum creatine kinase (CK) concentration (sometimes 5-10x the normal range) • Normal serum potassium concentration and muscle strength between attacks • Note: At the end of an attack of weakness, elimination of potassium via the kidney and reuptake of potassium by the muscle can cause transient hypokalemia that may lead to the misdiagnosis of • Elevated serum CK concentration with normal serum sodium concentration ## Suggestive Findings Hyperkalemic periodic paralysis (hyperPP) History of at least two attacks of flaccid limb weakness (which may also include weakness of the muscles of the eyes, throat, breathing muscles, and trunk) Onset or worsening of an attack as a result of oral potassium intake Disease manifestations before age 20 years Absence of cardiac arrhythmia between attacks Normal psychomotor development Typically, at least one affected first-degree relative Note: Absence of a family history suggestive of hyperPP does not preclude the diagnosis. During the attack, EMG demonstrates a reduced number of motor units or may be silent (no insertional or voluntary activity). In the intervals between attacks, EMG may reveal myotonic activity (bursts of muscle fiber action potentials with amplitude and frequency modulation, firing rate generally between 20 and 150 Hz), even though myotonic stiffness may not be clinically present. In some individuals, especially in those with permanent weakness, a myopathic pattern may be visible. Note: Approximately 50% of affected individuals have no detectable electric myotonia. Hyperkalemia (serum potassium concentration >5 mmol/L) or an increase of serum potassium concentration of at least 1.5 mmol/L. Note: Serum potassium concentration seldom reaches cardiotoxic levels, but changes in the EKG (increased amplitude of T waves) may occur. Elevated serum creatine kinase (CK) concentration (sometimes 5-10x the normal range) Normal serum potassium concentration and muscle strength between attacks Note: At the end of an attack of weakness, elimination of potassium via the kidney and reuptake of potassium by the muscle can cause transient hypokalemia that may lead to the misdiagnosis of Elevated serum CK concentration with normal serum sodium concentration • History of at least two attacks of flaccid limb weakness (which may also include weakness of the muscles of the eyes, throat, breathing muscles, and trunk) • Onset or worsening of an attack as a result of oral potassium intake • Disease manifestations before age 20 years • Absence of cardiac arrhythmia between attacks • Normal psychomotor development • Typically, at least one affected first-degree relative • Note: Absence of a family history suggestive of hyperPP does not preclude the diagnosis. • During the attack, EMG demonstrates a reduced number of motor units or may be silent (no insertional or voluntary activity). • In the intervals between attacks, EMG may reveal myotonic activity (bursts of muscle fiber action potentials with amplitude and frequency modulation, firing rate generally between 20 and 150 Hz), even though myotonic stiffness may not be clinically present. • In some individuals, especially in those with permanent weakness, a myopathic pattern may be visible. • Note: Approximately 50% of affected individuals have no detectable electric myotonia. • Hyperkalemia (serum potassium concentration >5 mmol/L) or an increase of serum potassium concentration of at least 1.5 mmol/L. • Note: Serum potassium concentration seldom reaches cardiotoxic levels, but changes in the EKG (increased amplitude of T waves) may occur. • Elevated serum creatine kinase (CK) concentration (sometimes 5-10x the normal range) • Normal serum potassium concentration and muscle strength between attacks • Note: At the end of an attack of weakness, elimination of potassium via the kidney and reuptake of potassium by the muscle can cause transient hypokalemia that may lead to the misdiagnosis of • Elevated serum CK concentration with normal serum sodium concentration ## Establishing the Diagnosis The diagnosis of hyperkalemic periodic paralysis (hyperPP) Note: Identification of a heterozygous Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Typically, 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; however, to date such variants have not been identified as a cause of this disorder. For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Hyperkalemic Periodic Paralysis (hyperPP) See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and 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. In a clinical setting in about one third of individuals with a typical phenotype of hyperPP, no pathogenic variant in SCN4A or in any other gene is identified on molecular genetic testing. In case of diagnostic uncertainty (i.e., in the absence of a measurement of ictal (during an attack) serum potassium concentration and normal molecular genetic studies), a provocative test may be employed to ensure the diagnosis. The availability of genetic testing and electrophysiologic studies largely obviates the need for such dangerous tests. Systemic provocative testing carries the risk of inducing a severe attack; therefore, such testing must be performed by an experienced physician and a stand-by anesthetist, with close monitoring of the EKG and serum concentration of potassium. The classic provocative test consists of the administration of 2-10 g potassium under clinical surveillance with serum potassium concentration and strength measured at 20-minute intervals. Usually, an attack is induced within an hour and lasts approximately 30 to 60 minutes, accompanied by an increase in serum potassium concentration, similar to spontaneously occurring attacks of weakness. Note: The test is contraindicated in individuals who already have hyperkalemia and in those individuals who do not have adequate renal or adrenal function. ## Option 1 Typically, 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; however, to date such variants have not been identified as a cause of this disorder. For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Hyperkalemic Periodic Paralysis (hyperPP) See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and 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. In a clinical setting in about one third of individuals with a typical phenotype of hyperPP, no pathogenic variant in SCN4A or in any other gene is identified on molecular genetic testing. ## Provocative Testing In case of diagnostic uncertainty (i.e., in the absence of a measurement of ictal (during an attack) serum potassium concentration and normal molecular genetic studies), a provocative test may be employed to ensure the diagnosis. The availability of genetic testing and electrophysiologic studies largely obviates the need for such dangerous tests. Systemic provocative testing carries the risk of inducing a severe attack; therefore, such testing must be performed by an experienced physician and a stand-by anesthetist, with close monitoring of the EKG and serum concentration of potassium. The classic provocative test consists of the administration of 2-10 g potassium under clinical surveillance with serum potassium concentration and strength measured at 20-minute intervals. Usually, an attack is induced within an hour and lasts approximately 30 to 60 minutes, accompanied by an increase in serum potassium concentration, similar to spontaneously occurring attacks of weakness. Note: The test is contraindicated in individuals who already have hyperkalemia and in those individuals who do not have adequate renal or adrenal function. ## Clinical Characteristics The attacks of flaccid muscle weakness associated with hyperkalemic periodic paralysis (hyperPP) usually begin in the first decade of life and increase in frequency and severity over time, with 25% experiencing their sentinel attack in the second decade of life. Initially infrequent, the attacks increase in frequency and severity over time until approximately age 50 years, after which the frequency declines considerably. Of note, attacks occur more frequently on holidays and weekends when people rest in bed longer than usual. In some individuals, paresthesias (probably induced by the hyperkalemia) herald the weakness. During an attack of weakness, the muscle stretch reflexes are abnormally diminished or absent. Dysphagia during an attack of weakness has also been described [ Individuals most commonly describe their attacks as stiffness followed by weakness, although many have described their attacks as some other permutation of weakness and/or stiffness. The arms and hands are just as frequently affected as the thighs and calves [ Frequency of attacks can vary greatly among individuals. Some have attacks every day, others several times a month; others have them every few months or less often. Usually, cardiac arrhythmia or respiratory insufficiency does not occur during the attacks. When present, respiratory insufficiency manifests as shortness of breath. In a study by No genotype-phenotype correlations have been identified. Usually, the penetrance is high (>90%). A few individuals with rare heterozygous pathogenic variants do not present with clinically detectable symptoms but have signs of myotonia detectable by EMG only [ Names for hyperPP no longer in use include adynamia episodica hereditaria and Gamstorp disease. The prevalence of hyperPP is approximately 0.17/100,000 (95% CI 0.13-0.20) [ ## Clinical Description The attacks of flaccid muscle weakness associated with hyperkalemic periodic paralysis (hyperPP) usually begin in the first decade of life and increase in frequency and severity over time, with 25% experiencing their sentinel attack in the second decade of life. Initially infrequent, the attacks increase in frequency and severity over time until approximately age 50 years, after which the frequency declines considerably. Of note, attacks occur more frequently on holidays and weekends when people rest in bed longer than usual. In some individuals, paresthesias (probably induced by the hyperkalemia) herald the weakness. During an attack of weakness, the muscle stretch reflexes are abnormally diminished or absent. Dysphagia during an attack of weakness has also been described [ Individuals most commonly describe their attacks as stiffness followed by weakness, although many have described their attacks as some other permutation of weakness and/or stiffness. The arms and hands are just as frequently affected as the thighs and calves [ Frequency of attacks can vary greatly among individuals. Some have attacks every day, others several times a month; others have them every few months or less often. Usually, cardiac arrhythmia or respiratory insufficiency does not occur during the attacks. When present, respiratory insufficiency manifests as shortness of breath. In a study by ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been identified. ## Penetrance Usually, the penetrance is high (>90%). A few individuals with rare heterozygous pathogenic variants do not present with clinically detectable symptoms but have signs of myotonia detectable by EMG only [ ## Nomenclature Names for hyperPP no longer in use include adynamia episodica hereditaria and Gamstorp disease. ## Prevalence The prevalence of hyperPP is approximately 0.17/100,000 (95% CI 0.13-0.20) [ ## Genetically Related (Allelic) Disorders Several types of myotonia and periodic paralyses (PP) are caused by pathogenic variants in Some See Selected ## Differential Diagnosis In addition to the allelic disorders described in Adult onset of clinical manifestations points to other diagnoses such as the Andersen-Tawil syndrome or secondary acquired forms of hyperPP. The following signs and symptoms suggest a diagnosis Associated sensory symptoms, including pain or tenderness Sensory loss could suggest polyneuropathy such as Guillain-Barré syndrome. Pain could suggest myositis; however, some individuals with hyperPP report paralytic episodes as painful and show symptoms of fibromyalgia (see Urinary retention or constipation, which may be observed in other causes of acute or subacute paralysis, but can occur rarely in hyperPP. (Bowel incontinence and bladder incontinence during attacks are reported in hyperPP.) Associated symptoms that suggest myasthenia or involvement of the neuromuscular junction, including: Ptosis (Lid lag myotonia, which may mimic ptosis, may rarely be reported in hyperPP; see Diplopia Dysphagia (may rarely be reported in hyperPP; see Dysarthria Alteration or loss of consciousness Abnormal movement History of fever days before an attack, which could suggest poliomyelitis or other virus-caused paralysis History of back pain days before an attack, which could suggest acute transverse myelitis or Guillain-Barré syndrome History of tick bite, which could suggest tick paralysis The four major differential diagnoses of hyperPP are The Different Categories of Periodic Paralyses (PP) with Membrane Excitability Disorder and Associated Findings ACZ = acetazolamide; CMAP = compound muscle action potential; DCP = dichlorphenamide; LET = long exercise test OMIM ATS anomalies include low-set ears, widely spaced eyes, small mandible, fifth-digit clinodactyly, syndactyly, short stature, and scoliosis. In a cohort of 60 Chinese individuals with primary periodic paralysis, 92.5% of those with a genetic diagnosis had pathogenic variants in Serum concentration of potassium during the paralytic attacks is normal or elevated. Some triggering factors for hypoPP attacks (e.g., carbohydrate-rich meals) are not found. Age of onset of paralytic attacks is lower. Duration of attacks is assumed to be shorter. However, this is questionable, according to surveys of affected individuals. Electromyography shows myotonic discharges in most individuals between attacks; however, the response patterns for short exercise test (SET) and long exercise test (LET) may be indiscernible; i.e., pattern IV or V defined by In normokalemic PP, the reaction to oral potassium administration may be different from that in hypoPP – anything from amelioration to worsening of the weakness [ Usually, the distinction between hypoPP and normo/hyperPP can be made on the basis of clinical, laboratory (i.e., kalemia during an attack), and EMG findings, and confirmed by molecular genetic testing [ Adrenal insufficiency is characterized by hyperkalemia, hyponatremia, and hypoglycemia. Adrenal insufficiency in infancy may be caused by congenital adrenal hyperplasia (most commonly caused by Adrenal cortical hypofunction (Addison disease) can be an autoimmune disorder with familial aggregation or combined with other endocrinopathies, particularly hypoparathyroidism. Addison disease also occurs in Recessive infantile hypoaldosteronism (corticosterone methyloxidase type II deficiency; OMIM Pseudohypoaldosteronism type I is characterized by neonatal salt-wasting resistant to mineralocorticoids. The autosomal recessive form (OMIM • Associated sensory symptoms, including pain or tenderness • Sensory loss could suggest polyneuropathy such as Guillain-Barré syndrome. • Pain could suggest myositis; however, some individuals with hyperPP report paralytic episodes as painful and show symptoms of fibromyalgia (see • Sensory loss could suggest polyneuropathy such as Guillain-Barré syndrome. • Pain could suggest myositis; however, some individuals with hyperPP report paralytic episodes as painful and show symptoms of fibromyalgia (see • Urinary retention or constipation, which may be observed in other causes of acute or subacute paralysis, but can occur rarely in hyperPP. (Bowel incontinence and bladder incontinence during attacks are reported in hyperPP.) • Associated symptoms that suggest myasthenia or involvement of the neuromuscular junction, including: • Ptosis (Lid lag myotonia, which may mimic ptosis, may rarely be reported in hyperPP; see • Diplopia • Dysphagia (may rarely be reported in hyperPP; see • Dysarthria • Ptosis (Lid lag myotonia, which may mimic ptosis, may rarely be reported in hyperPP; see • Diplopia • Dysphagia (may rarely be reported in hyperPP; see • Dysarthria • Alteration or loss of consciousness • Abnormal movement • History of fever days before an attack, which could suggest poliomyelitis or other virus-caused paralysis • History of back pain days before an attack, which could suggest acute transverse myelitis or Guillain-Barré syndrome • History of tick bite, which could suggest tick paralysis • Sensory loss could suggest polyneuropathy such as Guillain-Barré syndrome. • Pain could suggest myositis; however, some individuals with hyperPP report paralytic episodes as painful and show symptoms of fibromyalgia (see • Ptosis (Lid lag myotonia, which may mimic ptosis, may rarely be reported in hyperPP; see • Diplopia • Dysphagia (may rarely be reported in hyperPP; see • Dysarthria • Serum concentration of potassium during the paralytic attacks is normal or elevated. • Some triggering factors for hypoPP attacks (e.g., carbohydrate-rich meals) are not found. • Age of onset of paralytic attacks is lower. • Duration of attacks is assumed to be shorter. However, this is questionable, according to surveys of affected individuals. • Electromyography shows myotonic discharges in most individuals between attacks; however, the response patterns for short exercise test (SET) and long exercise test (LET) may be indiscernible; i.e., pattern IV or V defined by • In normokalemic PP, the reaction to oral potassium administration may be different from that in hypoPP – anything from amelioration to worsening of the weakness [ • Adrenal insufficiency is characterized by hyperkalemia, hyponatremia, and hypoglycemia. Adrenal insufficiency in infancy may be caused by congenital adrenal hyperplasia (most commonly caused by • Adrenal cortical hypofunction (Addison disease) can be an autoimmune disorder with familial aggregation or combined with other endocrinopathies, particularly hypoparathyroidism. Addison disease also occurs in • Recessive infantile hypoaldosteronism (corticosterone methyloxidase type II deficiency; OMIM • Pseudohypoaldosteronism type I is characterized by neonatal salt-wasting resistant to mineralocorticoids. The autosomal recessive form (OMIM ## Management No clinical practice guidelines for hyperkalemic periodic paralysis (hyperPP) have been published. To establish the extent of disease and needs in an individual diagnosed with hyperkalemic periodic paralysis (hyperPP), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Hyperkalemic Periodic Paralysis (hyperPP) Neuromuscular eval for myotonia, paramyotonia, & muscle weakness Perform MOI = mode of inheritance; STIR = short tau inversion recovery Medical geneticist, certified genetic counselor, certified advanced genetic nurse Treatment for hyperPP is symptomatic and not curative. Treatment of Manifestations in Individuals with Hyperkalemic Periodic Paralysis (hyperPP) Avoid opioids or depolarizing agents incl potassium, anticholinesterases, & succinylcholine, which can aggravate a myotonic reaction & induce masseter spasms & stiffness of respiratory muscles. Alterations of serum osmolarity, pH, & hypothermia-induced muscle shivering & mechanical stimuli can exacerbate myotonic reaction. Glucose infusion Maintain normal body temperature. Maintain serum potassium at low level. IV = intravenous One case report suggested that intravenous magnesium is beneficial as well [ Because the generalized muscle spasms associated with such attacks may lead to an increase in body temperature, individuals with hyperPP have been considered to be susceptible to Potassium-rich medications and foods (e.g., fruits, fruit juices) Fasting Strenuous work Exposure to cold Thiazide diuretics are preferable because they have fewer side effects than either acetazolamide or dichlorphenamide therapy. The dosage should be kept as low as possible (e.g., 25 mg hydrochlorothiazide daily or every other day). In severe cases, 50 mg or 75 mg of hydrochlorothiazide should be taken daily very early in the morning. Individuals should be monitored so that the serum potassium concentration does not fall below 3.3 mmol/L or the serum sodium concentration below 135 mmol/L [ Four weeks after start of diuretic treatment, effects should be evaluated by muscle strength measurement and MRI of proximal leg muscles. Recommended Surveillance for Individuals with Hyperkalemic Periodic Paralysis (hyperPP) If on continuous prophylactic diuretic treatment To judge how much normal muscle tissue is preserved and whether edema is present. Na Avoid the following: Opioids or depolarizing agents such as potassium, anticholinesterases, and succinylcholine as part of general anesthesia. These can aggravate a myotonic reaction and induce masseter spasms and stiffness of respiratory muscles, which may impair intubation; mechanical ventilation may also be impaired. Drugs known as ACE-inhibitors for the treatment of arterial hypertension. These may lead to hyperkalemia as a side effect, especially if they are combined with potassium-sparing diuretics (e.g., spironolactone) and/or renal function is impaired. Alterations of serum osmolarity, pH, and hypothermia-induced muscle shivering and mechanical stimuli during general anesthesia. These can exacerbate the myotonic reaction in individuals with hyperPP. See also It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from initiation of preventive measures, particularly those that would decrease the risk of unexpected acute paralysis or anesthetic events. Evaluations include: Molecular genetic testing if the pathogenic variant in the family is known; Full neurologic examination to rule out muscular weakness and EMG to rule out myotonia if the pathogenic variant in the family is not known. At-risk relatives who have not undergone molecular genetic testing or clinical evaluation (i.e., neurologic examination and EMG) must be considered at risk for hyperPP-related complications and precautions are indicated – particularly during anesthesia. See More than 90% of affected women report an increase in attack frequency during pregnancy. While approximately 80% reported improved muscle weakness during attacks, 75% also reported worse muscle stiffness during attacks [ Women who are chronically treated with a diuretic may continue treatment in pregnancy. Human data on prenatal exposure to acetazolamide have not demonstrated an increased risk of fetal malformations. Human data on the use of oral dichlorphenamide therapy during pregnancy – and whether it leads to an increased risk of malformations in exposed fetuses – are limited. See Search • Neuromuscular eval for myotonia, paramyotonia, & muscle weakness • Perform • Avoid opioids or depolarizing agents incl potassium, anticholinesterases, & succinylcholine, which can aggravate a myotonic reaction & induce masseter spasms & stiffness of respiratory muscles. • Alterations of serum osmolarity, pH, & hypothermia-induced muscle shivering & mechanical stimuli can exacerbate myotonic reaction. • Glucose infusion • Maintain normal body temperature. • Maintain serum potassium at low level. • Potassium-rich medications and foods (e.g., fruits, fruit juices) • Fasting • Strenuous work • Exposure to cold • Thiazide diuretics are preferable because they have fewer side effects than either acetazolamide or dichlorphenamide therapy. • The dosage should be kept as low as possible (e.g., 25 mg hydrochlorothiazide daily or every other day). In severe cases, 50 mg or 75 mg of hydrochlorothiazide should be taken daily very early in the morning. • Individuals should be monitored so that the serum potassium concentration does not fall below 3.3 mmol/L or the serum sodium concentration below 135 mmol/L [ • Opioids or depolarizing agents such as potassium, anticholinesterases, and succinylcholine as part of general anesthesia. These can aggravate a myotonic reaction and induce masseter spasms and stiffness of respiratory muscles, which may impair intubation; mechanical ventilation may also be impaired. • Drugs known as ACE-inhibitors for the treatment of arterial hypertension. These may lead to hyperkalemia as a side effect, especially if they are combined with potassium-sparing diuretics (e.g., spironolactone) and/or renal function is impaired. • Alterations of serum osmolarity, pH, and hypothermia-induced muscle shivering and mechanical stimuli during general anesthesia. These can exacerbate the myotonic reaction in individuals with hyperPP. • Molecular genetic testing if the pathogenic variant in the family is known; • Full neurologic examination to rule out muscular weakness and EMG to rule out myotonia 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 hyperkalemic periodic paralysis (hyperPP), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Hyperkalemic Periodic Paralysis (hyperPP) Neuromuscular eval for myotonia, paramyotonia, & muscle weakness Perform MOI = mode of inheritance; STIR = short tau inversion recovery Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Neuromuscular eval for myotonia, paramyotonia, & muscle weakness • Perform ## Treatment of Manifestations Treatment for hyperPP is symptomatic and not curative. Treatment of Manifestations in Individuals with Hyperkalemic Periodic Paralysis (hyperPP) Avoid opioids or depolarizing agents incl potassium, anticholinesterases, & succinylcholine, which can aggravate a myotonic reaction & induce masseter spasms & stiffness of respiratory muscles. Alterations of serum osmolarity, pH, & hypothermia-induced muscle shivering & mechanical stimuli can exacerbate myotonic reaction. Glucose infusion Maintain normal body temperature. Maintain serum potassium at low level. IV = intravenous One case report suggested that intravenous magnesium is beneficial as well [ Because the generalized muscle spasms associated with such attacks may lead to an increase in body temperature, individuals with hyperPP have been considered to be susceptible to • Avoid opioids or depolarizing agents incl potassium, anticholinesterases, & succinylcholine, which can aggravate a myotonic reaction & induce masseter spasms & stiffness of respiratory muscles. • Alterations of serum osmolarity, pH, & hypothermia-induced muscle shivering & mechanical stimuli can exacerbate myotonic reaction. • Glucose infusion • Maintain normal body temperature. • Maintain serum potassium at low level. ## Prevention of Primary Manifestations Potassium-rich medications and foods (e.g., fruits, fruit juices) Fasting Strenuous work Exposure to cold Thiazide diuretics are preferable because they have fewer side effects than either acetazolamide or dichlorphenamide therapy. The dosage should be kept as low as possible (e.g., 25 mg hydrochlorothiazide daily or every other day). In severe cases, 50 mg or 75 mg of hydrochlorothiazide should be taken daily very early in the morning. Individuals should be monitored so that the serum potassium concentration does not fall below 3.3 mmol/L or the serum sodium concentration below 135 mmol/L [ Four weeks after start of diuretic treatment, effects should be evaluated by muscle strength measurement and MRI of proximal leg muscles. • Potassium-rich medications and foods (e.g., fruits, fruit juices) • Fasting • Strenuous work • Exposure to cold • Thiazide diuretics are preferable because they have fewer side effects than either acetazolamide or dichlorphenamide therapy. • The dosage should be kept as low as possible (e.g., 25 mg hydrochlorothiazide daily or every other day). In severe cases, 50 mg or 75 mg of hydrochlorothiazide should be taken daily very early in the morning. • Individuals should be monitored so that the serum potassium concentration does not fall below 3.3 mmol/L or the serum sodium concentration below 135 mmol/L [ ## Surveillance Recommended Surveillance for Individuals with Hyperkalemic Periodic Paralysis (hyperPP) If on continuous prophylactic diuretic treatment To judge how much normal muscle tissue is preserved and whether edema is present. Na ## Agents/Circumstances to Avoid Avoid the following: Opioids or depolarizing agents such as potassium, anticholinesterases, and succinylcholine as part of general anesthesia. These can aggravate a myotonic reaction and induce masseter spasms and stiffness of respiratory muscles, which may impair intubation; mechanical ventilation may also be impaired. Drugs known as ACE-inhibitors for the treatment of arterial hypertension. These may lead to hyperkalemia as a side effect, especially if they are combined with potassium-sparing diuretics (e.g., spironolactone) and/or renal function is impaired. Alterations of serum osmolarity, pH, and hypothermia-induced muscle shivering and mechanical stimuli during general anesthesia. These can exacerbate the myotonic reaction in individuals with hyperPP. See also • Opioids or depolarizing agents such as potassium, anticholinesterases, and succinylcholine as part of general anesthesia. These can aggravate a myotonic reaction and induce masseter spasms and stiffness of respiratory muscles, which may impair intubation; mechanical ventilation may also be impaired. • Drugs known as ACE-inhibitors for the treatment of arterial hypertension. These may lead to hyperkalemia as a side effect, especially if they are combined with potassium-sparing diuretics (e.g., spironolactone) and/or renal function is impaired. • Alterations of serum osmolarity, pH, and hypothermia-induced muscle shivering and mechanical stimuli during general anesthesia. These can exacerbate the myotonic reaction in individuals with hyperPP. ## Evaluation of Relatives at Risk It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from initiation of preventive measures, particularly those that would decrease the risk of unexpected acute paralysis or anesthetic events. Evaluations include: Molecular genetic testing if the pathogenic variant in the family is known; Full neurologic examination to rule out muscular weakness and EMG to rule out myotonia if the pathogenic variant in the family is not known. At-risk relatives who have not undergone molecular genetic testing or clinical evaluation (i.e., neurologic examination and EMG) must be considered at risk for hyperPP-related complications and precautions are indicated – particularly during anesthesia. See • Molecular genetic testing if the pathogenic variant in the family is known; • Full neurologic examination to rule out muscular weakness and EMG to rule out myotonia if the pathogenic variant in the family is not known. ## Pregnancy Management More than 90% of affected women report an increase in attack frequency during pregnancy. While approximately 80% reported improved muscle weakness during attacks, 75% also reported worse muscle stiffness during attacks [ Women who are chronically treated with a diuretic may continue treatment in pregnancy. Human data on prenatal exposure to acetazolamide have not demonstrated an increased risk of fetal malformations. Human data on the use of oral dichlorphenamide therapy during pregnancy – and whether it leads to an increased risk of malformations in exposed fetuses – are limited. See ## Therapies Under Investigation Search ## Genetic Counseling Hyperkalemic periodic paralysis (hyperPP) is inherited in an autosomal dominant manner. Most individuals diagnosed with hyperPP have an affected parent. A proband with hyperPP may 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, 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 hyperPP may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed 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%. Substantial intrafamilial clinical variability may be observed among sibs who inherit the same If the proband has a known If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent or the 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 Differences in perspective may exist among medical professionals and within families regarding the use 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 hyperPP have an affected parent. • A proband with hyperPP may 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, 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 hyperPP may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed 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 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%. • Substantial intrafamilial clinical variability may be observed among sibs who inherit the same • If the proband has a known • If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent or the 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 Hyperkalemic periodic paralysis (hyperPP) is inherited in an autosomal dominant manner. ## Risk to Family Members Most individuals diagnosed with hyperPP have an affected parent. A proband with hyperPP may 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, 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 hyperPP may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed 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%. Substantial intrafamilial clinical variability may be observed among sibs who inherit the same If the proband has a known If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism. • Most individuals diagnosed with hyperPP have an affected parent. • A proband with hyperPP may 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, 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 hyperPP may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed 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 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%. • Substantial intrafamilial clinical variability may be observed among sibs who inherit the same • If the proband has a known • If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent or the 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 Differences in perspective may exist among medical professionals and within families regarding the use 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 Hyperkalemic Periodic Paralysis: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Hyperkalemic Periodic Paralysis ( All forms of periodic paralysis, regardless of pathogenic variant, share a common final mechanism, a long-lasting partial depolarization of the sarcolemma leading to inactivation of Na Normal Na Data from mouse models suggest that the lag in onset of clinical features of hyperPP during the first decade and the progression of symptoms during adolescence are a function of Na ## Molecular Pathogenesis All forms of periodic paralysis, regardless of pathogenic variant, share a common final mechanism, a long-lasting partial depolarization of the sarcolemma leading to inactivation of Na Normal Na Data from mouse models suggest that the lag in onset of clinical features of hyperPP during the first decade and the progression of symptoms during adolescence are a function of Na ## Chapter Notes Frank Weber is a clinical neurologist and, as a military physician, is a certified flight surgeon. After many years in hospital-based neurology, he is currently head of the department of research of the German Air Force Center of Aerospace Medicine. He was trained in clinical neurology at the University of Ulm and at the Technical University in Munich, where he met Frank Lehmann-Horn. He has a special interest in neuromuscular disorders and in clinical neurophysiology. His scientific interests include disorders of nerve and muscle and channelopathies of the peripheral nervous system and the muscle system, particularly sodium channels. Contact: [email protected] Thanks to the many patients who gave their consent to the publication of their data and to the Periodic Paralysis Association. This work was supported by the German Research Foundation (DFG) (JU470/1), the network on Excitation-contraction coupling and calcium signaling in health and disease of the IHP Program funded by the European Community, the non-profit Hertie Foundation, the IonNeurONet of German Ministry of Research (BMBF), The German Muscle Society (DGM), and the Else-Kröner-Fresenius Foundation. Karin Jurkat-Rott, MD, PhD; Ulm University (2003-2021)Frank Lehmann-Horn, MD, PhD; Ulm University (2003-2021 )Frank Weber, MD, PhD (2016-present) Dr Lehmann-Horn died in 2018 after a long illness. 1 July 2021 (ha) Comprehensive update posted live 28 January 2016 (me) Comprehensive update posted live 31 May 2011 (me) Comprehensive update posted live 11 August 2009 (cd) Revision: sequence analysis available clinically 25 April 2008 (me) Comprehensive update posted live 23 September 2005 (me) Comprehensive update posted live 2 March 2005 (cd) Revision: sequencing of select exons clinically available 18 July 2003 (me) Review posted live 27 January 2003 (kjr) Original submission • 1 July 2021 (ha) Comprehensive update posted live • 28 January 2016 (me) Comprehensive update posted live • 31 May 2011 (me) Comprehensive update posted live • 11 August 2009 (cd) Revision: sequence analysis available clinically • 25 April 2008 (me) Comprehensive update posted live • 23 September 2005 (me) Comprehensive update posted live • 2 March 2005 (cd) Revision: sequencing of select exons clinically available • 18 July 2003 (me) Review posted live • 27 January 2003 (kjr) Original submission ## Author Notes Frank Weber is a clinical neurologist and, as a military physician, is a certified flight surgeon. After many years in hospital-based neurology, he is currently head of the department of research of the German Air Force Center of Aerospace Medicine. He was trained in clinical neurology at the University of Ulm and at the Technical University in Munich, where he met Frank Lehmann-Horn. He has a special interest in neuromuscular disorders and in clinical neurophysiology. His scientific interests include disorders of nerve and muscle and channelopathies of the peripheral nervous system and the muscle system, particularly sodium channels. Contact: [email protected] ## Acknowledgments Thanks to the many patients who gave their consent to the publication of their data and to the Periodic Paralysis Association. This work was supported by the German Research Foundation (DFG) (JU470/1), the network on Excitation-contraction coupling and calcium signaling in health and disease of the IHP Program funded by the European Community, the non-profit Hertie Foundation, the IonNeurONet of German Ministry of Research (BMBF), The German Muscle Society (DGM), and the Else-Kröner-Fresenius Foundation. ## Author History Karin Jurkat-Rott, MD, PhD; Ulm University (2003-2021)Frank Lehmann-Horn, MD, PhD; Ulm University (2003-2021 )Frank Weber, MD, PhD (2016-present) Dr Lehmann-Horn died in 2018 after a long illness. ## Revision History 1 July 2021 (ha) Comprehensive update posted live 28 January 2016 (me) Comprehensive update posted live 31 May 2011 (me) Comprehensive update posted live 11 August 2009 (cd) Revision: sequence analysis available clinically 25 April 2008 (me) Comprehensive update posted live 23 September 2005 (me) Comprehensive update posted live 2 March 2005 (cd) Revision: sequencing of select exons clinically available 18 July 2003 (me) Review posted live 27 January 2003 (kjr) Original submission • 1 July 2021 (ha) Comprehensive update posted live • 28 January 2016 (me) Comprehensive update posted live • 31 May 2011 (me) Comprehensive update posted live • 11 August 2009 (cd) Revision: sequence analysis available clinically • 25 April 2008 (me) Comprehensive update posted live • 23 September 2005 (me) Comprehensive update posted live • 2 March 2005 (cd) Revision: sequencing of select exons clinically available • 18 July 2003 (me) Review posted live • 27 January 2003 (kjr) Original submission ## References ## Literature Cited	[ "Y Akaba, S Takahashi, Y Sasaki, H Kajino. Successful treatment of normokalemic periodic paralysis with hydrochlorothiazide.. Brain Dev. 2018;40:833-6", "T Ammar, W Lin, A Higgins, LJ Hayward, JM Renaud. Understanding the physiology of the asymptomatic diaphragm of the M1592V hyperkalemic periodic paralysis mouse.. J Gen Physiol. 2015;146:509-25", "MC Barker. Combined spinal/general anesthesia with postoperative femoral nerve block for total knee replacement in a patient with familial hyperkalemic periodic paralysis: a case report.. AANA J. 2010;78:191-4", "JN Benhammou, J Phan, H Lee, K Ghassemi, W Parsons, WW Grody, JR Pisegna. A sodium channel myotonia presenting with intermittent dysphagia as a manifestation of a rare SCN4A variant.. J Mol Neurosci. 2017;61:312-14", "A Bergareche, M Bednarz, E Sánchez, CE Krebs, J Ruiz-Martinez, P De La Riva, V Makarov, A Gorostidi, K Jurkat-Rott, JF Marti-Masso, C Paisán-Ruiz. SCN4A pore mutation pathogenetically contributes to autosomal dominant essential tremor and may increase susceptibility to epilepsy.. Hum Mol Genet. 2015;24:7111-20", "WG Bradley, R Taylor, DR Rice, I Hausmanowa-Petruzewicz, LS Adelman, M Jenkison, H Jedrzejowska, H Drac, WW Pendlebury. Progressive myopathy in hyperkalemic periodic paralysis.. Arch Neurol 1990;47:1013-7", "SC Cannon. Sodium channelopathies of skeletal muscle.. Handb Exp Pharmacol. 2018;246:309-30", "G Charles, C Zheng, F Lehmann-Horn, K Jurkat-Rott, J Levitt. Characterization of hyperkalemic periodic paralysis: a survey of genetically diagnosed individuals.. J Neurol 2013;260:2606-13", "BC Duan, LC Wong, WT Lee. Alternating hemiplegia and paroxysmal torticollis caused by SCN4A mutation: A new phenotype?. Neurology. 2019;93:673-4", "C Fan, F Lehmann-Horn, MA Weber, M Bednarz, JR Groome, MK Jonsson, K Jurkat-Rott. Transient compartment-like syndrome and normokalaemic periodic paralysis due to a Ca(v)1.1 mutation.. Brain. 2013;136:3775-86", "C Fan, N Mao, F Lehmann-Horn, J Bürmann, K. Jurkat-Rott. Effects of S906T polymorphism on the severity of a novel borderline mutation I692M in Nav1.4 cause periodic paralysis.. Clin Genet. 2017;91:859-67", "J Finsterer, SM Wakil, F Laccone. Pregnancy reduces severity and frequency of attacks in hyperkalemic periodic paralysis due to the mutation c.2111C>T in the SCN4A gene.. Ann Indian Acad Neurol. 2017;20:75-6", "E Fournier, M Arzel, D Sternberg, S Vicart, P Laforet, B Eymard, JC Willer, N Tabti, B Fontaine. Electromyography guides toward subgroups of mutations in muscle channelopathies.. Ann Neurol 2004;56:650-61", "A Giacobbe, S Subramony, M Chuquilin. Pain as a significant symptom in patients with periodic paralysis-A cross-sectional survey.. Muscle Nerve. 2021;63:897-901", "A Horga, DLR Rayan, E Matthews, R Sud, D Fialho, SCM Durran, JA Burge, S Portaro, MB Davis, A Haworth, MG Hanna. Prevelance study of genetically defined skeletal muscle channelopathies in England.. Neurology 2013;80:1472-75", "S Huang, W Zhang, X Chang, J Guo. Overlap of periodic paralysis and paramyotonia congenita caused by SCN4A gene mutations two family reports and literature review.. Channels (Austin) 2019;13:110-19", "HN Jeong, JS Yi, YH Lee, JH Lee, HY Shin, YC Choi, SM Kim. Lower-extremity magnetic resonance imaging in patients with hyperkalemic periodic paralysis carrying the SCN4A mutation T704M: 30-month follow-up of seven patients.. Neuromuscul Disord. 2018;28:837-45", "K Jurkat-Rott, J Groome, F Lehmann-Horn. Pathophysiological role of the omega pore current in channelopathies.. Front Pharmacol 2012;3:112", "K Jurkat-Rott, F Lehmann-Horn. Genotype-phenotype correlation and therapeutic rationale in hyperkalemic periodic paralysis.. Neurotherapeutics 2007;4:216-24", "S Khogali, B Lucas, T Ammar, D Dejong, M Barbalinardo, LJ Hayward, JM Renaud. Physiological basis for muscle stiffness and weakness in a knock-in M1592V mouse model of hyperkalemic periodic paralysis.. Physiol Rep. 2015;3", "W Klingler, F Lehmann-Horn, K Jurkat-Rott. Complications of anaesthesia in neuromuscular disorders.. Neuromuscul Disord 2005;15:195-206", "F Lehmann-Horn, G Kuther, K Ricker, P Grafe, K Ballanyi, R Rudel. Adynamia episodica hereditaria with myotonia: a non-inactivating sodium current and the effect of extracellular pH.. Muscle Nerve 1987;10:363-74", "S Luo, M Xu, J Sun, K Qiao, J Song, S Cai, W Zhu, L Zhou, J Xi, J Lu, X Ni, T Dou, C Zhao. Identification of gene mutations in patients with primary periodic paralysis using targeted next-generation sequencing.. BMC Neurol. 2019;19:92", "MJ Mackenzie, E Pickering, SM Yentis. Anaesthetic management of labour and caesarean delivery of a patient with hyperkalaemic periodic paralysis.. Int J Obstet Anesth 2006;15:329-31", "L Maggi, R Brugnoni, E Canioni, P Tonin, V Saletti, P Sola, SC Piccinelli, L Colleoni, P Ferrigno, A Pini, R Masson, F Manganelli, D Lietti, L Vercelli, G Ricci, C Bruno, G Tasca, A Pizzuti, A Padovani, C Fusco, E Pegoraro, L Ruggiero, S Ravaglia, G Siciliano, L Morandi, R Dubbioso, T Mongini, M Filosto, I Tramacere, R Mantegazza, P Bernasconi. Clinical and molecular spectrum of myotonia and periodic paralyses associated with mutations in SCN4A in a large cohort of Italian patients.. Front Neurol. 2020;11:646", "A Mankodi, C Grunseich, M Skov, L Cook, G Aue, E Purev, D Bakar, T Lehky, K Jurkat-Rott, TH Pedersen, RW Childs. Divalent cation-responsive myotonia and muscle paralysis in skeletal muscle sodium channelopathy.. Neuromuscul Disord. 2015;25:908-12", "AI McClatchey, D McKenna-Yasek, D Cros, HG Worthen, RW Kuncl, SM DeSilva, DR Cornblath, JF Gusella, RH Brown. Novel mutations in families with unusual and variable disorders of the skeletal muscle sodium channel.. Nat Genet. 1992;2:148-52", "TM Miller, MR Dias da Silva, HA Miller, H Kwiecinski, JR Mendell, R Tawil, P McManis, RC Griggs, C Angelini, S Servidei, J Petajan, MC Dalakas, LP Ranum, YH Fu, LJ Ptácek. Correlating phenotype and genotype in the periodic paralyses.. Neurology. 2004;63:1647-55", "A Modoni, A D'Amico, G Primiano, F Capozzoli, JF Desaphy, M Lo Monaco. Long-term safety and usefulness of mexiletine in a large cohort of patients affected by non-dystrophic myotonias.. Front Neurol. 2020;11:300", "NM Plaster, R Tawil, M Tristani-Firouzi, S Canun, S Bendahhou, A Tsunoda, MR Donaldson, ST Iannaccone, E Brunt, R Barohn, J Clark, F Deymeer, AL George, FA Fish, A Hahn, A Nitu, C Ozdemir, P Serdaroglu, SH Subramony, G Wolfe, YH Fu, LJ Ptácek. Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome.. Cell 2001;105:511-9", "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", "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", "VA Sansone, J Burge, MP McDermott, PC Smith, B Herr, R Tawil, S Pandya, J Kissel, E Ciafaloni, P Shieh, JW Ralph, A Amato, SC Cannon, J Trivedi, R Barohn, B Crum, H Mitsumoto, A Pestronk, G Meola, R Conwit, MG Hanna, RC Griggs. Randomized, placebo-controlled trials of dichlorphenamide in periodic paralysis.. Neurology. 2016;86:1408-16", "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", "BC Stunnenberg, J Raaphorst, JCW Deenen, TP Links, AA Wilde, DJ Verbove, EJ Kamsteeg, A van den Wijngaard, CG Faber, GJ van der Wilt, BGM van Engelen, G Drost, HB Ginjaar. Prevalence and mutation spectrum of skeletal muscle channelopathies in the Netherlands.. Neuromuscul Disord. 2018;28:402-7", "SV Tan, K Suetterlin, R Männikkö, E Matthews, MG Hanna, H Bostock. In vivo assessment of interictal sarcolemmal membrane properties in hypokalaemic and hyperkalaemic periodic paralysis.. Clin Neurophysiol. 2020;131:816-27", "N Vereb, F Montagnese, D Gläser, B. Schoser. Non-dystrophic myotonias: clinical and mutation spectrum of 70 German patients.. J Neurol. 2021;268:1708-20", "S Vicart, D Sternberg, E Fournier, F Ochsner, P Laforet, T Kuntzer, B Eymard, B Hainque, B Fontaine. New mutations of SCN4A cause a potassium-sensitive normokalemic periodic paralysis.. Neurology 2004;63:2120-7", "S Wagner, H Lerche, N Mitrovic, R Heine, AL George, F Lehmann-Horn. A novel sodium channel mutation causing a hyperkalemic paralytic and paramyotonic syndrome with variable clinical expressivity.. Neurology 1997;49:1018-25", "M-A Weber, S Nielles-Vallespin, M Essig, K Jurkat-Rott, H-U Kauczor, F Lehmann-Horn. Muscle Na+ channelopathies: MRI detects intracellular 23Na accumulation during episodic weakness.. Neurology 2006;67:1151-8" ]	18/7/2003	1/7/2021	11/8/2009	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
hyperchol	hyperchol	[ "Familial Hypercholesterolæmia", "Hyperlipoproteinemia Type IIA", "Familial Hypercholesterolæmia", "Hyperlipoproteinemia Type IIA", "Apolipoprotein B-100", "Low density lipoprotein receptor adapter protein 1", "Low-density lipoprotein receptor", "Proprotein convertase subtilisin/kexin type 9", "APOB", "LDLR", "LDLRAP1", "PCSK9", "Familial Hypercholesterolemia" ]	Familial Hypercholesterolemia	Hannah E Ison, Shoa L Clarke, Joshua W Knowles	Summary Familial hypercholesterolemia (FH) is characterized by significantly elevated low-density lipoprotein cholesterol (LDL-C) that leads to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age and increases the risk of premature cardiovascular events such as angina and myocardial infarction; stroke occurs more rarely. Xanthomas (cholesterol deposits in tendons) may be visible in the Achilles tendons or tendons of the hands and worsen with age as a result of extremely high cholesterol levels. Xanthelasmas (yellowish, waxy deposits) can occur around the eyelids. Individuals with FH may develop corneal arcus (white, gray, or blue opaque ring in the corneal margin as a result of cholesterol deposition) at a younger age than those without FH. Individuals with a more severe phenotype, often as a result of biallelic variants, can present with very significant elevations in LDL-C (>500 mg/dL), early-onset coronary artery disease (CAD; presenting as early as childhood in some), and calcific aortic valve disease. A clinical diagnosis of FH can be established in a proband with characteristic clinical features and significantly elevated LDL-C levels (typically >190 mg/dL in adults and >160 mg/dL in children). Three formal diagnostic criteria are used in Western countries. The molecular diagnosis of FH can be established by identification of heterozygous or biallelic pathogenic variants in Once the FH-causing pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.	## Diagnosis Familial hypercholesterolemia (FH) should be suspected in individuals with the following findings. Adults (untreated): Low-density lipoprotein cholesterol (LDL-C) levels >190 mg/dL (>4.9 mmol/L) Total cholesterol levels >310 mg/dL (>8 mmol/L) Children/adolescents (untreated): LDL-C levels >190 mg/dL (≥4.9 mmol/L) [ LDL-C levels >160 mg/dL, particularly when there is a first-degree relative with hyperlipidemia and/or premature coronary artery disease (onset in males age ≤55 years and females ≤65 years) [ LDL-C levels >130 mg/dL (>3.4 mmol/L) in those with a first-degree relative with FH [ Total cholesterol levels >230 mg/dL (>6 mmol/L) Xanthomas (cholesterol deposits in tendons) may be identified in adults but are unlikely to present in children with heterozygous familial hypercholesterolemia (HeFH). Note: Xanthomas can present within the first few years of life in those with a more severe phenotype due to biallelic variants [ Xanthelasmas (yellowish, waxy deposits that can occur around the eyelids) Corneal arcus (white, gray, or blue opaque ring in the corneal margin as a result of cholesterol deposition) is more likely to be FH-related when present in an individual younger than age 45 years. FH Elevated LDL-C levels Premature CAD Xanthomas/xanthelasmas Note: (1) Age-specific LDL-C or total cholesterol levels are more specific in determining the likelihood of FH (e.g., >95th percentile for age, sex, and country) [ The Note: The criteria used to establish the clinical diagnosis of FH in children varies substantially across medical centers within and outside of the United States. Some experts recommend the Simon Broome criteria in pediatric probands rather than the Dutch Lipid Clinic Network Criteria [ A A heterozygous pathogenic (or likely pathogenic) variant in A heterozygous pathogenic (or likely pathogenic) variant in A heterozygous gain-of-function pathogenic (or likely pathogenic) variant in Note: A whole-gene duplication of Biallelic loss-of-function 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 can be used for clinical decision making [ Molecular genetic testing approaches can include a A A For an introduction to multigene panels click Molecular Genetic Testing Used in Familial Hypercholesterolemia FH = familial hypercholesterolemia; 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 missense, nonsense, and splice site variants and small 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. Sequence analysis of To date, only ~30 Whole-gene duplication was reported in two unrelated families with FH [ FH disease-causing pathogenic variant(s) can be identified in ∼60%-80% of adult probands with a clinical diagnosis of FH. FH disease-causing pathogenic variant(s) can be identified in ∼60%-95% of pediatric probands in whom there is a strong clinical suspicion of FH [ • Adults (untreated): • Low-density lipoprotein cholesterol (LDL-C) levels >190 mg/dL (>4.9 mmol/L) • Total cholesterol levels >310 mg/dL (>8 mmol/L) • Low-density lipoprotein cholesterol (LDL-C) levels >190 mg/dL (>4.9 mmol/L) • Total cholesterol levels >310 mg/dL (>8 mmol/L) • Children/adolescents (untreated): • LDL-C levels >190 mg/dL (≥4.9 mmol/L) [ • LDL-C levels >160 mg/dL, particularly when there is a first-degree relative with hyperlipidemia and/or premature coronary artery disease (onset in males age ≤55 years and females ≤65 years) [ • LDL-C levels >130 mg/dL (>3.4 mmol/L) in those with a first-degree relative with FH [ • Total cholesterol levels >230 mg/dL (>6 mmol/L) • LDL-C levels >190 mg/dL (≥4.9 mmol/L) [ • LDL-C levels >160 mg/dL, particularly when there is a first-degree relative with hyperlipidemia and/or premature coronary artery disease (onset in males age ≤55 years and females ≤65 years) [ • LDL-C levels >130 mg/dL (>3.4 mmol/L) in those with a first-degree relative with FH [ • Total cholesterol levels >230 mg/dL (>6 mmol/L) • Low-density lipoprotein cholesterol (LDL-C) levels >190 mg/dL (>4.9 mmol/L) • Total cholesterol levels >310 mg/dL (>8 mmol/L) • LDL-C levels >190 mg/dL (≥4.9 mmol/L) [ • LDL-C levels >160 mg/dL, particularly when there is a first-degree relative with hyperlipidemia and/or premature coronary artery disease (onset in males age ≤55 years and females ≤65 years) [ • LDL-C levels >130 mg/dL (>3.4 mmol/L) in those with a first-degree relative with FH [ • Total cholesterol levels >230 mg/dL (>6 mmol/L) • Xanthomas (cholesterol deposits in tendons) may be identified in adults but are unlikely to present in children with heterozygous familial hypercholesterolemia (HeFH). • Note: Xanthomas can present within the first few years of life in those with a more severe phenotype due to biallelic variants [ • Xanthelasmas (yellowish, waxy deposits that can occur around the eyelids) • Corneal arcus (white, gray, or blue opaque ring in the corneal margin as a result of cholesterol deposition) is more likely to be FH-related when present in an individual younger than age 45 years. • FH • Elevated LDL-C levels • Premature CAD • Xanthomas/xanthelasmas • A heterozygous pathogenic (or likely pathogenic) variant in • A heterozygous pathogenic (or likely pathogenic) variant in • A heterozygous gain-of-function pathogenic (or likely pathogenic) variant in • Note: A whole-gene duplication of • Biallelic loss-of-function pathogenic (or likely pathogenic) variants in • A • A • For an introduction to multigene panels click ## Suggestive Findings Familial hypercholesterolemia (FH) should be suspected in individuals with the following findings. Adults (untreated): Low-density lipoprotein cholesterol (LDL-C) levels >190 mg/dL (>4.9 mmol/L) Total cholesterol levels >310 mg/dL (>8 mmol/L) Children/adolescents (untreated): LDL-C levels >190 mg/dL (≥4.9 mmol/L) [ LDL-C levels >160 mg/dL, particularly when there is a first-degree relative with hyperlipidemia and/or premature coronary artery disease (onset in males age ≤55 years and females ≤65 years) [ LDL-C levels >130 mg/dL (>3.4 mmol/L) in those with a first-degree relative with FH [ Total cholesterol levels >230 mg/dL (>6 mmol/L) Xanthomas (cholesterol deposits in tendons) may be identified in adults but are unlikely to present in children with heterozygous familial hypercholesterolemia (HeFH). Note: Xanthomas can present within the first few years of life in those with a more severe phenotype due to biallelic variants [ Xanthelasmas (yellowish, waxy deposits that can occur around the eyelids) Corneal arcus (white, gray, or blue opaque ring in the corneal margin as a result of cholesterol deposition) is more likely to be FH-related when present in an individual younger than age 45 years. FH Elevated LDL-C levels Premature CAD Xanthomas/xanthelasmas Note: (1) Age-specific LDL-C or total cholesterol levels are more specific in determining the likelihood of FH (e.g., >95th percentile for age, sex, and country) [ • Adults (untreated): • Low-density lipoprotein cholesterol (LDL-C) levels >190 mg/dL (>4.9 mmol/L) • Total cholesterol levels >310 mg/dL (>8 mmol/L) • Low-density lipoprotein cholesterol (LDL-C) levels >190 mg/dL (>4.9 mmol/L) • Total cholesterol levels >310 mg/dL (>8 mmol/L) • Children/adolescents (untreated): • LDL-C levels >190 mg/dL (≥4.9 mmol/L) [ • LDL-C levels >160 mg/dL, particularly when there is a first-degree relative with hyperlipidemia and/or premature coronary artery disease (onset in males age ≤55 years and females ≤65 years) [ • LDL-C levels >130 mg/dL (>3.4 mmol/L) in those with a first-degree relative with FH [ • Total cholesterol levels >230 mg/dL (>6 mmol/L) • LDL-C levels >190 mg/dL (≥4.9 mmol/L) [ • LDL-C levels >160 mg/dL, particularly when there is a first-degree relative with hyperlipidemia and/or premature coronary artery disease (onset in males age ≤55 years and females ≤65 years) [ • LDL-C levels >130 mg/dL (>3.4 mmol/L) in those with a first-degree relative with FH [ • Total cholesterol levels >230 mg/dL (>6 mmol/L) • Low-density lipoprotein cholesterol (LDL-C) levels >190 mg/dL (>4.9 mmol/L) • Total cholesterol levels >310 mg/dL (>8 mmol/L) • LDL-C levels >190 mg/dL (≥4.9 mmol/L) [ • LDL-C levels >160 mg/dL, particularly when there is a first-degree relative with hyperlipidemia and/or premature coronary artery disease (onset in males age ≤55 years and females ≤65 years) [ • LDL-C levels >130 mg/dL (>3.4 mmol/L) in those with a first-degree relative with FH [ • Total cholesterol levels >230 mg/dL (>6 mmol/L) • Xanthomas (cholesterol deposits in tendons) may be identified in adults but are unlikely to present in children with heterozygous familial hypercholesterolemia (HeFH). • Note: Xanthomas can present within the first few years of life in those with a more severe phenotype due to biallelic variants [ • Xanthelasmas (yellowish, waxy deposits that can occur around the eyelids) • Corneal arcus (white, gray, or blue opaque ring in the corneal margin as a result of cholesterol deposition) is more likely to be FH-related when present in an individual younger than age 45 years. • FH • Elevated LDL-C levels • Premature CAD • Xanthomas/xanthelasmas ## Establishing the Diagnosis The Note: The criteria used to establish the clinical diagnosis of FH in children varies substantially across medical centers within and outside of the United States. Some experts recommend the Simon Broome criteria in pediatric probands rather than the Dutch Lipid Clinic Network Criteria [ A A heterozygous pathogenic (or likely pathogenic) variant in A heterozygous pathogenic (or likely pathogenic) variant in A heterozygous gain-of-function pathogenic (or likely pathogenic) variant in Note: A whole-gene duplication of Biallelic loss-of-function 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 can be used for clinical decision making [ Molecular genetic testing approaches can include a A A For an introduction to multigene panels click Molecular Genetic Testing Used in Familial Hypercholesterolemia FH = familial hypercholesterolemia; 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 missense, nonsense, and splice site variants and small 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. Sequence analysis of To date, only ~30 Whole-gene duplication was reported in two unrelated families with FH [ FH disease-causing pathogenic variant(s) can be identified in ∼60%-80% of adult probands with a clinical diagnosis of FH. FH disease-causing pathogenic variant(s) can be identified in ∼60%-95% of pediatric probands in whom there is a strong clinical suspicion of FH [ • A heterozygous pathogenic (or likely pathogenic) variant in • A heterozygous pathogenic (or likely pathogenic) variant in • A heterozygous gain-of-function pathogenic (or likely pathogenic) variant in • Note: A whole-gene duplication of • Biallelic loss-of-function pathogenic (or likely pathogenic) variants in • A • A • For an introduction to multigene panels click ## Clinical Characteristics Elevated low-density lipoprotein cholesterol (LDL-C) leads to atherosclerotic plaque deposition in the coronary arteries and other arterial beds starting at an early age and worsening over time. Individuals with FH have elevated LDL-C levels starting soon after birth. When left untreated, this can lead to an increased risk of angina, myocardial infarction, peripheral artery disease, and potentially stroke [ Lipid-lowering therapy with statin-based regimens (see Management, Xanthomas represent cholesterol buildup in tendons of the body as a result of extremely high levels of LDL-C. Xanthomas may worsen with age in untreated persons. In persons treated with LDL-C-lowering therapy, the xanthomas can become smaller. Common locations: Tendonous xanthomas can occur in the elbows, hands, knees, and feet, particularly the Achilles tendon [ Interdigital xanthomas (between the fingers) occur in individuals with biallelic pathogenic variants in Xanthelasmas are patches of yellowish cholesterol deposits that often occur around the eyes [ Corneal arcus (white, gray, or blue opaque ring in the corneal margin) is caused by abnormal deposition of lipids in the cornea secondary to long-term exposure to elevated LDL-C levels. This feature develops with age and is concerning for FH when identified before age 45 years. Studies have found that this feature may present in an estimated 7%-30% of individuals with FH [ Individuals with biallelic pathogenic variants (either homozygous or compound heterozygous variants) in Familial Hypercholesterolemia: Phenotype Correlations by Gene Untreated adults often have LDL-C levels >500 mg/dL (>13 mmol/L). In addition to xanthelasmas & tendonous xanthomas, interdigital xanthomas (between fingers) can also occur & develop in childhood. Most persons develop severe CAD by their mid-20s. The rate of either death or coronary bypass surgery by teen years is high [ Statins are often relatively ineffective because their efficacy largely depends on upregulation of functional LDL receptors in liver [ Can be assoc w/↓ LDL-C levels & less severe presentation than Severe, early-onset FH has been reported in a few persons w/whole-gene duplication [ AD = autosomal dominant; AR = autosomal recessive; CAD = coronary artery disease; FH = familial hypercholesterolemia; HeFH = heterozygous familial hypercholesterolemia; HoFH = familial hypercholesterolemia due to biallelic (homozygous or compound heterozygous) pathogenic variants in Data on Penetrance is approximately 90% in persons heterozygous for the Penetrance in persons heterozygous for the Penetrance for other heterozygous While the term "homozygous" is generally used in genetics to denote the presence of the same pathogenic variant in both alleles of a given gene, the term "homozygous FH" or "HoFH" is used in the medical literature to denote the presence of any two pathogenic variants (compound heterozygous or homozygous) on both alleles of The term "autosomal recessive FH" refers to FH caused by biallelic pathogenic variants in The prevalence of HeFH in the general population was traditionally cited as 1:500; however, data suggest that it may be as high as ~1:250 [ The prevalence of HoFH due to biallelic pathogenic variants in The prevalence of autosomal recessive FH due to biallelic pathogenic variants in FH is more common in several populations ( Prevalence of Familial Hypercholesterolemia in Select Populations A common >10-kb Amish individuals heterozygous for • Tendonous xanthomas can occur in the elbows, hands, knees, and feet, particularly the Achilles tendon [ • Interdigital xanthomas (between the fingers) occur in individuals with biallelic pathogenic variants in • Untreated adults often have LDL-C levels >500 mg/dL (>13 mmol/L). In addition to xanthelasmas & tendonous xanthomas, interdigital xanthomas (between fingers) can also occur & develop in childhood. Most persons develop severe CAD by their mid-20s. The rate of either death or coronary bypass surgery by teen years is high [ • Statins are often relatively ineffective because their efficacy largely depends on upregulation of functional LDL receptors in liver [ • Can be assoc w/↓ LDL-C levels & less severe presentation than • Severe, early-onset FH has been reported in a few persons w/whole-gene duplication [ • Penetrance is approximately 90% in persons heterozygous for the • Penetrance in persons heterozygous for the • Penetrance for other heterozygous ## Clinical Description Elevated low-density lipoprotein cholesterol (LDL-C) leads to atherosclerotic plaque deposition in the coronary arteries and other arterial beds starting at an early age and worsening over time. Individuals with FH have elevated LDL-C levels starting soon after birth. When left untreated, this can lead to an increased risk of angina, myocardial infarction, peripheral artery disease, and potentially stroke [ Lipid-lowering therapy with statin-based regimens (see Management, Xanthomas represent cholesterol buildup in tendons of the body as a result of extremely high levels of LDL-C. Xanthomas may worsen with age in untreated persons. In persons treated with LDL-C-lowering therapy, the xanthomas can become smaller. Common locations: Tendonous xanthomas can occur in the elbows, hands, knees, and feet, particularly the Achilles tendon [ Interdigital xanthomas (between the fingers) occur in individuals with biallelic pathogenic variants in Xanthelasmas are patches of yellowish cholesterol deposits that often occur around the eyes [ Corneal arcus (white, gray, or blue opaque ring in the corneal margin) is caused by abnormal deposition of lipids in the cornea secondary to long-term exposure to elevated LDL-C levels. This feature develops with age and is concerning for FH when identified before age 45 years. Studies have found that this feature may present in an estimated 7%-30% of individuals with FH [ Individuals with biallelic pathogenic variants (either homozygous or compound heterozygous variants) in • Tendonous xanthomas can occur in the elbows, hands, knees, and feet, particularly the Achilles tendon [ • Interdigital xanthomas (between the fingers) occur in individuals with biallelic pathogenic variants in ## Heterozygous Familial Hypercholesterolemia (FH; HeFH) Elevated low-density lipoprotein cholesterol (LDL-C) leads to atherosclerotic plaque deposition in the coronary arteries and other arterial beds starting at an early age and worsening over time. Individuals with FH have elevated LDL-C levels starting soon after birth. When left untreated, this can lead to an increased risk of angina, myocardial infarction, peripheral artery disease, and potentially stroke [ Lipid-lowering therapy with statin-based regimens (see Management, Xanthomas represent cholesterol buildup in tendons of the body as a result of extremely high levels of LDL-C. Xanthomas may worsen with age in untreated persons. In persons treated with LDL-C-lowering therapy, the xanthomas can become smaller. Common locations: Tendonous xanthomas can occur in the elbows, hands, knees, and feet, particularly the Achilles tendon [ Interdigital xanthomas (between the fingers) occur in individuals with biallelic pathogenic variants in Xanthelasmas are patches of yellowish cholesterol deposits that often occur around the eyes [ Corneal arcus (white, gray, or blue opaque ring in the corneal margin) is caused by abnormal deposition of lipids in the cornea secondary to long-term exposure to elevated LDL-C levels. This feature develops with age and is concerning for FH when identified before age 45 years. Studies have found that this feature may present in an estimated 7%-30% of individuals with FH [ • Tendonous xanthomas can occur in the elbows, hands, knees, and feet, particularly the Achilles tendon [ • Interdigital xanthomas (between the fingers) occur in individuals with biallelic pathogenic variants in ## Homozygous (HoFH) and Autosomal Recessive FH Individuals with biallelic pathogenic variants (either homozygous or compound heterozygous variants) in ## Phenotype Correlations by Gene Familial Hypercholesterolemia: Phenotype Correlations by Gene Untreated adults often have LDL-C levels >500 mg/dL (>13 mmol/L). In addition to xanthelasmas & tendonous xanthomas, interdigital xanthomas (between fingers) can also occur & develop in childhood. Most persons develop severe CAD by their mid-20s. The rate of either death or coronary bypass surgery by teen years is high [ Statins are often relatively ineffective because their efficacy largely depends on upregulation of functional LDL receptors in liver [ Can be assoc w/↓ LDL-C levels & less severe presentation than Severe, early-onset FH has been reported in a few persons w/whole-gene duplication [ AD = autosomal dominant; AR = autosomal recessive; CAD = coronary artery disease; FH = familial hypercholesterolemia; HeFH = heterozygous familial hypercholesterolemia; HoFH = familial hypercholesterolemia due to biallelic (homozygous or compound heterozygous) pathogenic variants in Data on • Untreated adults often have LDL-C levels >500 mg/dL (>13 mmol/L). In addition to xanthelasmas & tendonous xanthomas, interdigital xanthomas (between fingers) can also occur & develop in childhood. Most persons develop severe CAD by their mid-20s. The rate of either death or coronary bypass surgery by teen years is high [ • Statins are often relatively ineffective because their efficacy largely depends on upregulation of functional LDL receptors in liver [ • Can be assoc w/↓ LDL-C levels & less severe presentation than • Severe, early-onset FH has been reported in a few persons w/whole-gene duplication [ ## Penetrance Penetrance is approximately 90% in persons heterozygous for the Penetrance in persons heterozygous for the Penetrance for other heterozygous • Penetrance is approximately 90% in persons heterozygous for the • Penetrance in persons heterozygous for the • Penetrance for other heterozygous ## Nomenclature While the term "homozygous" is generally used in genetics to denote the presence of the same pathogenic variant in both alleles of a given gene, the term "homozygous FH" or "HoFH" is used in the medical literature to denote the presence of any two pathogenic variants (compound heterozygous or homozygous) on both alleles of The term "autosomal recessive FH" refers to FH caused by biallelic pathogenic variants in ## Prevalence The prevalence of HeFH in the general population was traditionally cited as 1:500; however, data suggest that it may be as high as ~1:250 [ The prevalence of HoFH due to biallelic pathogenic variants in The prevalence of autosomal recessive FH due to biallelic pathogenic variants in FH is more common in several populations ( Prevalence of Familial Hypercholesterolemia in Select Populations A common >10-kb Amish individuals heterozygous for ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this Other phenotypes associated with germline pathogenic variants in Allelic Phenotypes Homozygous: hepatomegaly, steatorrhea, growth deficiency, deficiency of fat-soluble vitamins, GI, & neurologic dysfunction; plasma total cholesterol, LDL-C, & apo B levels typically <5% for age & sex Heterozygous: possible risk of liver dysfunction & hepatic steatosis; rarely (~5%-10% of persons), severe nonalcoholic steatosis → cirrhosis CAD = coronary artery disease; GI = gastrointestinal • Homozygous: hepatomegaly, steatorrhea, growth deficiency, deficiency of fat-soluble vitamins, GI, & neurologic dysfunction; plasma total cholesterol, LDL-C, & apo B levels typically <5% for age & sex • Heterozygous: possible risk of liver dysfunction & hepatic steatosis; rarely (~5%-10% of persons), severe nonalcoholic steatosis → cirrhosis ## Differential Diagnosis Genetic conditions with clinical and/or laboratory findings similar to those of familial hypercholesterolemia (FH) are summarized in Genetic Disorders with Feature(s) Similar to Those of Familial Hypercholesterolemia In infantile onset (Wolman disease): ↑ triglycerides, malnutrition, hepatosplenomegaly, liver disease, adrenal cortical insufficiency In adult onset (cholesterol-ester storage disease): hepatosplenomegaly &/or ↑ liver enzymes, ↑ triglycerides AD = autosomal dominant; AR = autosomal recessive; CAD = coronary artery disease; DiffDx = differential diagnosis; FH = familial hypercholesterolemia; LDL = low-density lipoprotein; LDL-C = low-density lipoprotein cholesterol; MOI = mode of inheritance Hypercholesterolemia secondary to acquired conditions including obesity, diabetes mellitus, obstructive liver disease, hypothyroidism, drugs (e.g., steroids), or kidney disease can also be associated with laboratory findings similar to those of FH [ • In infantile onset (Wolman disease): ↑ triglycerides, malnutrition, hepatosplenomegaly, liver disease, adrenal cortical insufficiency • In adult onset (cholesterol-ester storage disease): hepatosplenomegaly &/or ↑ liver enzymes, ↑ triglycerides ## Management To establish the extent of disease and needs of an individual diagnosed with familial hypercholesterolemia (FH), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Familial Hypercholesterolemia AR = autosomal recessive; FH = familial hypercholesterolemia; HDL-C = high-density lipoprotein cholesterol; HoFH = FH resulting from biallelic (homozygous or compound heterozygous) pathogenic variants in Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) All individuals with FH should be considered at high risk for coronary artery disease (CAD) and should be treated actively to lower cholesterol levels. Note that standard Framingham or other risk classification schemes are not applicable [ Treatment of Manifestations in Adults with Familial Hypercholesterolemia Regular physical activity Healthy diet (↓ saturated fat intake, ↑ intake of soluble fiber to 10-20 g/day) Weight control &/or weight loss as needed Ezetimibe Bile acid sequestrants PCSK9 inhibitors Bempedoic acid Clinically evident CAD or other atherosclerotic CVD; goal is LDL-C level of <70 mg/dL (<1.8 mmol/L) Diabetes mellitus or metabolic syndrome Family history of very early CAD (CAD diagnosed in men age <45 yrs; women age <55 yrs) Current smoking High lipoprotein(a) (≥50 mg/dL [≥1.3 mmol/L] using an isoform-insensitive assay) Consider low-dose aspirin (75-81 mg/day) in those w/CAD, prior stroke, or at high risk for CAD or stroke. Smoking cessation Measure serum lipoprotein(a). Treatment for diabetes mellitus Treatment of hypertension CAD = coronary artery disease; CVD = cardiovascular disease; FH = familial hypercholesterolemia; LDL-C = low-density lipoprotein cholesterol Current Recommended Drug Therapies for Adults with Familial Hypercholesterolemia Some guidelines call for the addition of n-3 polyunsaturated fatty acids or fibrates if triglycerides remain elevated after the LDL-C level is controlled. LDL = low-density lipoprotein; LDL-C = low-density lipoprotein cholesterol; LDLR = low-density lipoprotein receptor Often ineffective in HoFH due to biallelic pathogenic variants in Approved only for HoFH Guidelines for the management of children have been published by multiple national and international organizations [ Treatment of Manifestations in Children with Familial Hypercholesterolemia Regular physical activity & limited screen time Healthy diet: high in fiber, low in saturated fat (≤7% of calories), avoidance of trans fats, <200 mg/day of dietary cholesterol Maintenance of healthy weight Children w/LDL-C ≥190 mg/dL In children w/LDL-C 130-189 mg/dL, the initiation of statins depends on assessment of family history, risk factors, & comorbidities. Pharmacotherapy is typically considered as early as age 10 yrs, but statins may be used as early as age 8 yrs. Some experts recommend target LDL-C of ≤130 mg/dL or a 50% reduction. Treatment for diabetes mellitus Treatment of hypertension FH = familial hypercholesterolemia; LDL-C = low-density lipoprotein cholesterol The safety and efficacy of statins in children is supported by clinical trial data and by long-term observational data [ National Lipid Association guidelines for severe FH (also referred to as HoFH; see Treatment of Manifestations in Children and Adults with Severe Familial Hypercholesterolemia (HoFH) Referral to lipid specialist w/expertise in FH Multi-drug therapy usually required (See 40% mean reduction in LDL-C compared w/placebo; however, persons w/biallelic loss-of-function variants saw no response. To date, only evolocumab has been approved for children w/FH & HoFH. High-dose statins Ezetimibe Bile acid-binding resins Recombinant human monoclonal antibody that binds to & inhibits ANGPTL3 Available for adults & children ≥5 yrs w/HoFH Used in conjunction w/other lipid-lowering therapies CVD = cardiovascular disease; FH = familial hypercholesterolemia; LDL-C = low-density lipoprotein cholesterol; LDLR = low-density lipoprotein receptor To prevent primary manifestations, the following are recommended: Reduce saturated fat intake. Increase intake of soluble fiber to 10-20 g/day. Increase physical activity. Do not smoke. During treatment, individuals of any age with: FH should have lipid levels monitored as recommended; Severe FH (HoFH due to homozygous or compound heterozygous pathogenic variants in Additional recommended evaluations include those in Recommended Surveillance in Individuals with Familial Hypercholesterolemia In children: Begin at age 2 yrs & monitor closely. At a minimum reassess cholesterol levels between age 9-11 yrs. Some experts advocate for screening children for ↑ lipoprotein(a), but this practice is not universal. In adults: The interval of follow-up testing TBD by care team & based on presence of other risk factors HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; TBD = to be determined; TC = total cholesterol The following should be avoided: Smoking High intake of saturated and trans unsaturated fat Sedentary lifestyle Obesity Hypertension Type II diabetes mellitus The CDC has classified FH as a Tier 1 condition, indicating a significant benefit from performing family-based cascade screening. Cholesterol testing, with or without molecular testing in relatives of affected persons with FH, can be used to identify individuals with FH and provide them with lifesaving treatment. Early diagnosis and treatment of relatives at risk for FH can reduce morbidity and mortality [ The genetic status of at-risk family members can be clarified by EITHER of the following: Molecular genetic testing if the pathogenic variant(s) in the family are known; Measurement of low-density lipoprotein cholesterol (LDL-C) level if the pathogenic variant(s) in the family are not known. In children with a family history of FH, non-fasting lipid level should be measured by age two years. If lipid level is borderline, measure LDL-C level. An LDL-C level of >130 mg/dL in a child is suspicious for FH in the setting of a known family history of FH, and an LDL-C level of >160 mg/dL is relatively specific for FH. See Pregnant women should incorporate all the other recommended lifestyle changes, including low saturated and trans unsaturated fat intake, no smoking, and high dietary soluble fiber intake. Pharmacologic treatment during pregnancy: Statins are contraindicated in pregnancy because of concerns for teratogenicity; women with FH who are considering a pregnancy should be counseled of this risk and statins should be discontinued prior to conception. The use of statins during human pregnancy has not been definitively associated with adverse fetal outcome; however, the role of cholesterol in embryologic development has led to theoretic concerns about the effect of these medications on a developing fetus and a recommendation that alternative medications be considered during pregnancy and lactation. Nursing mothers should not take statins. Bile acid-binding resins (colesevelam, cholestyramine) are generally considered safe (Class B for pregnancy). Based primarily on animal studies, cholestyramine use during pregnancy has not been associated with an increased risk of fetal anomalies. However, use of cholestyramine could theoretically cause depletion of maternal fat-soluble vitamins, including vitamin K. LDL apheresis is also occasionally used. Use of PCSK9 inhibitors, ezetimibe, lomitapide, and bempedoic acid during pregnancy has not been well studied. Search • Regular physical activity • Healthy diet (↓ saturated fat intake, ↑ intake of soluble fiber to 10-20 g/day) • Weight control &/or weight loss as needed • Ezetimibe • Bile acid sequestrants • PCSK9 inhibitors • Bempedoic acid • Clinically evident CAD or other atherosclerotic CVD; goal is LDL-C level of <70 mg/dL (<1.8 mmol/L) • Diabetes mellitus or metabolic syndrome • Family history of very early CAD (CAD diagnosed in men age <45 yrs; women age <55 yrs) • Current smoking • High lipoprotein(a) (≥50 mg/dL [≥1.3 mmol/L] using an isoform-insensitive assay) • Consider low-dose aspirin (75-81 mg/day) in those w/CAD, prior stroke, or at high risk for CAD or stroke. • Smoking cessation • Measure serum lipoprotein(a). • Treatment for diabetes mellitus • Treatment of hypertension • Regular physical activity & limited screen time • Healthy diet: high in fiber, low in saturated fat (≤7% of calories), avoidance of trans fats, <200 mg/day of dietary cholesterol • Maintenance of healthy weight • Children w/LDL-C ≥190 mg/dL • In children w/LDL-C 130-189 mg/dL, the initiation of statins depends on assessment of family history, risk factors, & comorbidities. • Pharmacotherapy is typically considered as early as age 10 yrs, but statins may be used as early as age 8 yrs. • Some experts recommend target LDL-C of ≤130 mg/dL or a 50% reduction. • Treatment for diabetes mellitus • Treatment of hypertension • Referral to lipid specialist w/expertise in FH • Multi-drug therapy usually required (See • 40% mean reduction in LDL-C compared w/placebo; however, persons w/biallelic loss-of-function variants saw no response. • To date, only evolocumab has been approved for children w/FH & HoFH. • High-dose statins • Ezetimibe • Bile acid-binding resins • Recombinant human monoclonal antibody that binds to & inhibits ANGPTL3 • Available for adults & children ≥5 yrs w/HoFH • Used in conjunction w/other lipid-lowering therapies • Reduce saturated fat intake. • Increase intake of soluble fiber to 10-20 g/day. • Increase physical activity. • Do not smoke. • FH should have lipid levels monitored as recommended; • Severe FH (HoFH due to homozygous or compound heterozygous pathogenic variants in • In children: Begin at age 2 yrs & monitor closely. At a minimum reassess cholesterol levels between age 9-11 yrs. • Some experts advocate for screening children for ↑ lipoprotein(a), but this practice is not universal. • In adults: The interval of follow-up testing TBD by care team & based on presence of other risk factors • Smoking • High intake of saturated and trans unsaturated fat • Sedentary lifestyle • Obesity • Hypertension • Type II diabetes mellitus • Molecular genetic testing if the pathogenic variant(s) in the family are known; • Measurement of low-density lipoprotein cholesterol (LDL-C) level if the pathogenic variant(s) in the family are not known. • Statins are contraindicated in pregnancy because of concerns for teratogenicity; women with FH who are considering a pregnancy should be counseled of this risk and statins should be discontinued prior to conception. The use of statins during human pregnancy has not been definitively associated with adverse fetal outcome; however, the role of cholesterol in embryologic development has led to theoretic concerns about the effect of these medications on a developing fetus and a recommendation that alternative medications be considered during pregnancy and lactation. Nursing mothers should not take statins. • Bile acid-binding resins (colesevelam, cholestyramine) are generally considered safe (Class B for pregnancy). Based primarily on animal studies, cholestyramine use during pregnancy has not been associated with an increased risk of fetal anomalies. However, use of cholestyramine could theoretically cause depletion of maternal fat-soluble vitamins, including vitamin K. • LDL apheresis is also occasionally used. • Use of PCSK9 inhibitors, ezetimibe, lomitapide, and bempedoic acid during pregnancy has not been well studied. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with familial hypercholesterolemia (FH), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Familial Hypercholesterolemia AR = autosomal recessive; FH = familial hypercholesterolemia; HDL-C = high-density lipoprotein cholesterol; HoFH = FH resulting from biallelic (homozygous or compound heterozygous) pathogenic variants in Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) ## Treatment of Manifestations All individuals with FH should be considered at high risk for coronary artery disease (CAD) and should be treated actively to lower cholesterol levels. Note that standard Framingham or other risk classification schemes are not applicable [ Treatment of Manifestations in Adults with Familial Hypercholesterolemia Regular physical activity Healthy diet (↓ saturated fat intake, ↑ intake of soluble fiber to 10-20 g/day) Weight control &/or weight loss as needed Ezetimibe Bile acid sequestrants PCSK9 inhibitors Bempedoic acid Clinically evident CAD or other atherosclerotic CVD; goal is LDL-C level of <70 mg/dL (<1.8 mmol/L) Diabetes mellitus or metabolic syndrome Family history of very early CAD (CAD diagnosed in men age <45 yrs; women age <55 yrs) Current smoking High lipoprotein(a) (≥50 mg/dL [≥1.3 mmol/L] using an isoform-insensitive assay) Consider low-dose aspirin (75-81 mg/day) in those w/CAD, prior stroke, or at high risk for CAD or stroke. Smoking cessation Measure serum lipoprotein(a). Treatment for diabetes mellitus Treatment of hypertension CAD = coronary artery disease; CVD = cardiovascular disease; FH = familial hypercholesterolemia; LDL-C = low-density lipoprotein cholesterol Current Recommended Drug Therapies for Adults with Familial Hypercholesterolemia Some guidelines call for the addition of n-3 polyunsaturated fatty acids or fibrates if triglycerides remain elevated after the LDL-C level is controlled. LDL = low-density lipoprotein; LDL-C = low-density lipoprotein cholesterol; LDLR = low-density lipoprotein receptor Often ineffective in HoFH due to biallelic pathogenic variants in Approved only for HoFH Guidelines for the management of children have been published by multiple national and international organizations [ Treatment of Manifestations in Children with Familial Hypercholesterolemia Regular physical activity & limited screen time Healthy diet: high in fiber, low in saturated fat (≤7% of calories), avoidance of trans fats, <200 mg/day of dietary cholesterol Maintenance of healthy weight Children w/LDL-C ≥190 mg/dL In children w/LDL-C 130-189 mg/dL, the initiation of statins depends on assessment of family history, risk factors, & comorbidities. Pharmacotherapy is typically considered as early as age 10 yrs, but statins may be used as early as age 8 yrs. Some experts recommend target LDL-C of ≤130 mg/dL or a 50% reduction. Treatment for diabetes mellitus Treatment of hypertension FH = familial hypercholesterolemia; LDL-C = low-density lipoprotein cholesterol The safety and efficacy of statins in children is supported by clinical trial data and by long-term observational data [ National Lipid Association guidelines for severe FH (also referred to as HoFH; see Treatment of Manifestations in Children and Adults with Severe Familial Hypercholesterolemia (HoFH) Referral to lipid specialist w/expertise in FH Multi-drug therapy usually required (See 40% mean reduction in LDL-C compared w/placebo; however, persons w/biallelic loss-of-function variants saw no response. To date, only evolocumab has been approved for children w/FH & HoFH. High-dose statins Ezetimibe Bile acid-binding resins Recombinant human monoclonal antibody that binds to & inhibits ANGPTL3 Available for adults & children ≥5 yrs w/HoFH Used in conjunction w/other lipid-lowering therapies CVD = cardiovascular disease; FH = familial hypercholesterolemia; LDL-C = low-density lipoprotein cholesterol; LDLR = low-density lipoprotein receptor • Regular physical activity • Healthy diet (↓ saturated fat intake, ↑ intake of soluble fiber to 10-20 g/day) • Weight control &/or weight loss as needed • Ezetimibe • Bile acid sequestrants • PCSK9 inhibitors • Bempedoic acid • Clinically evident CAD or other atherosclerotic CVD; goal is LDL-C level of <70 mg/dL (<1.8 mmol/L) • Diabetes mellitus or metabolic syndrome • Family history of very early CAD (CAD diagnosed in men age <45 yrs; women age <55 yrs) • Current smoking • High lipoprotein(a) (≥50 mg/dL [≥1.3 mmol/L] using an isoform-insensitive assay) • Consider low-dose aspirin (75-81 mg/day) in those w/CAD, prior stroke, or at high risk for CAD or stroke. • Smoking cessation • Measure serum lipoprotein(a). • Treatment for diabetes mellitus • Treatment of hypertension • Regular physical activity & limited screen time • Healthy diet: high in fiber, low in saturated fat (≤7% of calories), avoidance of trans fats, <200 mg/day of dietary cholesterol • Maintenance of healthy weight • Children w/LDL-C ≥190 mg/dL • In children w/LDL-C 130-189 mg/dL, the initiation of statins depends on assessment of family history, risk factors, & comorbidities. • Pharmacotherapy is typically considered as early as age 10 yrs, but statins may be used as early as age 8 yrs. • Some experts recommend target LDL-C of ≤130 mg/dL or a 50% reduction. • Treatment for diabetes mellitus • Treatment of hypertension • Referral to lipid specialist w/expertise in FH • Multi-drug therapy usually required (See • 40% mean reduction in LDL-C compared w/placebo; however, persons w/biallelic loss-of-function variants saw no response. • To date, only evolocumab has been approved for children w/FH & HoFH. • High-dose statins • Ezetimibe • Bile acid-binding resins • Recombinant human monoclonal antibody that binds to & inhibits ANGPTL3 • Available for adults & children ≥5 yrs w/HoFH • Used in conjunction w/other lipid-lowering therapies ## Adults with FH All individuals with FH should be considered at high risk for coronary artery disease (CAD) and should be treated actively to lower cholesterol levels. Note that standard Framingham or other risk classification schemes are not applicable [ Treatment of Manifestations in Adults with Familial Hypercholesterolemia Regular physical activity Healthy diet (↓ saturated fat intake, ↑ intake of soluble fiber to 10-20 g/day) Weight control &/or weight loss as needed Ezetimibe Bile acid sequestrants PCSK9 inhibitors Bempedoic acid Clinically evident CAD or other atherosclerotic CVD; goal is LDL-C level of <70 mg/dL (<1.8 mmol/L) Diabetes mellitus or metabolic syndrome Family history of very early CAD (CAD diagnosed in men age <45 yrs; women age <55 yrs) Current smoking High lipoprotein(a) (≥50 mg/dL [≥1.3 mmol/L] using an isoform-insensitive assay) Consider low-dose aspirin (75-81 mg/day) in those w/CAD, prior stroke, or at high risk for CAD or stroke. Smoking cessation Measure serum lipoprotein(a). Treatment for diabetes mellitus Treatment of hypertension CAD = coronary artery disease; CVD = cardiovascular disease; FH = familial hypercholesterolemia; LDL-C = low-density lipoprotein cholesterol Current Recommended Drug Therapies for Adults with Familial Hypercholesterolemia Some guidelines call for the addition of n-3 polyunsaturated fatty acids or fibrates if triglycerides remain elevated after the LDL-C level is controlled. LDL = low-density lipoprotein; LDL-C = low-density lipoprotein cholesterol; LDLR = low-density lipoprotein receptor Often ineffective in HoFH due to biallelic pathogenic variants in Approved only for HoFH • Regular physical activity • Healthy diet (↓ saturated fat intake, ↑ intake of soluble fiber to 10-20 g/day) • Weight control &/or weight loss as needed • Ezetimibe • Bile acid sequestrants • PCSK9 inhibitors • Bempedoic acid • Clinically evident CAD or other atherosclerotic CVD; goal is LDL-C level of <70 mg/dL (<1.8 mmol/L) • Diabetes mellitus or metabolic syndrome • Family history of very early CAD (CAD diagnosed in men age <45 yrs; women age <55 yrs) • Current smoking • High lipoprotein(a) (≥50 mg/dL [≥1.3 mmol/L] using an isoform-insensitive assay) • Consider low-dose aspirin (75-81 mg/day) in those w/CAD, prior stroke, or at high risk for CAD or stroke. • Smoking cessation • Measure serum lipoprotein(a). • Treatment for diabetes mellitus • Treatment of hypertension ## Children with FH Guidelines for the management of children have been published by multiple national and international organizations [ Treatment of Manifestations in Children with Familial Hypercholesterolemia Regular physical activity & limited screen time Healthy diet: high in fiber, low in saturated fat (≤7% of calories), avoidance of trans fats, <200 mg/day of dietary cholesterol Maintenance of healthy weight Children w/LDL-C ≥190 mg/dL In children w/LDL-C 130-189 mg/dL, the initiation of statins depends on assessment of family history, risk factors, & comorbidities. Pharmacotherapy is typically considered as early as age 10 yrs, but statins may be used as early as age 8 yrs. Some experts recommend target LDL-C of ≤130 mg/dL or a 50% reduction. Treatment for diabetes mellitus Treatment of hypertension FH = familial hypercholesterolemia; LDL-C = low-density lipoprotein cholesterol The safety and efficacy of statins in children is supported by clinical trial data and by long-term observational data [ • Regular physical activity & limited screen time • Healthy diet: high in fiber, low in saturated fat (≤7% of calories), avoidance of trans fats, <200 mg/day of dietary cholesterol • Maintenance of healthy weight • Children w/LDL-C ≥190 mg/dL • In children w/LDL-C 130-189 mg/dL, the initiation of statins depends on assessment of family history, risk factors, & comorbidities. • Pharmacotherapy is typically considered as early as age 10 yrs, but statins may be used as early as age 8 yrs. • Some experts recommend target LDL-C of ≤130 mg/dL or a 50% reduction. • Treatment for diabetes mellitus • Treatment of hypertension ## Children and Adults with HoFH National Lipid Association guidelines for severe FH (also referred to as HoFH; see Treatment of Manifestations in Children and Adults with Severe Familial Hypercholesterolemia (HoFH) Referral to lipid specialist w/expertise in FH Multi-drug therapy usually required (See 40% mean reduction in LDL-C compared w/placebo; however, persons w/biallelic loss-of-function variants saw no response. To date, only evolocumab has been approved for children w/FH & HoFH. High-dose statins Ezetimibe Bile acid-binding resins Recombinant human monoclonal antibody that binds to & inhibits ANGPTL3 Available for adults & children ≥5 yrs w/HoFH Used in conjunction w/other lipid-lowering therapies CVD = cardiovascular disease; FH = familial hypercholesterolemia; LDL-C = low-density lipoprotein cholesterol; LDLR = low-density lipoprotein receptor • Referral to lipid specialist w/expertise in FH • Multi-drug therapy usually required (See • 40% mean reduction in LDL-C compared w/placebo; however, persons w/biallelic loss-of-function variants saw no response. • To date, only evolocumab has been approved for children w/FH & HoFH. • High-dose statins • Ezetimibe • Bile acid-binding resins • Recombinant human monoclonal antibody that binds to & inhibits ANGPTL3 • Available for adults & children ≥5 yrs w/HoFH • Used in conjunction w/other lipid-lowering therapies ## Prevention of Primary Manifestations To prevent primary manifestations, the following are recommended: Reduce saturated fat intake. Increase intake of soluble fiber to 10-20 g/day. Increase physical activity. Do not smoke. • Reduce saturated fat intake. • Increase intake of soluble fiber to 10-20 g/day. • Increase physical activity. • Do not smoke. ## Surveillance During treatment, individuals of any age with: FH should have lipid levels monitored as recommended; Severe FH (HoFH due to homozygous or compound heterozygous pathogenic variants in Additional recommended evaluations include those in Recommended Surveillance in Individuals with Familial Hypercholesterolemia In children: Begin at age 2 yrs & monitor closely. At a minimum reassess cholesterol levels between age 9-11 yrs. Some experts advocate for screening children for ↑ lipoprotein(a), but this practice is not universal. In adults: The interval of follow-up testing TBD by care team & based on presence of other risk factors HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; TBD = to be determined; TC = total cholesterol • FH should have lipid levels monitored as recommended; • Severe FH (HoFH due to homozygous or compound heterozygous pathogenic variants in • In children: Begin at age 2 yrs & monitor closely. At a minimum reassess cholesterol levels between age 9-11 yrs. • Some experts advocate for screening children for ↑ lipoprotein(a), but this practice is not universal. • In adults: The interval of follow-up testing TBD by care team & based on presence of other risk factors ## Agents/Circumstances to Avoid The following should be avoided: Smoking High intake of saturated and trans unsaturated fat Sedentary lifestyle Obesity Hypertension Type II diabetes mellitus • Smoking • High intake of saturated and trans unsaturated fat • Sedentary lifestyle • Obesity • Hypertension • Type II diabetes mellitus ## Evaluation of Relatives at Risk The CDC has classified FH as a Tier 1 condition, indicating a significant benefit from performing family-based cascade screening. Cholesterol testing, with or without molecular testing in relatives of affected persons with FH, can be used to identify individuals with FH and provide them with lifesaving treatment. Early diagnosis and treatment of relatives at risk for FH can reduce morbidity and mortality [ The genetic status of at-risk family members can be clarified by EITHER of the following: Molecular genetic testing if the pathogenic variant(s) in the family are known; Measurement of low-density lipoprotein cholesterol (LDL-C) level if the pathogenic variant(s) in the family are not known. In children with a family history of FH, non-fasting lipid level should be measured by age two years. If lipid level is borderline, measure LDL-C level. An LDL-C level of >130 mg/dL in a child is suspicious for FH in the setting of a known family history of FH, and an LDL-C level of >160 mg/dL is relatively specific for FH. See • Molecular genetic testing if the pathogenic variant(s) in the family are known; • Measurement of low-density lipoprotein cholesterol (LDL-C) level if the pathogenic variant(s) in the family are not known. ## Pregnancy Management Pregnant women should incorporate all the other recommended lifestyle changes, including low saturated and trans unsaturated fat intake, no smoking, and high dietary soluble fiber intake. Pharmacologic treatment during pregnancy: Statins are contraindicated in pregnancy because of concerns for teratogenicity; women with FH who are considering a pregnancy should be counseled of this risk and statins should be discontinued prior to conception. The use of statins during human pregnancy has not been definitively associated with adverse fetal outcome; however, the role of cholesterol in embryologic development has led to theoretic concerns about the effect of these medications on a developing fetus and a recommendation that alternative medications be considered during pregnancy and lactation. Nursing mothers should not take statins. Bile acid-binding resins (colesevelam, cholestyramine) are generally considered safe (Class B for pregnancy). Based primarily on animal studies, cholestyramine use during pregnancy has not been associated with an increased risk of fetal anomalies. However, use of cholestyramine could theoretically cause depletion of maternal fat-soluble vitamins, including vitamin K. LDL apheresis is also occasionally used. Use of PCSK9 inhibitors, ezetimibe, lomitapide, and bempedoic acid during pregnancy has not been well studied. • Statins are contraindicated in pregnancy because of concerns for teratogenicity; women with FH who are considering a pregnancy should be counseled of this risk and statins should be discontinued prior to conception. The use of statins during human pregnancy has not been definitively associated with adverse fetal outcome; however, the role of cholesterol in embryologic development has led to theoretic concerns about the effect of these medications on a developing fetus and a recommendation that alternative medications be considered during pregnancy and lactation. Nursing mothers should not take statins. • Bile acid-binding resins (colesevelam, cholestyramine) are generally considered safe (Class B for pregnancy). Based primarily on animal studies, cholestyramine use during pregnancy has not been associated with an increased risk of fetal anomalies. However, use of cholestyramine could theoretically cause depletion of maternal fat-soluble vitamins, including vitamin K. • LDL apheresis is also occasionally used. • Use of PCSK9 inhibitors, ezetimibe, lomitapide, and bempedoic acid during pregnancy has not been well studied. ## Therapies Under Investigation Search ## Genetic Counseling Almost all individuals with FH resulting from a heterozygous pathogenic variant in The proportion of probands with FH who have a Recommendations for the parents of the proband include the following: Measurement of cholesterol (recommended for both the parents of a proband with a known Targeted molecular genetic testing if an If the proband has a known pathogenic variant that is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. Although most individuals diagnosed with FH have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, lack of knowledge regarding family member's cholesterol levels and heart disease history, or late onset of the disorder in the affected parent. If heterozygous family members have been on statins for many years, there may not be a prominent family history of premature CAD. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed. The parents of an individual with biallelic pathogenic variants in If one 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 having FH is 50%. If both parents of the proband are affected with FH and are known to have an FH-related pathogenic variant, there is a 50% risk that sibs will inherit one pathogenic variant and have FH, a 25% risk that sibs will inherit two pathogenic variants and have severe FH, and a 25% chance that sibs will inherit neither of the familial pathogenic variants. The severity of HoFH varies. HoFH caused by homozygous loss-of-function If the proband has a known FH-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 should still be considered at risk for FH because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism. All sibs should undergo predictive genetic testing and cholesterol screening. Each child of an individual with FH caused by a heterozygous pathogenic variant in All children of an individual with HoFH (i.e., biallelic FH-related pathogenic variants) will inherit a pathogenic variant and have FH. If the reproductive partner of a proband is heterozygous for an FH-related pathogenic variant in the same gene as the proband or a different FH-related gene, offspring are at risk of inheriting two pathogenic variants and having severe FH. Cholesterol screening – followed by genetic counseling and genetic testing if cholesterol levels and family history are concerning for FH – should be offered to the reproductive partner to assess this risk. (FH is more common in several populations [see The parents of an individual with Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for 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 Individuals who are heterozygous for an The offspring of an individual with If the reproductive partner of a proband is heterozygous for an Carrier testing for at-risk relatives requires prior identification of the See Management, Young women with FH should receive counseling regarding contraindications of lipid-lowering therapies during pregnancy (see Management, The proband's reproductive partner should be offered cholesterol screening, followed by genetic counseling and genetic testing if cholesterol levels and family history are concerning for FH. Ideally, this should be offered prior to conception to assess the risk of having a child with HoFH. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is 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 FH-causing pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • Almost all individuals with FH resulting from a heterozygous pathogenic variant in • The proportion of probands with FH who have a • Recommendations for the parents of the proband include the following: • Measurement of cholesterol (recommended for both the parents of a proband with a known • Targeted molecular genetic testing if an • Measurement of cholesterol (recommended for both the parents of a proband with a known • Targeted molecular genetic testing if an • If the proband has a known pathogenic variant that is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte 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. • Although most individuals diagnosed with FH have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, lack of knowledge regarding family member's cholesterol levels and heart disease history, or late onset of the disorder in the affected parent. If heterozygous family members have been on statins for many years, there may not be a prominent family history of premature CAD. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed. • The parents of an individual with biallelic pathogenic variants in • Measurement of cholesterol (recommended for both the parents of a proband with a known • Targeted molecular genetic testing if an • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If one 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 having FH is 50%. • If both parents of the proband are affected with FH and are known to have an FH-related pathogenic variant, there is a 50% risk that sibs will inherit one pathogenic variant and have FH, a 25% risk that sibs will inherit two pathogenic variants and have severe FH, and a 25% chance that sibs will inherit neither of the familial pathogenic variants. • The severity of HoFH varies. HoFH caused by homozygous loss-of-function • If the proband has a known FH-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 should still be considered at risk for FH because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism. All sibs should undergo predictive genetic testing and cholesterol screening. • Each child of an individual with FH caused by a heterozygous pathogenic variant in • All children of an individual with HoFH (i.e., biallelic FH-related pathogenic variants) will inherit a pathogenic variant and have FH. • If the reproductive partner of a proband is heterozygous for an FH-related pathogenic variant in the same gene as the proband or a different FH-related gene, offspring are at risk of inheriting two pathogenic variants and having severe FH. Cholesterol screening – followed by genetic counseling and genetic testing if cholesterol levels and family history are concerning for FH – should be offered to the reproductive partner to assess this risk. (FH is more common in several populations [see • The parents of an individual with • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for 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 • Individuals who are heterozygous for an • The offspring of an individual with • If the reproductive partner of a proband is heterozygous for an • Young women with FH should receive counseling regarding contraindications of lipid-lowering therapies during pregnancy (see Management, • The proband's reproductive partner should be offered cholesterol screening, followed by genetic counseling and genetic testing if cholesterol levels and family history are concerning for FH. Ideally, this should be offered prior to conception to assess the risk of having a child with HoFH. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance Almost all individuals with FH resulting from a heterozygous pathogenic variant in The proportion of probands with FH who have a Recommendations for the parents of the proband include the following: Measurement of cholesterol (recommended for both the parents of a proband with a known Targeted molecular genetic testing if an If the proband has a known pathogenic variant that is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. Although most individuals diagnosed with FH have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, lack of knowledge regarding family member's cholesterol levels and heart disease history, or late onset of the disorder in the affected parent. If heterozygous family members have been on statins for many years, there may not be a prominent family history of premature CAD. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed. The parents of an individual with biallelic pathogenic variants in If one 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 having FH is 50%. If both parents of the proband are affected with FH and are known to have an FH-related pathogenic variant, there is a 50% risk that sibs will inherit one pathogenic variant and have FH, a 25% risk that sibs will inherit two pathogenic variants and have severe FH, and a 25% chance that sibs will inherit neither of the familial pathogenic variants. The severity of HoFH varies. HoFH caused by homozygous loss-of-function If the proband has a known FH-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 should still be considered at risk for FH because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism. All sibs should undergo predictive genetic testing and cholesterol screening. Each child of an individual with FH caused by a heterozygous pathogenic variant in All children of an individual with HoFH (i.e., biallelic FH-related pathogenic variants) will inherit a pathogenic variant and have FH. If the reproductive partner of a proband is heterozygous for an FH-related pathogenic variant in the same gene as the proband or a different FH-related gene, offspring are at risk of inheriting two pathogenic variants and having severe FH. Cholesterol screening – followed by genetic counseling and genetic testing if cholesterol levels and family history are concerning for FH – should be offered to the reproductive partner to assess this risk. (FH is more common in several populations [see • Almost all individuals with FH resulting from a heterozygous pathogenic variant in • The proportion of probands with FH who have a • Recommendations for the parents of the proband include the following: • Measurement of cholesterol (recommended for both the parents of a proband with a known • Targeted molecular genetic testing if an • Measurement of cholesterol (recommended for both the parents of a proband with a known • Targeted molecular genetic testing if an • If the proband has a known pathogenic variant that is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte 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. • Although most individuals diagnosed with FH have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, lack of knowledge regarding family member's cholesterol levels and heart disease history, or late onset of the disorder in the affected parent. If heterozygous family members have been on statins for many years, there may not be a prominent family history of premature CAD. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed. • The parents of an individual with biallelic pathogenic variants in • Measurement of cholesterol (recommended for both the parents of a proband with a known • Targeted molecular genetic testing if an • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If one 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 having FH is 50%. • If both parents of the proband are affected with FH and are known to have an FH-related pathogenic variant, there is a 50% risk that sibs will inherit one pathogenic variant and have FH, a 25% risk that sibs will inherit two pathogenic variants and have severe FH, and a 25% chance that sibs will inherit neither of the familial pathogenic variants. • The severity of HoFH varies. HoFH caused by homozygous loss-of-function • If the proband has a known FH-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 should still be considered at risk for FH because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism. All sibs should undergo predictive genetic testing and cholesterol screening. • Each child of an individual with FH caused by a heterozygous pathogenic variant in • All children of an individual with HoFH (i.e., biallelic FH-related pathogenic variants) will inherit a pathogenic variant and have FH. • If the reproductive partner of a proband is heterozygous for an FH-related pathogenic variant in the same gene as the proband or a different FH-related gene, offspring are at risk of inheriting two pathogenic variants and having severe FH. Cholesterol screening – followed by genetic counseling and genetic testing if cholesterol levels and family history are concerning for FH – should be offered to the reproductive partner to assess this risk. (FH is more common in several populations [see The parents of an individual with Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for 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 Individuals who are heterozygous for an The offspring of an individual with If the reproductive partner of a proband is heterozygous for an Carrier testing for at-risk relatives requires prior identification of the • The parents of an individual with • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for 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 • Individuals who are heterozygous for an • The offspring of an individual with • If the reproductive partner of a proband is heterozygous for an ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues See Management, Young women with FH should receive counseling regarding contraindications of lipid-lowering therapies during pregnancy (see Management, The proband's reproductive partner should be offered cholesterol screening, followed by genetic counseling and genetic testing if cholesterol levels and family history are concerning for FH. Ideally, this should be offered prior to conception to assess the risk of having a child with HoFH. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • Young women with FH should receive counseling regarding contraindications of lipid-lowering therapies during pregnancy (see Management, • The proband's reproductive partner should be offered cholesterol screening, followed by genetic counseling and genetic testing if cholesterol levels and family history are concerning for FH. Ideally, this should be offered prior to conception to assess the risk of having a child with HoFH. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is 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 FH-causing pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources AAS Secretariat 959 East Walnut Street Suite 220 Pasadena CA 91106 Austria Spain Germany Wien Austria PCNA National Office 613 Williamson Street Suite 200 Madison WI 53703 United Kingdom Japan 6816 Southpoint Parkway Suite 1000 Jacksonville FL 32216 • • • • AAS Secretariat • • • 959 East Walnut Street • Suite 220 • Pasadena CA 91106 • • • • • • • Austria • • • Spain • • • Germany • • • Wien • Austria • • • • • PCNA National Office • 613 Williamson Street • Suite 200 • Madison WI 53703 • • • United Kingdom • • • Japan • • • • • 6816 Southpoint Parkway • Suite 1000 • Jacksonville FL 32216 • • • ## Molecular Genetics Familial Hypercholesterolemia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Familial Hypercholesterolemia ( The PCSK9 protein product binds to LDLRs and promotes their degradation in intracellular acidic compartments. Pathogenic variants in The LDLRAP1 protein plays an important role in moving LDLRs and their attached LDL particles into the liver cells for recycling. Biallelic loss-of-function Familial Hypercholesterolemia: Mechanism of Disease Causation Genes from Familial Hypercholesterolemia: Gene-Specific Laboratory Considerations Genes from Familial Hypercholesterolemia: Notable Pathogenic Variants by Gene 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 ( Genes from Variant designation that does not conform to current naming conventions. In this case, numbering is based on mature peptide before cleavage of signal peptide and corresponding nucleotides. ## Molecular Pathogenesis The PCSK9 protein product binds to LDLRs and promotes their degradation in intracellular acidic compartments. Pathogenic variants in The LDLRAP1 protein plays an important role in moving LDLRs and their attached LDL particles into the liver cells for recycling. Biallelic loss-of-function Familial Hypercholesterolemia: Mechanism of Disease Causation Genes from Familial Hypercholesterolemia: Gene-Specific Laboratory Considerations Genes from Familial Hypercholesterolemia: Notable Pathogenic Variants by Gene 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 ( Genes from Variant designation that does not conform to current naming conventions. In this case, numbering is based on mature peptide before cleavage of signal peptide and corresponding nucleotides. ## Chapter Notes The FH Foundation, AHA, NIH, Doris Duke Foundation Shoa L Clarke, MD, PhD (2022-present)Hannah E Ison, MS, LCGC (2022-present)Joshua W Knowles, MD, PhD (2014-present)Mitchel Pariani, MS, LCGC; Stanford Center for Inherited Cardiovascular Disease (2016-2022)Emily Youngblom, PhD, MPH; University of Washington School of Public Health (2014-2022) 30 January 2025 (sw) Revision: long-term safety and efficacy of evinacumab in HoFH [ 7 July 2022 (sw) Comprehensive update posted live 8 December 2016 (sw) Comprehensive update posted live 2 January 2014 (me) Review posted live 5 August 2013 (jl) Original submission • 30 January 2025 (sw) Revision: long-term safety and efficacy of evinacumab in HoFH [ • 7 July 2022 (sw) Comprehensive update posted live • 8 December 2016 (sw) Comprehensive update posted live • 2 January 2014 (me) Review posted live • 5 August 2013 (jl) Original submission ## Author Notes ## Acknowledgments The FH Foundation, AHA, NIH, Doris Duke Foundation ## Author History Shoa L Clarke, MD, PhD (2022-present)Hannah E Ison, MS, LCGC (2022-present)Joshua W Knowles, MD, PhD (2014-present)Mitchel Pariani, MS, LCGC; Stanford Center for Inherited Cardiovascular Disease (2016-2022)Emily Youngblom, PhD, MPH; University of Washington School of Public Health (2014-2022) ## Revision History 30 January 2025 (sw) Revision: long-term safety and efficacy of evinacumab in HoFH [ 7 July 2022 (sw) Comprehensive update posted live 8 December 2016 (sw) Comprehensive update posted live 2 January 2014 (me) Review posted live 5 August 2013 (jl) Original submission • 30 January 2025 (sw) Revision: long-term safety and efficacy of evinacumab in HoFH [ • 7 July 2022 (sw) Comprehensive update posted live • 8 December 2016 (sw) Comprehensive update posted live • 2 January 2014 (me) Review posted live • 5 August 2013 (jl) Original submission ## References Chora JR, Iacocca MA, Tichý L, Wand H, Kurtz CL, Zimmermann H, Leon A, Williams M, Humphries SE, Hooper AJ, Trinder M, Brunham LR, Costa Pereira A, Jannes CE, Chen M, Chonis J, Wang J, Kim S, Johnston T, Soucek P, Kramarek M, Leigh SE, Carrié A, Sijbrands EJ, Hegele RA, Freiberger T, Knowles JW, Bourbon M, et al. The Clinical Genome Resource (ClinGen) Familial Hypercholesterolemia Variant Curation Expert Panel consensus guidelines for LDLR variant classification. Genet Med. 2022;24:293-306. [ de Ferranti SD, Steinberger J, Ameduri R, Baker A, Gooding H, Kelly AS, Mietus-Snyder M, Mitsnefes MM, Peterson AL, St-Pierre J, Urbina EM. Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the American Heart Association. Circulation. 2019;139:e603-34. [ DeMott K, Nherera L, Shaw EJ, Minhas R, Humphries SE, Kathoria M, Ritchie G, Nunes V, Davies D, Lee P, McDowell I, Neil A, Qureshi N, Rowlands P, Seed M, Stracey H, Thorogood M, Watson M. Clinical guidelines and evidence review for familial hypercholesterolæmia: the identification and management of adults and children with familial hypercholesterolæmia. London: National Collaborating Centre for Primary Care and Royal College of General Practitioners. Available Descamps OS, Tenoutasse S, Stephenne X, Gies I, Beauloye V, Lebrethon MC, De Beaufort C, De Waele K, Scheen A, Rietzschel E, Mangano A, Panier JP, Ducobu J, Langlois M, Balligand JL, Legat P, Blaton V, Muls E, Van Gaal L, Sokal E, Rooman R, Carpentier Y, De Backer G, Heller FR. Management of familial hypercholesterolemia in children and young adults: consensus paper developed by a panel of lipidologists, cardiologists, pædiatricians, nutritionists, gastroenterologists, general practitioners and a patient organization. Atherosclerosis. 2011;218:272-80. [ Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents; National Heart, Lung, and Blood Institute. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report. Available Goldberg AC, Hopkins PN, Toth PP, Ballantyne CM, Rader DJ, Robinson JG, Daniels SR, Gidding SS, de Ferranti SD, Ito MK, McGowan MP, Moriarty PM, Cromwell WC, Ross JL, Ziajka PE, et al. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5:S1-8. [ Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Orringer CE, Peralta CA, Saseen JJ, Smith SC Jr, Sperling L, Virani SS, Yeboah J. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139:e1082-e1143. [ Hegele RA, Borén J, Ginsberg HN, Arca M, Averna M, Binder CJ, Calabresi L, Chapman MJ, Cuchel M, von Eckardstein A, Frikke-Schmidt R. Rare dyslipidaemias, from phenotype to genotype to management: a European Atherosclerosis Society task force consensus statement. Lancet Diabetes Endocrinol. 2020;8:50-67. [ Hopkins PN, Toth PP, Ballantyne CM, Rader DJ, et al. Familial hypercholesterolemias: prevalence, genetics, diagnosis and screening recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5:S9-17. [ Ito MK, McGowan MP, Moriarty PM, et al. Management of familial hypercholesterolemias in adult patients: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5:S38-45. [ Martin AC, Coakley J, Forbes DA, Sullivan DR, Watts GF. Familial hypercholesterolæmia in children and adolescents: a new paediatric model of care. J Paediatr Child Health. 2013;49:E263-72. [ Sturm AC, Knowles JW, Gidding SS, Ahmad ZS, Ahmed CD, Ballantyne CM, Baum SJ, Bourbon M, Carrié A, Cuchel M, de Ferranti SD, Defesche JC, Freiberger T, Hershberger RE, Hovingh GK, Karayan L, Kastelein JJP, Kindt I, Lane SR, Leigh SE, Linton MF, Mata P, Neal WA, Nordestgaard BG, Santos RD, Harada-Shiba M, Sijbrands EJ, Stitziel NO, Yamashita S, Wilemon KA, Ledbetter DH, Rader DJ. Convened by the Familial Hypercholesterolemia Foundation. Clinical genetic testing for familial hypercholesterolemia: JACC Scientific Expert Panel. J Am Coll Cardiol. 2018;72:662-80. [ • Chora JR, Iacocca MA, Tichý L, Wand H, Kurtz CL, Zimmermann H, Leon A, Williams M, Humphries SE, Hooper AJ, Trinder M, Brunham LR, Costa Pereira A, Jannes CE, Chen M, Chonis J, Wang J, Kim S, Johnston T, Soucek P, Kramarek M, Leigh SE, Carrié A, Sijbrands EJ, Hegele RA, Freiberger T, Knowles JW, Bourbon M, et al. The Clinical Genome Resource (ClinGen) Familial Hypercholesterolemia Variant Curation Expert Panel consensus guidelines for LDLR variant classification. Genet Med. 2022;24:293-306. [ • de Ferranti SD, Steinberger J, Ameduri R, Baker A, Gooding H, Kelly AS, Mietus-Snyder M, Mitsnefes MM, Peterson AL, St-Pierre J, Urbina EM. Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the American Heart Association. Circulation. 2019;139:e603-34. [ • DeMott K, Nherera L, Shaw EJ, Minhas R, Humphries SE, Kathoria M, Ritchie G, Nunes V, Davies D, Lee P, McDowell I, Neil A, Qureshi N, Rowlands P, Seed M, Stracey H, Thorogood M, Watson M. Clinical guidelines and evidence review for familial hypercholesterolæmia: the identification and management of adults and children with familial hypercholesterolæmia. London: National Collaborating Centre for Primary Care and Royal College of General Practitioners. Available • Descamps OS, Tenoutasse S, Stephenne X, Gies I, Beauloye V, Lebrethon MC, De Beaufort C, De Waele K, Scheen A, Rietzschel E, Mangano A, Panier JP, Ducobu J, Langlois M, Balligand JL, Legat P, Blaton V, Muls E, Van Gaal L, Sokal E, Rooman R, Carpentier Y, De Backer G, Heller FR. Management of familial hypercholesterolemia in children and young adults: consensus paper developed by a panel of lipidologists, cardiologists, pædiatricians, nutritionists, gastroenterologists, general practitioners and a patient organization. Atherosclerosis. 2011;218:272-80. [ • Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents; National Heart, Lung, and Blood Institute. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report. Available • Goldberg AC, Hopkins PN, Toth PP, Ballantyne CM, Rader DJ, Robinson JG, Daniels SR, Gidding SS, de Ferranti SD, Ito MK, McGowan MP, Moriarty PM, Cromwell WC, Ross JL, Ziajka PE, et al. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5:S1-8. [ • Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Orringer CE, Peralta CA, Saseen JJ, Smith SC Jr, Sperling L, Virani SS, Yeboah J. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139:e1082-e1143. [ • Hegele RA, Borén J, Ginsberg HN, Arca M, Averna M, Binder CJ, Calabresi L, Chapman MJ, Cuchel M, von Eckardstein A, Frikke-Schmidt R. Rare dyslipidaemias, from phenotype to genotype to management: a European Atherosclerosis Society task force consensus statement. Lancet Diabetes Endocrinol. 2020;8:50-67. [ • Hopkins PN, Toth PP, Ballantyne CM, Rader DJ, et al. Familial hypercholesterolemias: prevalence, genetics, diagnosis and screening recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5:S9-17. [ • Ito MK, McGowan MP, Moriarty PM, et al. Management of familial hypercholesterolemias in adult patients: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5:S38-45. [ • Martin AC, Coakley J, Forbes DA, Sullivan DR, Watts GF. Familial hypercholesterolæmia in children and adolescents: a new paediatric model of care. J Paediatr Child Health. 2013;49:E263-72. [ • Sturm AC, Knowles JW, Gidding SS, Ahmad ZS, Ahmed CD, Ballantyne CM, Baum SJ, Bourbon M, Carrié A, Cuchel M, de Ferranti SD, Defesche JC, Freiberger T, Hershberger RE, Hovingh GK, Karayan L, Kastelein JJP, Kindt I, Lane SR, Leigh SE, Linton MF, Mata P, Neal WA, Nordestgaard BG, Santos RD, Harada-Shiba M, Sijbrands EJ, Stitziel NO, Yamashita S, Wilemon KA, Ledbetter DH, Rader DJ. Convened by the Familial Hypercholesterolemia Foundation. Clinical genetic testing for familial hypercholesterolemia: JACC Scientific Expert Panel. J Am Coll Cardiol. 2018;72:662-80. [ ## Published Guidelines / Consensus Statements Chora JR, Iacocca MA, Tichý L, Wand H, Kurtz CL, Zimmermann H, Leon A, Williams M, Humphries SE, Hooper AJ, Trinder M, Brunham LR, Costa Pereira A, Jannes CE, Chen M, Chonis J, Wang J, Kim S, Johnston T, Soucek P, Kramarek M, Leigh SE, Carrié A, Sijbrands EJ, Hegele RA, Freiberger T, Knowles JW, Bourbon M, et al. The Clinical Genome Resource (ClinGen) Familial Hypercholesterolemia Variant Curation Expert Panel consensus guidelines for LDLR variant classification. Genet Med. 2022;24:293-306. [ de Ferranti SD, Steinberger J, Ameduri R, Baker A, Gooding H, Kelly AS, Mietus-Snyder M, Mitsnefes MM, Peterson AL, St-Pierre J, Urbina EM. Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the American Heart Association. Circulation. 2019;139:e603-34. [ DeMott K, Nherera L, Shaw EJ, Minhas R, Humphries SE, Kathoria M, Ritchie G, Nunes V, Davies D, Lee P, McDowell I, Neil A, Qureshi N, Rowlands P, Seed M, Stracey H, Thorogood M, Watson M. Clinical guidelines and evidence review for familial hypercholesterolæmia: the identification and management of adults and children with familial hypercholesterolæmia. London: National Collaborating Centre for Primary Care and Royal College of General Practitioners. Available Descamps OS, Tenoutasse S, Stephenne X, Gies I, Beauloye V, Lebrethon MC, De Beaufort C, De Waele K, Scheen A, Rietzschel E, Mangano A, Panier JP, Ducobu J, Langlois M, Balligand JL, Legat P, Blaton V, Muls E, Van Gaal L, Sokal E, Rooman R, Carpentier Y, De Backer G, Heller FR. Management of familial hypercholesterolemia in children and young adults: consensus paper developed by a panel of lipidologists, cardiologists, pædiatricians, nutritionists, gastroenterologists, general practitioners and a patient organization. Atherosclerosis. 2011;218:272-80. [ Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents; National Heart, Lung, and Blood Institute. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report. Available Goldberg AC, Hopkins PN, Toth PP, Ballantyne CM, Rader DJ, Robinson JG, Daniels SR, Gidding SS, de Ferranti SD, Ito MK, McGowan MP, Moriarty PM, Cromwell WC, Ross JL, Ziajka PE, et al. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5:S1-8. [ Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Orringer CE, Peralta CA, Saseen JJ, Smith SC Jr, Sperling L, Virani SS, Yeboah J. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139:e1082-e1143. [ Hegele RA, Borén J, Ginsberg HN, Arca M, Averna M, Binder CJ, Calabresi L, Chapman MJ, Cuchel M, von Eckardstein A, Frikke-Schmidt R. Rare dyslipidaemias, from phenotype to genotype to management: a European Atherosclerosis Society task force consensus statement. Lancet Diabetes Endocrinol. 2020;8:50-67. [ Hopkins PN, Toth PP, Ballantyne CM, Rader DJ, et al. Familial hypercholesterolemias: prevalence, genetics, diagnosis and screening recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5:S9-17. [ Ito MK, McGowan MP, Moriarty PM, et al. Management of familial hypercholesterolemias in adult patients: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5:S38-45. [ Martin AC, Coakley J, Forbes DA, Sullivan DR, Watts GF. Familial hypercholesterolæmia in children and adolescents: a new paediatric model of care. J Paediatr Child Health. 2013;49:E263-72. [ Sturm AC, Knowles JW, Gidding SS, Ahmad ZS, Ahmed CD, Ballantyne CM, Baum SJ, Bourbon M, Carrié A, Cuchel M, de Ferranti SD, Defesche JC, Freiberger T, Hershberger RE, Hovingh GK, Karayan L, Kastelein JJP, Kindt I, Lane SR, Leigh SE, Linton MF, Mata P, Neal WA, Nordestgaard BG, Santos RD, Harada-Shiba M, Sijbrands EJ, Stitziel NO, Yamashita S, Wilemon KA, Ledbetter DH, Rader DJ. Convened by the Familial Hypercholesterolemia Foundation. Clinical genetic testing for familial hypercholesterolemia: JACC Scientific Expert Panel. J Am Coll Cardiol. 2018;72:662-80. [ • Chora JR, Iacocca MA, Tichý L, Wand H, Kurtz CL, Zimmermann H, Leon A, Williams M, Humphries SE, Hooper AJ, Trinder M, Brunham LR, Costa Pereira A, Jannes CE, Chen M, Chonis J, Wang J, Kim S, Johnston T, Soucek P, Kramarek M, Leigh SE, Carrié A, Sijbrands EJ, Hegele RA, Freiberger T, Knowles JW, Bourbon M, et al. The Clinical Genome Resource (ClinGen) Familial Hypercholesterolemia Variant Curation Expert Panel consensus guidelines for LDLR variant classification. Genet Med. 2022;24:293-306. [ • de Ferranti SD, Steinberger J, Ameduri R, Baker A, Gooding H, Kelly AS, Mietus-Snyder M, Mitsnefes MM, Peterson AL, St-Pierre J, Urbina EM. Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the American Heart Association. Circulation. 2019;139:e603-34. [ • DeMott K, Nherera L, Shaw EJ, Minhas R, Humphries SE, Kathoria M, Ritchie G, Nunes V, Davies D, Lee P, McDowell I, Neil A, Qureshi N, Rowlands P, Seed M, Stracey H, Thorogood M, Watson M. Clinical guidelines and evidence review for familial hypercholesterolæmia: the identification and management of adults and children with familial hypercholesterolæmia. London: National Collaborating Centre for Primary Care and Royal College of General Practitioners. Available • Descamps OS, Tenoutasse S, Stephenne X, Gies I, Beauloye V, Lebrethon MC, De Beaufort C, De Waele K, Scheen A, Rietzschel E, Mangano A, Panier JP, Ducobu J, Langlois M, Balligand JL, Legat P, Blaton V, Muls E, Van Gaal L, Sokal E, Rooman R, Carpentier Y, De Backer G, Heller FR. Management of familial hypercholesterolemia in children and young adults: consensus paper developed by a panel of lipidologists, cardiologists, pædiatricians, nutritionists, gastroenterologists, general practitioners and a patient organization. Atherosclerosis. 2011;218:272-80. [ • Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents; National Heart, Lung, and Blood Institute. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report. Available • Goldberg AC, Hopkins PN, Toth PP, Ballantyne CM, Rader DJ, Robinson JG, Daniels SR, Gidding SS, de Ferranti SD, Ito MK, McGowan MP, Moriarty PM, Cromwell WC, Ross JL, Ziajka PE, et al. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5:S1-8. [ • Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Orringer CE, Peralta CA, Saseen JJ, Smith SC Jr, Sperling L, Virani SS, Yeboah J. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139:e1082-e1143. [ • Hegele RA, Borén J, Ginsberg HN, Arca M, Averna M, Binder CJ, Calabresi L, Chapman MJ, Cuchel M, von Eckardstein A, Frikke-Schmidt R. Rare dyslipidaemias, from phenotype to genotype to management: a European Atherosclerosis Society task force consensus statement. Lancet Diabetes Endocrinol. 2020;8:50-67. [ • Hopkins PN, Toth PP, Ballantyne CM, Rader DJ, et al. Familial hypercholesterolemias: prevalence, genetics, diagnosis and screening recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5:S9-17. [ • Ito MK, McGowan MP, Moriarty PM, et al. Management of familial hypercholesterolemias in adult patients: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5:S38-45. [ • Martin AC, Coakley J, Forbes DA, Sullivan DR, Watts GF. Familial hypercholesterolæmia in children and adolescents: a new paediatric model of care. J Paediatr Child Health. 2013;49:E263-72. [ • Sturm AC, Knowles JW, Gidding SS, Ahmad ZS, Ahmed CD, Ballantyne CM, Baum SJ, Bourbon M, Carrié A, Cuchel M, de Ferranti SD, Defesche JC, Freiberger T, Hershberger RE, Hovingh GK, Karayan L, Kastelein JJP, Kindt I, Lane SR, Leigh SE, Linton MF, Mata P, Neal WA, Nordestgaard BG, Santos RD, Harada-Shiba M, Sijbrands EJ, Stitziel NO, Yamashita S, Wilemon KA, Ledbetter DH, Rader DJ. Convened by the Familial Hypercholesterolemia Foundation. Clinical genetic testing for familial hypercholesterolemia: JACC Scientific Expert Panel. J Am Coll Cardiol. 2018;72:662-80. [ ## Literature Cited LDL cholesterol burden in individuals with or without familial hypercholesterolemia as a function of the age of initiation of statin therapy Data derived from	[]	2/1/2014	7/7/2022	30/1/2025	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
hyperek	hyperek	[ "Glycine receptor subunit alpha-1", "Glycine receptor subunit beta", "Sodium- and chloride-dependent glycine transporter 2", "GLRA1", "GLRB", "SLC6A5", "Hereditary Hyperekplexia", "Overview" ]	Hereditary Hyperekplexia Overview	Bettina Balint, Rhys Thomas	Summary The goals of this overview on hereditary hyperekplexia (HPX) caused by dysfunction of glycinergic inhibitory transmission is to: Describe the Review the Provide an Review Inform	## Hereditary Hyperekplexia: Clinical Characteristics Hereditary hyperekplexia (HPX), an inherited neuronal disorder caused by genetic defects leading to dysfunction of glycinergic inhibitory transmission, is characterized by the clinical core features of exaggerated startle responses to unexpected sensory stimuli and stiffness. HPX, a rare and underdiagnosed disorder, is manifest immediately after birth and commonly improves with age [ The term hyperekplexia is used to denote excessive or exaggerated startle that typically does not habituate. Hyperekplexia can be an acquired feature of many disorders, particularly when there is pontine pathology; it may also be observed in infants and children with complex genetic disorders associated with developmental delay/intellectual disability often resulting from an inborn error of metabolism or brain malformation (see The frequency of startle responses varies considerably among individuals and over time, and often disappears or remits with medication between infancy and adolescence [ Factors that increase the frequency of the startle responses include emotional tension (even the expectation of being frightened), nervousness, and fatigue. Holding objects or drinking alcohol reduces the intensity and frequency of startle responses. The exaggerated head-retraction reflex (HRR) is an exaggerated startle response to tactile stimuli and is elicited by gentle taps particularly to the tip of the nose, but also to the nose ridge, the glabella, upper lip, and chin [ The excessive startle reflex has major implications for daily life as it cannot be suppressed and unexpected stimuli from the outside world cannot be regulated. This is a prominent problem for some infants when the simple activities of feeding or being dressed produce paroxysms of startle responses. In later life, the excessive startle reflex and associated generalized stiffness increase the risk of falls and injury. The generalized stiffness evident immediately after birth usually normalizes during the first years of life (by age 2 years; range: 0.7-5 years) [ Other complications of severe attacks of stiffness: Episodes of tonic neonatal cyanosis (i.e., attacks of apnea in neonates with HPX) [ Frequent occurrence of inguinal, umbilical, or epigastric hernias, paralytic ileus, and congenital dislocation of the hip [ In some children, delayed motor milestones and mild developmental delay or learning difficulties (particularly speech acquisition); children later catch up [ Periodic limb movements in sleep (PLMS) and hypnagogic myoclonus (myoclonus occurring when falling asleep) Epilepsy; estimated prevalence in hyperekplexia of 7%-12% [ The differential diagnosis of abnormal startle can be divided into the following: Complex genetic neurodevelopmental disorders Acquired causes Note: It is this group of disorders that is most likely to be confused with hereditary hyperekplexia resulting from dysfunction of glycinergic inhibitory transmission. Complex Genetic Neurodevelopmental Disorders with an Excessive Startle Response Severe ID Epilepsy (often intractable focal seizures or febrile seizures) Dysmorphic features Profound DD & progressive encephalopathy Microcephaly Hypotonia followed by spastic quadriplegia Seizures Epileptic encephalopathy w/myoclonic epilepsy Myoclonic seizures provoked by tactile stimuli & spontaneous & reflex seizures to noise & touch Congenital or infantile cataracts Neutropenia Other neurologic signs: hypotonia, spasticity, ataxia, dystonia, epilepsy, or ID Dysmorphic features, camptodactyly Facial & bulbar weakness Hyperekplexia is rare in this entity (single case report) Later onset of hyperekplexia (not congenital but in childhood) & atypical pattern (no generalized stiffness induced by startle) No congenital stiffness Progressive neurologic involvement w/additional signs (ID, ataxia, spasticity) Microcephaly Intractable seizures Severe psychomotor retardation Hypotonia combined w/hyperreflexia Usually lethal in infancy DD or regression Visual impairment Epilepsy Later: macrocephaly, decerebrate posturing, dysphagia, progression to unresponsive vegetative state ID Facial dysmorphism, tapering digits, & skeletal deformity Besides hyperekplexia, there may be other types of stimulus-induced drop attacks (e.g., cataplexy-like episodes) Hypotonia > hypertonicity Arthrogryposis Respiratory failure Dysmorphic features Encephalopathy Progressive epileptic encephalopathy Other neurologic features: opisthotonus, spastic quadriplegia, pyramidal signs Microcephaly, dysmorphic features Hypotonia Progressive epileptic encephalopathy Generalized clonus ("jitteriness") Delayed developmental (motor & cognitive) milestones Other neurologic signs: spasticity, chorea, visual impairment, epilepsy AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked OMIM phenotype entry or citation is provided if a related In this diverse group of disorders, the startle reflex itself is not excessive, but rather induces another clinical feature that is more prominent and characteristic than the startle response [ Startle epilepsy (normal startle triggers seizures) Paroxysmal kinesigenic choreoathetosis (See Creutzfeldt-Jakob disease (See Subacute sclerosing panencephalitis In addition to excessive startling, behavioral and/or psychiatric findings are observed in the following groups of disorders: Culture-specific syndromes, in which an exaggerated startle response, evoked by auditory, sensory, or visual stimuli occurs within a community [ Anxiety disorders, functional neurologic disorders Tics and Gilles de la Tourette syndrome, in which an exaggerated startle reflex has been described in some, but not all, affected individuals • The generalized stiffness evident immediately after birth usually normalizes during the first years of life (by age 2 years; range: 0.7-5 years) [ • Episodes of tonic neonatal cyanosis (i.e., attacks of apnea in neonates with HPX) [ • Frequent occurrence of inguinal, umbilical, or epigastric hernias, paralytic ileus, and congenital dislocation of the hip [ • In some children, delayed motor milestones and mild developmental delay or learning difficulties (particularly speech acquisition); children later catch up [ • Periodic limb movements in sleep (PLMS) and hypnagogic myoclonus (myoclonus occurring when falling asleep) • Epilepsy; estimated prevalence in hyperekplexia of 7%-12% [ • Complex genetic neurodevelopmental disorders • Acquired causes • Note: It is this group of disorders that is most likely to be confused with hereditary hyperekplexia resulting from dysfunction of glycinergic inhibitory transmission. • Complex genetic neurodevelopmental disorders • Acquired causes • Complex genetic neurodevelopmental disorders • Acquired causes • Severe ID • Epilepsy (often intractable focal seizures or febrile seizures) • Dysmorphic features • Profound DD & progressive encephalopathy • Microcephaly • Hypotonia followed by spastic quadriplegia • Seizures • Epileptic encephalopathy w/myoclonic epilepsy • Myoclonic seizures provoked by tactile stimuli & spontaneous & reflex seizures to noise & touch • Congenital or infantile cataracts • Neutropenia • Other neurologic signs: hypotonia, spasticity, ataxia, dystonia, epilepsy, or ID • Dysmorphic features, camptodactyly • Facial & bulbar weakness • Hyperekplexia is rare in this entity (single case report) • Later onset of hyperekplexia (not congenital but in childhood) & atypical pattern (no generalized stiffness induced by startle) • No congenital stiffness • Progressive neurologic involvement w/additional signs (ID, ataxia, spasticity) • Microcephaly • Intractable seizures • Severe psychomotor retardation • Hypotonia combined w/hyperreflexia • Usually lethal in infancy • DD or regression • Visual impairment • Epilepsy • Later: macrocephaly, decerebrate posturing, dysphagia, progression to unresponsive vegetative state • ID • Facial dysmorphism, tapering digits, & skeletal deformity • Besides hyperekplexia, there may be other types of stimulus-induced drop attacks (e.g., cataplexy-like episodes) • Hypotonia > hypertonicity • Arthrogryposis • Respiratory failure • Dysmorphic features • Encephalopathy • Progressive epileptic encephalopathy • Other neurologic features: opisthotonus, spastic quadriplegia, pyramidal signs • Microcephaly, dysmorphic features • Hypotonia • Progressive epileptic encephalopathy • Generalized clonus ("jitteriness") • Delayed developmental (motor & cognitive) milestones • Other neurologic signs: spasticity, chorea, visual impairment, epilepsy • Startle epilepsy (normal startle triggers seizures) • Paroxysmal kinesigenic choreoathetosis (See • Creutzfeldt-Jakob disease (See • Subacute sclerosing panencephalitis • Culture-specific syndromes, in which an exaggerated startle response, evoked by auditory, sensory, or visual stimuli occurs within a community [ • Anxiety disorders, functional neurologic disorders • Tics and Gilles de la Tourette syndrome, in which an exaggerated startle reflex has been described in some, but not all, affected individuals ## HPX Core Features The frequency of startle responses varies considerably among individuals and over time, and often disappears or remits with medication between infancy and adolescence [ Factors that increase the frequency of the startle responses include emotional tension (even the expectation of being frightened), nervousness, and fatigue. Holding objects or drinking alcohol reduces the intensity and frequency of startle responses. The exaggerated head-retraction reflex (HRR) is an exaggerated startle response to tactile stimuli and is elicited by gentle taps particularly to the tip of the nose, but also to the nose ridge, the glabella, upper lip, and chin [ The excessive startle reflex has major implications for daily life as it cannot be suppressed and unexpected stimuli from the outside world cannot be regulated. This is a prominent problem for some infants when the simple activities of feeding or being dressed produce paroxysms of startle responses. In later life, the excessive startle reflex and associated generalized stiffness increase the risk of falls and injury. The generalized stiffness evident immediately after birth usually normalizes during the first years of life (by age 2 years; range: 0.7-5 years) [ Other complications of severe attacks of stiffness: Episodes of tonic neonatal cyanosis (i.e., attacks of apnea in neonates with HPX) [ Frequent occurrence of inguinal, umbilical, or epigastric hernias, paralytic ileus, and congenital dislocation of the hip [ In some children, delayed motor milestones and mild developmental delay or learning difficulties (particularly speech acquisition); children later catch up [ Periodic limb movements in sleep (PLMS) and hypnagogic myoclonus (myoclonus occurring when falling asleep) Epilepsy; estimated prevalence in hyperekplexia of 7%-12% [ • The generalized stiffness evident immediately after birth usually normalizes during the first years of life (by age 2 years; range: 0.7-5 years) [ • Episodes of tonic neonatal cyanosis (i.e., attacks of apnea in neonates with HPX) [ • Frequent occurrence of inguinal, umbilical, or epigastric hernias, paralytic ileus, and congenital dislocation of the hip [ • In some children, delayed motor milestones and mild developmental delay or learning difficulties (particularly speech acquisition); children later catch up [ • Periodic limb movements in sleep (PLMS) and hypnagogic myoclonus (myoclonus occurring when falling asleep) • Epilepsy; estimated prevalence in hyperekplexia of 7%-12% [ ## Differential Diagnosis The differential diagnosis of abnormal startle can be divided into the following: Complex genetic neurodevelopmental disorders Acquired causes Note: It is this group of disorders that is most likely to be confused with hereditary hyperekplexia resulting from dysfunction of glycinergic inhibitory transmission. Complex Genetic Neurodevelopmental Disorders with an Excessive Startle Response Severe ID Epilepsy (often intractable focal seizures or febrile seizures) Dysmorphic features Profound DD & progressive encephalopathy Microcephaly Hypotonia followed by spastic quadriplegia Seizures Epileptic encephalopathy w/myoclonic epilepsy Myoclonic seizures provoked by tactile stimuli & spontaneous & reflex seizures to noise & touch Congenital or infantile cataracts Neutropenia Other neurologic signs: hypotonia, spasticity, ataxia, dystonia, epilepsy, or ID Dysmorphic features, camptodactyly Facial & bulbar weakness Hyperekplexia is rare in this entity (single case report) Later onset of hyperekplexia (not congenital but in childhood) & atypical pattern (no generalized stiffness induced by startle) No congenital stiffness Progressive neurologic involvement w/additional signs (ID, ataxia, spasticity) Microcephaly Intractable seizures Severe psychomotor retardation Hypotonia combined w/hyperreflexia Usually lethal in infancy DD or regression Visual impairment Epilepsy Later: macrocephaly, decerebrate posturing, dysphagia, progression to unresponsive vegetative state ID Facial dysmorphism, tapering digits, & skeletal deformity Besides hyperekplexia, there may be other types of stimulus-induced drop attacks (e.g., cataplexy-like episodes) Hypotonia > hypertonicity Arthrogryposis Respiratory failure Dysmorphic features Encephalopathy Progressive epileptic encephalopathy Other neurologic features: opisthotonus, spastic quadriplegia, pyramidal signs Microcephaly, dysmorphic features Hypotonia Progressive epileptic encephalopathy Generalized clonus ("jitteriness") Delayed developmental (motor & cognitive) milestones Other neurologic signs: spasticity, chorea, visual impairment, epilepsy AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked OMIM phenotype entry or citation is provided if a related In this diverse group of disorders, the startle reflex itself is not excessive, but rather induces another clinical feature that is more prominent and characteristic than the startle response [ Startle epilepsy (normal startle triggers seizures) Paroxysmal kinesigenic choreoathetosis (See Creutzfeldt-Jakob disease (See Subacute sclerosing panencephalitis In addition to excessive startling, behavioral and/or psychiatric findings are observed in the following groups of disorders: Culture-specific syndromes, in which an exaggerated startle response, evoked by auditory, sensory, or visual stimuli occurs within a community [ Anxiety disorders, functional neurologic disorders Tics and Gilles de la Tourette syndrome, in which an exaggerated startle reflex has been described in some, but not all, affected individuals • Complex genetic neurodevelopmental disorders • Acquired causes • Note: It is this group of disorders that is most likely to be confused with hereditary hyperekplexia resulting from dysfunction of glycinergic inhibitory transmission. • Complex genetic neurodevelopmental disorders • Acquired causes • Complex genetic neurodevelopmental disorders • Acquired causes • Severe ID • Epilepsy (often intractable focal seizures or febrile seizures) • Dysmorphic features • Profound DD & progressive encephalopathy • Microcephaly • Hypotonia followed by spastic quadriplegia • Seizures • Epileptic encephalopathy w/myoclonic epilepsy • Myoclonic seizures provoked by tactile stimuli & spontaneous & reflex seizures to noise & touch • Congenital or infantile cataracts • Neutropenia • Other neurologic signs: hypotonia, spasticity, ataxia, dystonia, epilepsy, or ID • Dysmorphic features, camptodactyly • Facial & bulbar weakness • Hyperekplexia is rare in this entity (single case report) • Later onset of hyperekplexia (not congenital but in childhood) & atypical pattern (no generalized stiffness induced by startle) • No congenital stiffness • Progressive neurologic involvement w/additional signs (ID, ataxia, spasticity) • Microcephaly • Intractable seizures • Severe psychomotor retardation • Hypotonia combined w/hyperreflexia • Usually lethal in infancy • DD or regression • Visual impairment • Epilepsy • Later: macrocephaly, decerebrate posturing, dysphagia, progression to unresponsive vegetative state • ID • Facial dysmorphism, tapering digits, & skeletal deformity • Besides hyperekplexia, there may be other types of stimulus-induced drop attacks (e.g., cataplexy-like episodes) • Hypotonia > hypertonicity • Arthrogryposis • Respiratory failure • Dysmorphic features • Encephalopathy • Progressive epileptic encephalopathy • Other neurologic features: opisthotonus, spastic quadriplegia, pyramidal signs • Microcephaly, dysmorphic features • Hypotonia • Progressive epileptic encephalopathy • Generalized clonus ("jitteriness") • Delayed developmental (motor & cognitive) milestones • Other neurologic signs: spasticity, chorea, visual impairment, epilepsy • Startle epilepsy (normal startle triggers seizures) • Paroxysmal kinesigenic choreoathetosis (See • Creutzfeldt-Jakob disease (See • Subacute sclerosing panencephalitis • Culture-specific syndromes, in which an exaggerated startle response, evoked by auditory, sensory, or visual stimuli occurs within a community [ • Anxiety disorders, functional neurologic disorders • Tics and Gilles de la Tourette syndrome, in which an exaggerated startle reflex has been described in some, but not all, affected individuals ## Conditions with an Abnormal, Exaggerated Startle Complex Genetic Neurodevelopmental Disorders with an Excessive Startle Response Severe ID Epilepsy (often intractable focal seizures or febrile seizures) Dysmorphic features Profound DD & progressive encephalopathy Microcephaly Hypotonia followed by spastic quadriplegia Seizures Epileptic encephalopathy w/myoclonic epilepsy Myoclonic seizures provoked by tactile stimuli & spontaneous & reflex seizures to noise & touch Congenital or infantile cataracts Neutropenia Other neurologic signs: hypotonia, spasticity, ataxia, dystonia, epilepsy, or ID Dysmorphic features, camptodactyly Facial & bulbar weakness Hyperekplexia is rare in this entity (single case report) Later onset of hyperekplexia (not congenital but in childhood) & atypical pattern (no generalized stiffness induced by startle) No congenital stiffness Progressive neurologic involvement w/additional signs (ID, ataxia, spasticity) Microcephaly Intractable seizures Severe psychomotor retardation Hypotonia combined w/hyperreflexia Usually lethal in infancy DD or regression Visual impairment Epilepsy Later: macrocephaly, decerebrate posturing, dysphagia, progression to unresponsive vegetative state ID Facial dysmorphism, tapering digits, & skeletal deformity Besides hyperekplexia, there may be other types of stimulus-induced drop attacks (e.g., cataplexy-like episodes) Hypotonia > hypertonicity Arthrogryposis Respiratory failure Dysmorphic features Encephalopathy Progressive epileptic encephalopathy Other neurologic features: opisthotonus, spastic quadriplegia, pyramidal signs Microcephaly, dysmorphic features Hypotonia Progressive epileptic encephalopathy Generalized clonus ("jitteriness") Delayed developmental (motor & cognitive) milestones Other neurologic signs: spasticity, chorea, visual impairment, epilepsy AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked OMIM phenotype entry or citation is provided if a related • Severe ID • Epilepsy (often intractable focal seizures or febrile seizures) • Dysmorphic features • Profound DD & progressive encephalopathy • Microcephaly • Hypotonia followed by spastic quadriplegia • Seizures • Epileptic encephalopathy w/myoclonic epilepsy • Myoclonic seizures provoked by tactile stimuli & spontaneous & reflex seizures to noise & touch • Congenital or infantile cataracts • Neutropenia • Other neurologic signs: hypotonia, spasticity, ataxia, dystonia, epilepsy, or ID • Dysmorphic features, camptodactyly • Facial & bulbar weakness • Hyperekplexia is rare in this entity (single case report) • Later onset of hyperekplexia (not congenital but in childhood) & atypical pattern (no generalized stiffness induced by startle) • No congenital stiffness • Progressive neurologic involvement w/additional signs (ID, ataxia, spasticity) • Microcephaly • Intractable seizures • Severe psychomotor retardation • Hypotonia combined w/hyperreflexia • Usually lethal in infancy • DD or regression • Visual impairment • Epilepsy • Later: macrocephaly, decerebrate posturing, dysphagia, progression to unresponsive vegetative state • ID • Facial dysmorphism, tapering digits, & skeletal deformity • Besides hyperekplexia, there may be other types of stimulus-induced drop attacks (e.g., cataplexy-like episodes) • Hypotonia > hypertonicity • Arthrogryposis • Respiratory failure • Dysmorphic features • Encephalopathy • Progressive epileptic encephalopathy • Other neurologic features: opisthotonus, spastic quadriplegia, pyramidal signs • Microcephaly, dysmorphic features • Hypotonia • Progressive epileptic encephalopathy • Generalized clonus ("jitteriness") • Delayed developmental (motor & cognitive) milestones • Other neurologic signs: spasticity, chorea, visual impairment, epilepsy ## Startle-Induced Manifestations in Other Disorders In this diverse group of disorders, the startle reflex itself is not excessive, but rather induces another clinical feature that is more prominent and characteristic than the startle response [ Startle epilepsy (normal startle triggers seizures) Paroxysmal kinesigenic choreoathetosis (See Creutzfeldt-Jakob disease (See Subacute sclerosing panencephalitis • Startle epilepsy (normal startle triggers seizures) • Paroxysmal kinesigenic choreoathetosis (See • Creutzfeldt-Jakob disease (See • Subacute sclerosing panencephalitis ## Neuropsychiatric Startle Syndromes In addition to excessive startling, behavioral and/or psychiatric findings are observed in the following groups of disorders: Culture-specific syndromes, in which an exaggerated startle response, evoked by auditory, sensory, or visual stimuli occurs within a community [ Anxiety disorders, functional neurologic disorders Tics and Gilles de la Tourette syndrome, in which an exaggerated startle reflex has been described in some, but not all, affected individuals • Culture-specific syndromes, in which an exaggerated startle response, evoked by auditory, sensory, or visual stimuli occurs within a community [ • Anxiety disorders, functional neurologic disorders • Tics and Gilles de la Tourette syndrome, in which an exaggerated startle reflex has been described in some, but not all, affected individuals ## Hereditary Hyperekplexia: Causes To date, three genes are known to be associated with hereditary hyperekplexia (HPX): AD = autosomal dominant; AR = autosomal recessive; HPX = hereditary hyperekplexia; MOI = mode of inheritance ~85% were AR and ~15% were AD [ Since the study of Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small 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 Deletion of exons 1 through 7 is common in the Turkish population [ The following were observed in the study of Individuals with Children with Individuals without a molecularly confirmed diagnosis of HPX compared to those with a molecular diagnosis were more likely to have first clinical manifestations after age one month (P<0.001). In contrast, the characteristic "stiffness, startles, and stumbles" of hyperekplexia, apnea attacks (50 of 89), and delayed development (47 of 92) were frequently reported in both groups. Individuals with a molecularly confirmed diagnosis of HPX typically are not dysmorphic and brain imaging reveals a structurally normal brain. • Individuals with • Children with • Individuals without a molecularly confirmed diagnosis of HPX compared to those with a molecular diagnosis were more likely to have first clinical manifestations after age one month (P<0.001). In contrast, the characteristic "stiffness, startles, and stumbles" of hyperekplexia, apnea attacks (50 of 89), and delayed development (47 of 92) were frequently reported in both groups. • Individuals with a molecularly confirmed diagnosis of HPX typically are not dysmorphic and brain imaging reveals a structurally normal brain. ## Phenotype Correlations by Gene The following were observed in the study of Individuals with Children with Individuals without a molecularly confirmed diagnosis of HPX compared to those with a molecular diagnosis were more likely to have first clinical manifestations after age one month (P<0.001). In contrast, the characteristic "stiffness, startles, and stumbles" of hyperekplexia, apnea attacks (50 of 89), and delayed development (47 of 92) were frequently reported in both groups. Individuals with a molecularly confirmed diagnosis of HPX typically are not dysmorphic and brain imaging reveals a structurally normal brain. • Individuals with • Children with • Individuals without a molecularly confirmed diagnosis of HPX compared to those with a molecular diagnosis were more likely to have first clinical manifestations after age one month (P<0.001). In contrast, the characteristic "stiffness, startles, and stumbles" of hyperekplexia, apnea attacks (50 of 89), and delayed development (47 of 92) were frequently reported in both groups. • Individuals with a molecularly confirmed diagnosis of HPX typically are not dysmorphic and brain imaging reveals a structurally normal brain. ## Hereditary Hyperekplexia: Evaluation Strategy to Identify the Genetic Cause in a Proband Establishing a specific genetic cause of HPX can aid genetic counseling (see 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 ## Hereditary Hyperekplexia: Management Clonazepam is the treatment of choice for HPX [ Other drugs, mostly described in case reports, which have shown variable results include: carbamazepine, clobazam, phenytoin, diazepam, valproate, 5-hydroxytryptophan, piracetam, and phenobarbital. For an overview see Physical and cognitive therapy to reduce the fear of falling and thereby improve walking can be considered; no randomized trials have assessed the effectiveness of such treatment. Attacks of tonic neonatal cyanosis can be stopped by the Vigevano maneuver, consisting of forced flexion of the head and legs towards the trunk [ ## Treatment of Manifestations Clonazepam is the treatment of choice for HPX [ Other drugs, mostly described in case reports, which have shown variable results include: carbamazepine, clobazam, phenytoin, diazepam, valproate, 5-hydroxytryptophan, piracetam, and phenobarbital. For an overview see Physical and cognitive therapy to reduce the fear of falling and thereby improve walking can be considered; no randomized trials have assessed the effectiveness of such treatment. Attacks of tonic neonatal cyanosis can be stopped by the Vigevano maneuver, consisting of forced flexion of the head and legs towards the trunk [ ## Hereditary Hyperekplexia: Genetic Counseling The parents of a child with autosomal recessive HPX 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 autosomal recessive HPX-causing pathogenic variant and to allow reliable recurrence risk assessment. ( Heterozygotes (carriers) are asymptomatic and are not at risk of developing hyperekplexia. If both parents are known to be heterozygous for an autosomal recessive HPX-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Most individuals diagnosed with autosomal dominant HPX have an affected parent. In rare cases, an individual diagnosed with autosomal dominant HPX has 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 leukocyte DNA of either parent, the proband most likely has 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 having the same pathogenic variant is 50%. However, because autosomal dominant hereditary hyperekplexia is not 100% penetrant, sibs who inherit a pathogenic variant may or may not manifest features of HPX [ If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [ If the parents have not been tested for the 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 increased risk for hereditary hyperekplexia because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism. Once the HPX-causing pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The parents of a child with autosomal recessive HPX 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 autosomal recessive HPX-causing pathogenic variant and to allow reliable recurrence risk assessment. ( • Heterozygotes (carriers) are asymptomatic and are not at risk of developing hyperekplexia. • If both parents are known to be heterozygous for an autosomal recessive HPX-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • Most individuals diagnosed with autosomal dominant HPX have an affected parent. • In rare cases, an individual diagnosed with autosomal dominant HPX has 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 leukocyte DNA of either parent, the proband most likely has 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 having the same pathogenic variant is 50%. However, because autosomal dominant hereditary hyperekplexia is not 100% penetrant, sibs who inherit a pathogenic variant may or may not manifest features of HPX [ • If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [ • If the parents have not been tested for the 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 increased risk for hereditary hyperekplexia because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism. ## Mode of Inheritance ## Autosomal Recessive Inheritance – Risk to Family Members The parents of a child with autosomal recessive HPX 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 autosomal recessive HPX-causing pathogenic variant and to allow reliable recurrence risk assessment. ( Heterozygotes (carriers) are asymptomatic and are not at risk of developing hyperekplexia. If both parents are known to be heterozygous for an autosomal recessive HPX-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The parents of a child with autosomal recessive HPX 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 autosomal recessive HPX-causing pathogenic variant and to allow reliable recurrence risk assessment. ( • Heterozygotes (carriers) are asymptomatic and are not at risk of developing hyperekplexia. • If both parents are known to be heterozygous for an autosomal recessive HPX-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Autosomal Dominant Inheritance – Risk to Family Members Most individuals diagnosed with autosomal dominant HPX have an affected parent. In rare cases, an individual diagnosed with autosomal dominant HPX has 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 leukocyte DNA of either parent, the proband most likely has 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 having the same pathogenic variant is 50%. However, because autosomal dominant hereditary hyperekplexia is not 100% penetrant, sibs who inherit a pathogenic variant may or may not manifest features of HPX [ If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [ If the parents have not been tested for the 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 increased risk for hereditary hyperekplexia because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism. • Most individuals diagnosed with autosomal dominant HPX have an affected parent. • In rare cases, an individual diagnosed with autosomal dominant HPX has 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 leukocyte DNA of either parent, the proband most likely has 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 having the same pathogenic variant is 50%. However, because autosomal dominant hereditary hyperekplexia is not 100% penetrant, sibs who inherit a pathogenic variant may or may not manifest features of HPX [ • If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [ • If the parents have not been tested for the 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 increased risk for hereditary hyperekplexia because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism. ## Prenatal Testing and Preimplantation Genetic Testing Once the HPX-causing pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • ## Chapter Notes Bettina Balint, MD (2019-present)Mark I Rees, PhD; Swansea University (2007-2019)Rhys Thomas, PhD, FRCP (2019-present)Marina AJ Tijssen, MD; University Medical Center Groningen (2007-2019) 19 December 2019 (bp) Comprehensive update posted live; scope changed to overview 4 October 2012 (me) Comprehensive update posted live 31 July 2007 (me) Review posted live 6 July 2006 (sgr) Original submission • 19 December 2019 (bp) Comprehensive update posted live; scope changed to overview • 4 October 2012 (me) Comprehensive update posted live • 31 July 2007 (me) Review posted live • 6 July 2006 (sgr) Original submission ## Author History Bettina Balint, MD (2019-present)Mark I Rees, PhD; Swansea University (2007-2019)Rhys Thomas, PhD, FRCP (2019-present)Marina AJ Tijssen, MD; University Medical Center Groningen (2007-2019) ## Revision History 19 December 2019 (bp) Comprehensive update posted live; scope changed to overview 4 October 2012 (me) Comprehensive update posted live 31 July 2007 (me) Review posted live 6 July 2006 (sgr) Original submission • 19 December 2019 (bp) Comprehensive update posted live; scope changed to overview • 4 October 2012 (me) Comprehensive update posted live • 31 July 2007 (me) Review posted live • 6 July 2006 (sgr) Original submission ## References ## Literature Cited	[]	31/7/2007	19/12/2019	19/5/2009	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
hypo-mcc	hypo-mcc	[ "Hyccin", "HYCC1", "Hypomyelination and Congenital Cataract" ]	Hypomyelination and Congenital Cataract	Nicole I Wolf, Roberta Biancheri, Federico Zara, Claudio Bruno, Elisabetta Gazzerro, Andrea Rossi, Marjo S van der Knaap, Carlo Minetti	Summary Hypomyelination and congenital cataract (HCC) is usually characterized by bilateral congenital cataracts and normal psychomotor or only mildly delayed development in the first year of life, followed by slowly progressive neurologic impairment manifest as ataxia, spasticity (brisk tendon reflexes and bilateral extensor plantar responses), and mild-to-moderate cognitive impairment. Dysarthria and truncal hypotonia are observed. Cerebellar signs (truncal titubation and intention tremor) and peripheral neuropathy (muscle weakness and wasting of the legs) are present in the majority of affected individuals. Seizures can occur. Cataracts may be absent in some individuals. The diagnosis of HCC can be established in individuals with typical clinical findings, characteristic abnormalities on brain MRI, and biallelic pathogenic variants in HCC is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a	## Diagnosis Hypomyelination and congenital cataract (HCC) Bilateral congenital cataracts. One individual had juvenile cataract [ Nystagmus present from the first few weeks of life Classic presentation shows normal or mildly delayed psychomotor development in the first year of life, followed by slowly progressive neurologic impairment manifest as: Ataxia Spasticity Loss of the ability to walk Mild-to-moderate cognitive impairment Uncommon presentations [ Early-onset severe variant. Hypotonia and feeding difficulties in the neonatal period, developmental delay in the first months of life, and wheelchair dependency in early childhood Late-onset mild variant. Normal development in the first two years of life with subsequent sudden motor regression Diffusely abnormal supratentorial white matter in all individuals Abnormal white matter signal behavior consistent with hypomyelination: Hyperintense on T Isointense to slightly hypointense on T Areas of higher T White matter bulk loss in older individuals ( Medullary centers of the cerebellar hemispheres showing mildly increased T Sparing of the cortical and deep gray matter structures The diagnosis of HCC Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular testing approaches can include 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 cataracts and/or leukodystrophy, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Hypomyelination and Congenital Cataract See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Missense and splice-site variants in all probands were identified by sequence analysis of the entire coding region and the exon-intron 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. One such analysis involving • Bilateral congenital cataracts. One individual had juvenile cataract [ • Nystagmus present from the first few weeks of life • Classic presentation shows normal or mildly delayed psychomotor development in the first year of life, followed by slowly progressive neurologic impairment manifest as: • Ataxia • Spasticity • Loss of the ability to walk • Mild-to-moderate cognitive impairment • Ataxia • Spasticity • Loss of the ability to walk • Mild-to-moderate cognitive impairment • Uncommon presentations [ • Early-onset severe variant. Hypotonia and feeding difficulties in the neonatal period, developmental delay in the first months of life, and wheelchair dependency in early childhood • Late-onset mild variant. Normal development in the first two years of life with subsequent sudden motor regression • Early-onset severe variant. Hypotonia and feeding difficulties in the neonatal period, developmental delay in the first months of life, and wheelchair dependency in early childhood • Late-onset mild variant. Normal development in the first two years of life with subsequent sudden motor regression • Ataxia • Spasticity • Loss of the ability to walk • Mild-to-moderate cognitive impairment • Early-onset severe variant. Hypotonia and feeding difficulties in the neonatal period, developmental delay in the first months of life, and wheelchair dependency in early childhood • Late-onset mild variant. Normal development in the first two years of life with subsequent sudden motor regression • Diffusely abnormal supratentorial white matter in all individuals • Abnormal white matter signal behavior consistent with hypomyelination: • Hyperintense on T • Isointense to slightly hypointense on T • Hyperintense on T • Isointense to slightly hypointense on T • Areas of higher T • White matter bulk loss in older individuals ( • Medullary centers of the cerebellar hemispheres showing mildly increased T • Sparing of the cortical and deep gray matter structures • Hyperintense on T • Isointense to slightly hypointense on T ## Suggestive Findings Hypomyelination and congenital cataract (HCC) Bilateral congenital cataracts. One individual had juvenile cataract [ Nystagmus present from the first few weeks of life Classic presentation shows normal or mildly delayed psychomotor development in the first year of life, followed by slowly progressive neurologic impairment manifest as: Ataxia Spasticity Loss of the ability to walk Mild-to-moderate cognitive impairment Uncommon presentations [ Early-onset severe variant. Hypotonia and feeding difficulties in the neonatal period, developmental delay in the first months of life, and wheelchair dependency in early childhood Late-onset mild variant. Normal development in the first two years of life with subsequent sudden motor regression Diffusely abnormal supratentorial white matter in all individuals Abnormal white matter signal behavior consistent with hypomyelination: Hyperintense on T Isointense to slightly hypointense on T Areas of higher T White matter bulk loss in older individuals ( Medullary centers of the cerebellar hemispheres showing mildly increased T Sparing of the cortical and deep gray matter structures • Bilateral congenital cataracts. One individual had juvenile cataract [ • Nystagmus present from the first few weeks of life • Classic presentation shows normal or mildly delayed psychomotor development in the first year of life, followed by slowly progressive neurologic impairment manifest as: • Ataxia • Spasticity • Loss of the ability to walk • Mild-to-moderate cognitive impairment • Ataxia • Spasticity • Loss of the ability to walk • Mild-to-moderate cognitive impairment • Uncommon presentations [ • Early-onset severe variant. Hypotonia and feeding difficulties in the neonatal period, developmental delay in the first months of life, and wheelchair dependency in early childhood • Late-onset mild variant. Normal development in the first two years of life with subsequent sudden motor regression • Early-onset severe variant. Hypotonia and feeding difficulties in the neonatal period, developmental delay in the first months of life, and wheelchair dependency in early childhood • Late-onset mild variant. Normal development in the first two years of life with subsequent sudden motor regression • Ataxia • Spasticity • Loss of the ability to walk • Mild-to-moderate cognitive impairment • Early-onset severe variant. Hypotonia and feeding difficulties in the neonatal period, developmental delay in the first months of life, and wheelchair dependency in early childhood • Late-onset mild variant. Normal development in the first two years of life with subsequent sudden motor regression • Diffusely abnormal supratentorial white matter in all individuals • Abnormal white matter signal behavior consistent with hypomyelination: • Hyperintense on T • Isointense to slightly hypointense on T • Hyperintense on T • Isointense to slightly hypointense on T • Areas of higher T • White matter bulk loss in older individuals ( • Medullary centers of the cerebellar hemispheres showing mildly increased T • Sparing of the cortical and deep gray matter structures • Hyperintense on T • Isointense to slightly hypointense on T ## Establishing the Diagnosis The diagnosis of HCC Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular testing approaches can include 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 cataracts and/or leukodystrophy, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Hypomyelination and Congenital Cataract See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Missense and splice-site variants in all probands were identified by sequence analysis of the entire coding region and the exon-intron 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. One such analysis involving ## Option 1 For an introduction to multigene panels click ## Option 2 When the phenotype is indistinguishable from many other inherited disorders characterized by cataracts and/or leukodystrophy, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Hypomyelination and Congenital Cataract See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Missense and splice-site variants in all probands were identified by sequence analysis of the entire coding region and the exon-intron 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. One such analysis involving ## Clinical Characteristics Hypomyelination and congenital cataract (HCC) phenotype is quite consistent in the affected individuals described to date. Hypomyelination and Congenital Cataract: Frequency of Select Features Feeding issues occur as a result of neurologic impairment. Swallowing may become difficult, and growth may be affected by suboptimal intake. Dysarthria Truncal hypotonia Pyramidal signs and spasticity. Tendon reflexes may be decreased or lost as a result of peripheral neuropathy. Cerebellar signs/ataxia (including truncal titubation and intention tremor) Peripheral neuropathy, present in most individuals, manifest as muscle weakness, wasting of the legs and ataxia. Peripheral neuropathy is absent in individuals with a milder form of the disorder (see Seizures including those triggered by fever may occur, but are not a predominant clinical feature. Sural nerve biopsy of individuals with peripheral neuropathy shows a slight-to-severe reduction in density of myelinated fibers, with several axons surrounded by a thin myelin sheath or devoid of myelin. Uncompaction of the myelin sheath, which in some fibers appears redundant and irregularly folded, is occasionally seen. Electron microscopy confirms the presence of axons devoid of myelin, together with thinly myelinated fibers, sometimes surrounded by few Schwann cells processes, forming small onion bulbs. Pathogenic variants leading to the complete absence of Pathogenic variants leading to a partial protein deficiency are associated with the milder form without peripheral nervous system involvement. An individual with deletion of exons 8 and 9 did not have congenital cataracts; cataracts developed at age nine years. A second individual had congenital unilateral cataract. However, of the four children in this family who survived beyond age two years, none was able to walk even with support after age six years [ Because of the limited number of individuals with HCC described so far, these correlations should be further confirmed. Penetrance is complete. HCC is likely a rare disorder. No epidemiologic studies are available. • Dysarthria • Truncal hypotonia • Pyramidal signs and spasticity. Tendon reflexes may be decreased or lost as a result of peripheral neuropathy. • Cerebellar signs/ataxia (including truncal titubation and intention tremor) • Peripheral neuropathy, present in most individuals, manifest as muscle weakness, wasting of the legs and ataxia. Peripheral neuropathy is absent in individuals with a milder form of the disorder (see • Sural nerve biopsy of individuals with peripheral neuropathy shows a slight-to-severe reduction in density of myelinated fibers, with several axons surrounded by a thin myelin sheath or devoid of myelin. • Uncompaction of the myelin sheath, which in some fibers appears redundant and irregularly folded, is occasionally seen. • Electron microscopy confirms the presence of axons devoid of myelin, together with thinly myelinated fibers, sometimes surrounded by few Schwann cells processes, forming small onion bulbs. ## Clinical Description Hypomyelination and congenital cataract (HCC) phenotype is quite consistent in the affected individuals described to date. Hypomyelination and Congenital Cataract: Frequency of Select Features Feeding issues occur as a result of neurologic impairment. Swallowing may become difficult, and growth may be affected by suboptimal intake. Dysarthria Truncal hypotonia Pyramidal signs and spasticity. Tendon reflexes may be decreased or lost as a result of peripheral neuropathy. Cerebellar signs/ataxia (including truncal titubation and intention tremor) Peripheral neuropathy, present in most individuals, manifest as muscle weakness, wasting of the legs and ataxia. Peripheral neuropathy is absent in individuals with a milder form of the disorder (see Seizures including those triggered by fever may occur, but are not a predominant clinical feature. Sural nerve biopsy of individuals with peripheral neuropathy shows a slight-to-severe reduction in density of myelinated fibers, with several axons surrounded by a thin myelin sheath or devoid of myelin. Uncompaction of the myelin sheath, which in some fibers appears redundant and irregularly folded, is occasionally seen. Electron microscopy confirms the presence of axons devoid of myelin, together with thinly myelinated fibers, sometimes surrounded by few Schwann cells processes, forming small onion bulbs. • Dysarthria • Truncal hypotonia • Pyramidal signs and spasticity. Tendon reflexes may be decreased or lost as a result of peripheral neuropathy. • Cerebellar signs/ataxia (including truncal titubation and intention tremor) • Peripheral neuropathy, present in most individuals, manifest as muscle weakness, wasting of the legs and ataxia. Peripheral neuropathy is absent in individuals with a milder form of the disorder (see • Sural nerve biopsy of individuals with peripheral neuropathy shows a slight-to-severe reduction in density of myelinated fibers, with several axons surrounded by a thin myelin sheath or devoid of myelin. • Uncompaction of the myelin sheath, which in some fibers appears redundant and irregularly folded, is occasionally seen. • Electron microscopy confirms the presence of axons devoid of myelin, together with thinly myelinated fibers, sometimes surrounded by few Schwann cells processes, forming small onion bulbs. ## Genotype-Phenotype Correlations Pathogenic variants leading to the complete absence of Pathogenic variants leading to a partial protein deficiency are associated with the milder form without peripheral nervous system involvement. An individual with deletion of exons 8 and 9 did not have congenital cataracts; cataracts developed at age nine years. A second individual had congenital unilateral cataract. However, of the four children in this family who survived beyond age two years, none was able to walk even with support after age six years [ Because of the limited number of individuals with HCC described so far, these correlations should be further confirmed. ## Penetrance Penetrance is complete. ## Prevalence HCC is likely a rare disorder. No epidemiologic studies are available. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The association of congenital cataract and CNS hypomyelination is typical of hypomyelination and congenital cataract (HCC). However, the differential diagnosis with other hypomyelinating disorders should include the disorders summarized in Hypomyelinating Disorders of Interest in the Differential Diagnosis of Hypomyelination and Congenital Cataract AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; HCC = hypomyelination and congenital cataract; MOI = mode of inheritance; XL = X-linked ## Management To establish the extent of disease and needs in an individual diagnosed with hypomyelination and congenital cataract (HCC), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Hypomyelination and Congenital Cataract Incl motor, adaptive, cognitive, & speech-language eval for dysarthria Eval for early intervention / special education Gross motor & fine motor skills Contractures, clubfoot, & kyphoscoliosis Mobility, activities of daily living, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) To incl eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk. Community or Social work involvement for parental support; 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 Hypomyelination and Congenital Cataract Adjuvant therapies incl PT, OT, & speech therapy for persons w/identified DDs Individualized education plans for learning disorders & school performance issues Pharmacologic agents (e.g., baclofen, incl intrathecal baclofen) Orthopedics / physical medicine & rehab / PT/OT incl stretching to help avoid contractures & falls Many ASMs may be effective; none has been demonstrated effective specifically for HCC. Education of parents/caregivers ASM = anti-seizure medication; DD = developmental delay; HCC = hypomyelination and congenital cataract; ID = intellectual disability; OT = occupational therapy; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Recommended Surveillance for Individuals with Hypomyelination and Congenital Cataract Measurement of growth parameters Eval of nutritional status & safety of oral intake OT = occupational therapy; PT = physical therapy None are known. Some individuals are prone to febrile seizures. See Search • Incl motor, adaptive, cognitive, & speech-language eval for dysarthria • Eval for early intervention / special education • Gross motor & fine motor skills • Contractures, clubfoot, & kyphoscoliosis • Mobility, activities of daily living, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • To incl eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk. • Community or • Social work involvement for parental support; • Home nursing referral. • Adjuvant therapies incl PT, OT, & speech therapy for persons w/identified DDs • Individualized education plans for learning disorders & school performance issues • Pharmacologic agents (e.g., baclofen, incl intrathecal baclofen) • Orthopedics / physical medicine & rehab / PT/OT incl stretching to help avoid contractures & falls • Many ASMs may be effective; none has been demonstrated effective specifically for HCC. • Education of parents/caregivers • 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 hypomyelination and congenital cataract (HCC), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Hypomyelination and Congenital Cataract Incl motor, adaptive, cognitive, & speech-language eval for dysarthria Eval for early intervention / special education Gross motor & fine motor skills Contractures, clubfoot, & kyphoscoliosis Mobility, activities of daily living, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) To incl eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk. Community or Social work involvement for parental support; Home nursing referral. MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Incl motor, adaptive, cognitive, & speech-language eval for dysarthria • Eval for early intervention / special education • Gross motor & fine motor skills • Contractures, clubfoot, & kyphoscoliosis • Mobility, activities of daily living, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • To incl eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk. • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Treatment of Manifestations in Individuals with Hypomyelination and Congenital Cataract Adjuvant therapies incl PT, OT, & speech therapy for persons w/identified DDs Individualized education plans for learning disorders & school performance issues Pharmacologic agents (e.g., baclofen, incl intrathecal baclofen) Orthopedics / physical medicine & rehab / PT/OT incl stretching to help avoid contractures & falls Many ASMs may be effective; none has been demonstrated effective specifically for HCC. Education of parents/caregivers ASM = anti-seizure medication; DD = developmental delay; HCC = hypomyelination and congenital cataract; ID = intellectual disability; OT = occupational therapy; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see • Adjuvant therapies incl PT, OT, & speech therapy for persons w/identified DDs • Individualized education plans for learning disorders & school performance issues • Pharmacologic agents (e.g., baclofen, incl intrathecal baclofen) • Orthopedics / physical medicine & rehab / PT/OT incl stretching to help avoid contractures & falls • Many ASMs may be effective; none has been demonstrated effective specifically for HCC. • Education of parents/caregivers ## Surveillance Recommended Surveillance for Individuals with Hypomyelination and Congenital Cataract 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 None are known. Some individuals are prone to febrile seizures. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Hypomyelination and congenital cataract (HCC) is inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a 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 obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • If both parents are known to be heterozygous for a • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is 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 Hypomyelination and congenital cataract (HCC) is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • If both parents are known to be heterozygous for a • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is 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 Hypomyelination and Congenital Cataract: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Hypomyelination and Congenital Cataract ( Splicing variants (c.414+1G>T and c.51+1G>A) lead to the premature truncation of protein. Missense variant c.158T>C does not alter mRNA expression but leads to severe protein deficit through unknown cellular pathways. The genomic deletion 531-439_743+348del is expected to result in a 308-amino acid deletion. The effect of the latter variant was not investigated by immunoblot analysis. Notable Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions ## Molecular Pathogenesis Splicing variants (c.414+1G>T and c.51+1G>A) lead to the premature truncation of protein. Missense variant c.158T>C does not alter mRNA expression but leads to severe protein deficit through unknown cellular pathways. The genomic deletion 531-439_743+348del is expected to result in a 308-amino acid deletion. The effect of the latter variant was not investigated by immunoblot analysis. Notable Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions ## Chapter Notes We thank the 14 January 2021 (sw) Comprehensive update posted live 4 June 2015 (me) Comprehensive update posted live 27 October 2011 (cd) Revision: mutation scanning and deletion/duplication analysis no longer available clinically; sequence analysis now available clinically 27 January 2011 (cd) Revision: prenatal testing available clinically 16 November 2010 (me) Comprehensive update posted live 14 October 2008 (me) Review posted live 14 May 2008 (rb) Original submission • 14 January 2021 (sw) Comprehensive update posted live • 4 June 2015 (me) Comprehensive update posted live • 27 October 2011 (cd) Revision: mutation scanning and deletion/duplication analysis no longer available clinically; sequence analysis now available clinically • 27 January 2011 (cd) Revision: prenatal testing available clinically • 16 November 2010 (me) Comprehensive update posted live • 14 October 2008 (me) Review posted live • 14 May 2008 (rb) Original submission ## Acknowledgments We thank the ## Revision History 14 January 2021 (sw) Comprehensive update posted live 4 June 2015 (me) Comprehensive update posted live 27 October 2011 (cd) Revision: mutation scanning and deletion/duplication analysis no longer available clinically; sequence analysis now available clinically 27 January 2011 (cd) Revision: prenatal testing available clinically 16 November 2010 (me) Comprehensive update posted live 14 October 2008 (me) Review posted live 14 May 2008 (rb) Original submission • 14 January 2021 (sw) Comprehensive update posted live • 4 June 2015 (me) Comprehensive update posted live • 27 October 2011 (cd) Revision: mutation scanning and deletion/duplication analysis no longer available clinically; sequence analysis now available clinically • 27 January 2011 (cd) Revision: prenatal testing available clinically • 16 November 2010 (me) Comprehensive update posted live • 14 October 2008 (me) Review posted live • 14 May 2008 (rb) Original submission ## References ## Literature Cited Axial T Axial T Axial T Axial T Coronal T	[]	14/10/2008	14/1/2021	27/10/2011	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
hypochondroplasia	hypochondroplasia	[ "Fibroblast growth factor receptor 3", "FGFR3", "Hypochondroplasia" ]	Hypochondroplasia	Michael B Bober, Gary A Bellus, Sarah M Nikkel, George E Tiller	Summary Hypochondroplasia is a skeletal dysplasia characterized by short stature; stocky build; disproportionately short arms and legs; broad, short hands and feet; mild joint laxity; and macrocephaly. Radiologic features include shortening of long bones with mild metaphyseal flare; narrowing of the inferior lumbar interpedicular distances; short, broad femoral neck; and squared, shortened ilia. The skeletal features are very similar to those seen in achondroplasia but tend to be milder. Medical complications common to achondroplasia (e.g., spinal stenosis, tibial bowing, obstructive apnea) occur less frequently in hypochondroplasia but intellectual disability and epilepsy may be more prevalent. Children usually present as toddlers or at early school age with decreased growth velocity leading to short stature and limb disproportion. Other features also become more prominent over time. The diagnosis of hypochondroplasia is established in a proband with characteristic clinical and radiographic features. Identification of a heterozygous Hypochondroplasia is inherited in an autosomal dominant manner. The majority of individuals with hypochondroplasia have parents of average stature and have hypochondroplasia as the result of a	## Diagnosis The clinical and radiologic diagnostic criteria for hypochondroplasia remain controversial for several reasons, including the following: No single radiologic or clinical feature is unique to hypochondroplasia. The expression of many of the established diagnostic features in affected individuals is variable. Locus heterogeneity has been established. Genetic heterogeneity and lack of agreement on a definitive set of diagnostic criteria have made it difficult to compare data from the many studies reported in the literature [ Hypochondroplasia Short stature (adult height 128-165 cm; 2-3 SD below the mean in children) Stocky build Shortening of the proximal or middle segments of the extremities (respectively, rhizomelia or mesomelia) Limitation of elbow extension Broad, short hands and feet with brachydactyly Generalized, mild joint laxity Macrocephaly with relatively normal facies Less common but significant clinical features: Scoliosis Bowed legs (genu varum) (usually mild) Lumbar lordosis with protruding abdomen Mild-to-moderate intellectual disability Learning disabilities Adult-onset osteoarthritis Acanthosis nigricans Temporal lobe epilepsy Shortening of long bones with mild metaphyseal flare (especially femora and tibiae) Narrowing of the inferior lumbar interpedicular distances (or failure to widen) Mild-to-moderate brachydactyly Short, broad femoral neck Squared, shortened ilia Less common but significant radiologic features: Elongation of the distal fibula Shortening (anterior-posterior) of the lumbar pedicles Dorsal concavity of the lumbar vertebral bodies Shortening of the distal ulna Long ulnar styloid (seen only in adults) Prominence of muscle insertions on long bones Shallow "chevron" deformity of distal femur metaphysis Low articulation of sacrum on pelvis with a horizontal orientation Flattened acetabular roof The diagnosis of hypochondroplasia Note: A consensus opinion of which or how many of these features must be present to confirm a clinical diagnosis does not currently exist. Radiographic features vary significantly among affected individuals. Many of these features are not present in affected infants but develop later in life. The mild end of the hypochondroplasia phenotypic spectrum may overlap with idiopathic or familial short stature, making it difficult to establish a definitive clinical diagnosis in these individuals. 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 hypochondroplasia is broad, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of hypochondroplasia, molecular genetic testing approaches can include Targeted analysis for pathogenic variants Sequence analysis of For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by skeletal dysplasia, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Hypochondroplasia See See The two most common pathogenic variants [ Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and 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 deletions or duplications involving Using diagnostic criteria based solely on the radiographic finding of decreased interpediculate distance between L1 and L5, • No single radiologic or clinical feature is unique to hypochondroplasia. • The expression of many of the established diagnostic features in affected individuals is variable. • Locus heterogeneity has been established. • Short stature (adult height 128-165 cm; 2-3 SD below the mean in children) • Stocky build • Shortening of the proximal or middle segments of the extremities (respectively, rhizomelia or mesomelia) • Limitation of elbow extension • Broad, short hands and feet with brachydactyly • Generalized, mild joint laxity • Macrocephaly with relatively normal facies • Scoliosis • Bowed legs (genu varum) (usually mild) • Lumbar lordosis with protruding abdomen • Mild-to-moderate intellectual disability • Learning disabilities • Adult-onset osteoarthritis • Acanthosis nigricans • Temporal lobe epilepsy • Shortening of long bones with mild metaphyseal flare (especially femora and tibiae) • Narrowing of the inferior lumbar interpedicular distances (or failure to widen) • Mild-to-moderate brachydactyly • Short, broad femoral neck • Squared, shortened ilia • Elongation of the distal fibula • Shortening (anterior-posterior) of the lumbar pedicles • Dorsal concavity of the lumbar vertebral bodies • Shortening of the distal ulna • Long ulnar styloid (seen only in adults) • Prominence of muscle insertions on long bones • Shallow "chevron" deformity of distal femur metaphysis • Low articulation of sacrum on pelvis with a horizontal orientation • Flattened acetabular roof • Targeted analysis for pathogenic variants • Sequence analysis of ## Suggestive Findings Hypochondroplasia Short stature (adult height 128-165 cm; 2-3 SD below the mean in children) Stocky build Shortening of the proximal or middle segments of the extremities (respectively, rhizomelia or mesomelia) Limitation of elbow extension Broad, short hands and feet with brachydactyly Generalized, mild joint laxity Macrocephaly with relatively normal facies Less common but significant clinical features: Scoliosis Bowed legs (genu varum) (usually mild) Lumbar lordosis with protruding abdomen Mild-to-moderate intellectual disability Learning disabilities Adult-onset osteoarthritis Acanthosis nigricans Temporal lobe epilepsy Shortening of long bones with mild metaphyseal flare (especially femora and tibiae) Narrowing of the inferior lumbar interpedicular distances (or failure to widen) Mild-to-moderate brachydactyly Short, broad femoral neck Squared, shortened ilia Less common but significant radiologic features: Elongation of the distal fibula Shortening (anterior-posterior) of the lumbar pedicles Dorsal concavity of the lumbar vertebral bodies Shortening of the distal ulna Long ulnar styloid (seen only in adults) Prominence of muscle insertions on long bones Shallow "chevron" deformity of distal femur metaphysis Low articulation of sacrum on pelvis with a horizontal orientation Flattened acetabular roof • Short stature (adult height 128-165 cm; 2-3 SD below the mean in children) • Stocky build • Shortening of the proximal or middle segments of the extremities (respectively, rhizomelia or mesomelia) • Limitation of elbow extension • Broad, short hands and feet with brachydactyly • Generalized, mild joint laxity • Macrocephaly with relatively normal facies • Scoliosis • Bowed legs (genu varum) (usually mild) • Lumbar lordosis with protruding abdomen • Mild-to-moderate intellectual disability • Learning disabilities • Adult-onset osteoarthritis • Acanthosis nigricans • Temporal lobe epilepsy • Shortening of long bones with mild metaphyseal flare (especially femora and tibiae) • Narrowing of the inferior lumbar interpedicular distances (or failure to widen) • Mild-to-moderate brachydactyly • Short, broad femoral neck • Squared, shortened ilia • Elongation of the distal fibula • Shortening (anterior-posterior) of the lumbar pedicles • Dorsal concavity of the lumbar vertebral bodies • Shortening of the distal ulna • Long ulnar styloid (seen only in adults) • Prominence of muscle insertions on long bones • Shallow "chevron" deformity of distal femur metaphysis • Low articulation of sacrum on pelvis with a horizontal orientation • Flattened acetabular roof ## Establishing the Diagnosis The diagnosis of hypochondroplasia Note: A consensus opinion of which or how many of these features must be present to confirm a clinical diagnosis does not currently exist. Radiographic features vary significantly among affected individuals. Many of these features are not present in affected infants but develop later in life. The mild end of the hypochondroplasia phenotypic spectrum may overlap with idiopathic or familial short stature, making it difficult to establish a definitive clinical diagnosis in these individuals. 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 hypochondroplasia is broad, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of hypochondroplasia, molecular genetic testing approaches can include Targeted analysis for pathogenic variants Sequence analysis of For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by skeletal dysplasia, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Hypochondroplasia See See The two most common pathogenic variants [ Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and 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 deletions or duplications involving Using diagnostic criteria based solely on the radiographic finding of decreased interpediculate distance between L1 and L5, • Targeted analysis for pathogenic variants • Sequence analysis of ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of hypochondroplasia, molecular genetic testing approaches can include Targeted analysis for pathogenic variants Sequence analysis of For an introduction to multigene panels click • Targeted analysis for pathogenic variants • Sequence analysis of ## Option 2 When the phenotype is indistinguishable from many other inherited disorders characterized by skeletal dysplasia, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Hypochondroplasia See See The two most common pathogenic variants [ Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and 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 deletions or duplications involving Using diagnostic criteria based solely on the radiographic finding of decreased interpediculate distance between L1 and L5, ## Clinical Characteristics Unlike achondroplasia, motor milestones are usually not significantly delayed and symptoms resulting from spinal cord compression (e.g., apnea, neuropathy) are less common [ Other than Individuals with Pathogenic variants resulting in Somatic mosaicism has not been reported in hypochondroplasia. Because of evidence that the height range in hypochondroplasia may overlap that of the unaffected population, individuals with hypochondroplasia may not be recognized as having a skeletal dysplasia unless an astute physician recognizes their disproportionate short stature. To date, however, all reported individuals with an No studies attempting to determine the prevalence of • Individuals with • Pathogenic variants resulting in ## Clinical Description Unlike achondroplasia, motor milestones are usually not significantly delayed and symptoms resulting from spinal cord compression (e.g., apnea, neuropathy) are less common [ ## Genotype-Phenotype Correlations Other than Individuals with Pathogenic variants resulting in Somatic mosaicism has not been reported in hypochondroplasia. • Individuals with • Pathogenic variants resulting in ## Penetrance Because of evidence that the height range in hypochondroplasia may overlap that of the unaffected population, individuals with hypochondroplasia may not be recognized as having a skeletal dysplasia unless an astute physician recognizes their disproportionate short stature. To date, however, all reported individuals with an ## Prevalence No studies attempting to determine the prevalence of ## Genetically Related (Allelic) Disorders Other phenotypes associated with germline pathogenic variants in Short-limb dwarfism syndrome that is usually lethal in the perinatal period TD type I characterized by micromelia w/bowed femurs TD type II characterized by micromelia w/straight femurs & uniform presence of moderate-to-severe cloverleaf skull deformity Most affected infants die of respiratory insufficiency shortly after birth; rare long-term survivors have been reported. Crouzon syndrome w/acanthosis nigricans Isolated coronal synostosis (incl • Short-limb dwarfism syndrome that is usually lethal in the perinatal period • TD type I characterized by micromelia w/bowed femurs • TD type II characterized by micromelia w/straight femurs & uniform presence of moderate-to-severe cloverleaf skull deformity • Most affected infants die of respiratory insufficiency shortly after birth; rare long-term survivors have been reported. • Crouzon syndrome w/acanthosis nigricans • Isolated coronal synostosis (incl ## Differential Diagnosis Numerous forms of skeletal dysplasia with disproportionate limbs are recognized and are characterized by clinical and radiologic features that distinguish them from hypochondroplasia and Conditions with a known genetic etiology that may be confused with hypochondroplasia are summarized in Genes of Interest in the Differential Diagnosis of Hypochondroplasia AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; SEMDJL1 = spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures See Disorders of Other conditions to consider in the differential diagnosis of hypochondroplasia: Short stature caused by disturbances in the growth hormone axis Constitutive short stature • Short stature caused by disturbances in the growth hormone axis • Constitutive short stature ## Management Management of children with hypochondroplasia usually does not differ significantly from that of children with normal stature except for genetic counseling issues and dealing with parental concerns about short stature. However, because the phenotype of To establish the extent of disease and needs in an individual diagnosed with hypochondroplasia, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Hypochondroplasia Assess for signs/symptoms of sleep apnea; refer for polysomnography if needed. Neurologic exam for signs of spinal cord compression (e.g., severe hypotonia, hyperreflexia, clonus, & asymmetries) MRI or CT of the foramen magnum if spinal cord compression suggested by findings on neurologic exam or central apnea identified on sleep study Referral to a pediatric neurologist or neurosurgeon if needed To incl motor, adaptive, cognitive, & speech/language eval Eval for early intervention / special education Treatment of Manifestations in Individuals with Hypochondroplasia Management is influenced by parental expectations & concerns. Address parents' expectations & prejudices re child's height rather than attempting to treat child. No one ASM has been demonstrated effective specifically for this disorder. Education of parents/caregivers Assist w/adaptation to short stature through peer support, personal example, & social awareness programs; Provide info on employment, education, disability rights, adoption of children of short stature, medical issues, suitable clothing, adaptive devices, & parenting through local meetings, workshops, seminars, & a national newsletter. ASM = anti-seizure medication; DD/ID = developmental delay / intellectual disability; LPA = Little People of America, Inc. Education of parents/caregivers regarding common seizure presentations is appropriate. For information on nonmedical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, and modified assignments. Recommended Surveillance for Individuals with Hypochondroplasia See There is a paucity of literature regarding pregnancy management in women with skeletal dysplasias. However, a number of women with hypochondroplasia have had unremarkable pregnancies and deliveries. In comparison to women who have achondroplasia, vaginal deliveries are possible, although for each pregnancy, pelvic outlet capacity should be assessed in relation to fetal head size. Epidural or spinal anesthetic can be used, but a consultation with an anesthesiologist prior to delivery is recommended to assess the spinal anatomy. If present, spinal stenosis may be aggravated during pregnancy due to the normal physiologic changes to the shape of the spine that occur as gestation progresses. Trials of growth hormone therapy in hypochondroplasia have shown mixed results. Those differences in individual responses published prior to gene discovery in 1995 [ Since data about final adult height in growth hormone-treated individuals with hypochondroplasia are not available, the ultimate success of this approach remains uncertain. Growth hormone therapy should still be considered experimental and controversial in this condition. Surgical limb lengthening procedures have been used to treat achondroplasia and hypochondroplasia for more than 15 years. Although the complication rate was high initially, outcomes have steadily improved and significant increases in overall height have been reported [ Search • Assess for signs/symptoms of sleep apnea; refer for polysomnography if needed. • Neurologic exam for signs of spinal cord compression (e.g., severe hypotonia, hyperreflexia, clonus, & asymmetries) • MRI or CT of the foramen magnum if spinal cord compression suggested by findings on neurologic exam or central apnea identified on sleep study • Referral to a pediatric neurologist or neurosurgeon if needed • To incl motor, adaptive, cognitive, & speech/language eval • Eval for early intervention / special education • Management is influenced by parental expectations & concerns. • Address parents' expectations & prejudices re child's height rather than attempting to treat child. • No one ASM has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Assist w/adaptation to short stature through peer support, personal example, & social awareness programs; • Provide info on employment, education, disability rights, adoption of children of short stature, medical issues, suitable clothing, adaptive devices, & parenting through local meetings, workshops, seminars, & a national newsletter. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in 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, and modified assignments. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in 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. • In comparison to women who have achondroplasia, vaginal deliveries are possible, although for each pregnancy, pelvic outlet capacity should be assessed in relation to fetal head size. • Epidural or spinal anesthetic can be used, but a consultation with an anesthesiologist prior to delivery is recommended to assess the spinal anatomy. • If present, spinal stenosis may be aggravated during pregnancy due to the normal physiologic changes to the shape of the spine that occur as gestation progresses. ## Evaluations Following Initial Diagnosis Management of children with hypochondroplasia usually does not differ significantly from that of children with normal stature except for genetic counseling issues and dealing with parental concerns about short stature. However, because the phenotype of To establish the extent of disease and needs in an individual diagnosed with hypochondroplasia, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Hypochondroplasia Assess for signs/symptoms of sleep apnea; refer for polysomnography if needed. Neurologic exam for signs of spinal cord compression (e.g., severe hypotonia, hyperreflexia, clonus, & asymmetries) MRI or CT of the foramen magnum if spinal cord compression suggested by findings on neurologic exam or central apnea identified on sleep study Referral to a pediatric neurologist or neurosurgeon if needed To incl motor, adaptive, cognitive, & speech/language eval Eval for early intervention / special education • Assess for signs/symptoms of sleep apnea; refer for polysomnography if needed. • Neurologic exam for signs of spinal cord compression (e.g., severe hypotonia, hyperreflexia, clonus, & asymmetries) • MRI or CT of the foramen magnum if spinal cord compression suggested by findings on neurologic exam or central apnea identified on sleep study • Referral to a pediatric neurologist or neurosurgeon if needed • To incl motor, adaptive, cognitive, & speech/language eval • Eval for early intervention / special education ## Treatment of Manifestations Treatment of Manifestations in Individuals with Hypochondroplasia Management is influenced by parental expectations & concerns. Address parents' expectations & prejudices re child's height rather than attempting to treat child. No one ASM has been demonstrated effective specifically for this disorder. Education of parents/caregivers Assist w/adaptation to short stature through peer support, personal example, & social awareness programs; Provide info on employment, education, disability rights, adoption of children of short stature, medical issues, suitable clothing, adaptive devices, & parenting through local meetings, workshops, seminars, & a national newsletter. ASM = anti-seizure medication; DD/ID = developmental delay / intellectual disability; LPA = Little People of America, Inc. Education of parents/caregivers regarding common seizure presentations is appropriate. For information on nonmedical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, and modified assignments. • Management is influenced by parental expectations & concerns. • Address parents' expectations & prejudices re child's height rather than attempting to treat child. • No one ASM has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Assist w/adaptation to short stature through peer support, personal example, & social awareness programs; • Provide info on employment, education, disability rights, adoption of children of short stature, medical issues, suitable clothing, adaptive devices, & parenting through local meetings, workshops, seminars, & a national newsletter. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in 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, and modified assignments. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, and modified assignments. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in 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, and modified assignments. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in 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 ## Surveillance Recommended Surveillance for Individuals with Hypochondroplasia ## Evaluation of Relatives at Risk See ## Pregnancy Management There is a paucity of literature regarding pregnancy management in women with skeletal dysplasias. However, a number of women with hypochondroplasia have had unremarkable pregnancies and deliveries. In comparison to women who have achondroplasia, vaginal deliveries are possible, although for each pregnancy, pelvic outlet capacity should be assessed in relation to fetal head size. Epidural or spinal anesthetic can be used, but a consultation with an anesthesiologist prior to delivery is recommended to assess the spinal anatomy. If present, spinal stenosis may be aggravated during pregnancy due to the normal physiologic changes to the shape of the spine that occur as gestation progresses. • In comparison to women who have achondroplasia, vaginal deliveries are possible, although for each pregnancy, pelvic outlet capacity should be assessed in relation to fetal head size. • Epidural or spinal anesthetic can be used, but a consultation with an anesthesiologist prior to delivery is recommended to assess the spinal anatomy. • If present, spinal stenosis may be aggravated during pregnancy due to the normal physiologic changes to the shape of the spine that occur as gestation progresses. ## Therapies Under Investigation Trials of growth hormone therapy in hypochondroplasia have shown mixed results. Those differences in individual responses published prior to gene discovery in 1995 [ Since data about final adult height in growth hormone-treated individuals with hypochondroplasia are not available, the ultimate success of this approach remains uncertain. Growth hormone therapy should still be considered experimental and controversial in this condition. Surgical limb lengthening procedures have been used to treat achondroplasia and hypochondroplasia for more than 15 years. Although the complication rate was high initially, outcomes have steadily improved and significant increases in overall height have been reported [ Search ## Growth Hormone Therapy Trials of growth hormone therapy in hypochondroplasia have shown mixed results. Those differences in individual responses published prior to gene discovery in 1995 [ Since data about final adult height in growth hormone-treated individuals with hypochondroplasia are not available, the ultimate success of this approach remains uncertain. Growth hormone therapy should still be considered experimental and controversial in this condition. ## Surgical Limb Lengthening Surgical limb lengthening procedures have been used to treat achondroplasia and hypochondroplasia for more than 15 years. Although the complication rate was high initially, outcomes have steadily improved and significant increases in overall height have been reported [ Search ## Genetic Counseling Hypochondroplasia is inherited in an autosomal dominant manner. The majority of individuals with hypochondroplasia have parents of average stature and have hypochondroplasia as the result of a There appears to be a paternal age effect in some simplex occurrences of hypochondroplasia [ In some instances, one or both parents have hypochondroplasia. Molecular genetic testing is recommended for the parents of a proband with an apparent If an The family history of some individuals diagnosed with hypochondroplasia may appear to be negative because of failure to recognize the disorder in family members (the height range in hypochondroplasia may overlap that of the average range; see Note: Because the skeletal features of hypochondroplasia are milder than those of achondroplasia and the incidence of disabilities is lower, the reproductive fitness of individuals with hypochondroplasia is most likely greater than that of individuals with achondroplasia. It is likely that the number of families with multiple affected members is higher for hypochondroplasia than for achondroplasia, and that the percentage of cases of hypochondroplasia attributable to If one parent of the proband is affected, the risk to the sibs is 50%. If both parents have hypochondroplasia or one has hypochondroplasia and the other has a different autosomal dominant skeletal dysplasia, the risk to sibs is more complex (see If the proband has a known An individual with hypochondroplasia who has a reproductive partner of average stature is at a 50% risk of having a child with hypochondroplasia. When the proband and the proband's reproductive partner have the same or different skeletal dysplasias, genetic counseling is more complicated. In general, if both members of a couple have a dominantly inherited skeletal dysplasia, each child has a 25% chance of having average stature, a 25% chance of having the same skeletal dysplasia as the father, a 25% chance of having the same skeletal dysplasia as the mother, and a 25% chance of inheriting a pathogenic variant from both parents and being at risk for a potentially poor pregnancy outcome. Individuals who are compound heterozygotes for Poor outcomes have been reported for individuals who are compound heterozygotes for achondroplasia and spondyloepiphyseal dysplasia congenita [ Compound heterozygotes for either achondroplasia and dyschondrosteosis or hypochondroplasia and dyschondrosteosis have phenotypes that do not appear to be more severe than that of either parent [ Genetic counseling of couples both of whom have hypochondroplasia is complicated by (1) genetic heterogeneity and (2) lack of information about the phenotypes and prognosis for offspring who inherit a pathogenic variant from both parents. No reports address the following phenotypes: Individuals with hypochondroplasia who are homozygous for Individuals who are compound heterozygotes for an Similarly, the following phenotypes have not been described: Individuals who are compound heterozygotes for a non- Individuals who are compound heterozygotes for hypochondroplasia (as a result of either an Therefore, it is not possible to provide information about prognosis for all at-risk offspring. Genetic counseling for hypochondroplasia presents dilemmas relating to ethical and genetic issues. Hypochondroplasia is considered a mild disorder in which the chief physical disability is generally short stature. Many affected individuals do not think of themselves as disabled. However, some parents may consider short stature a significant physical, emotional, and/or social disability. Furthermore, a child with hypochondroplasia may have intellectual disability or a learning disability. An additional issue is genetic heterogeneity (i.e., pathogenic variants in more than one gene causing hypochondroplasia), which may result in an inability to predict phenotype or prognosis and/or make diagnosis difficult. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. Genetic counseling is recommended if both parents have a skeletal dysplasia. If significant macrocephaly is noted, it is appropriate to consider delivery by cesarean section to reduce the risk of potential CNS complications associated with a vaginal delivery. Guidelines for prenatal diagnosis of skeletal dysplasias are available [ Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The majority of individuals with hypochondroplasia have parents of average stature and have hypochondroplasia as the result of a • There appears to be a paternal age effect in some simplex occurrences of hypochondroplasia [ • In some instances, one or both parents have hypochondroplasia. • Molecular genetic testing is recommended for the parents of a proband with an apparent • If an • The family history of some individuals diagnosed with hypochondroplasia may appear to be negative because of failure to recognize the disorder in family members (the height range in hypochondroplasia may overlap that of the average range; see • Note: Because the skeletal features of hypochondroplasia are milder than those of achondroplasia and the incidence of disabilities is lower, the reproductive fitness of individuals with hypochondroplasia is most likely greater than that of individuals with achondroplasia. It is likely that the number of families with multiple affected members is higher for hypochondroplasia than for achondroplasia, and that the percentage of cases of hypochondroplasia attributable to • If one parent of the proband is affected, the risk to the sibs is 50%. • If both parents have hypochondroplasia or one has hypochondroplasia and the other has a different autosomal dominant skeletal dysplasia, the risk to sibs is more complex (see • If the proband has a known • An individual with hypochondroplasia who has a reproductive partner of average stature is at a 50% risk of having a child with hypochondroplasia. • When the proband and the proband's reproductive partner have the same or different skeletal dysplasias, genetic counseling is more complicated. In general, if both members of a couple have a dominantly inherited skeletal dysplasia, each child has a 25% chance of having average stature, a 25% chance of having the same skeletal dysplasia as the father, a 25% chance of having the same skeletal dysplasia as the mother, and a 25% chance of inheriting a pathogenic variant from both parents and being at risk for a potentially poor pregnancy outcome. • Individuals who are compound heterozygotes for • Poor outcomes have been reported for individuals who are compound heterozygotes for achondroplasia and spondyloepiphyseal dysplasia congenita [ • Compound heterozygotes for either achondroplasia and dyschondrosteosis or hypochondroplasia and dyschondrosteosis have phenotypes that do not appear to be more severe than that of either parent [ • Individuals who are compound heterozygotes for • Poor outcomes have been reported for individuals who are compound heterozygotes for achondroplasia and spondyloepiphyseal dysplasia congenita [ • Compound heterozygotes for either achondroplasia and dyschondrosteosis or hypochondroplasia and dyschondrosteosis have phenotypes that do not appear to be more severe than that of either parent [ • Genetic counseling of couples both of whom have hypochondroplasia is complicated by (1) genetic heterogeneity and (2) lack of information about the phenotypes and prognosis for offspring who inherit a pathogenic variant from both parents. No reports address the following phenotypes: • Individuals with hypochondroplasia who are homozygous for • Individuals who are compound heterozygotes for an • Individuals with hypochondroplasia who are homozygous for • Individuals who are compound heterozygotes for an • Similarly, the following phenotypes have not been described: • Individuals who are compound heterozygotes for a non- • Individuals who are compound heterozygotes for hypochondroplasia (as a result of either an • Individuals who are compound heterozygotes for a non- • Individuals who are compound heterozygotes for hypochondroplasia (as a result of either an • Therefore, it is not possible to provide information about prognosis for all at-risk offspring. • Individuals who are compound heterozygotes for • Poor outcomes have been reported for individuals who are compound heterozygotes for achondroplasia and spondyloepiphyseal dysplasia congenita [ • Compound heterozygotes for either achondroplasia and dyschondrosteosis or hypochondroplasia and dyschondrosteosis have phenotypes that do not appear to be more severe than that of either parent [ • Individuals with hypochondroplasia who are homozygous for • Individuals who are compound heterozygotes for an • Individuals who are compound heterozygotes for a non- • Individuals who are compound heterozygotes for hypochondroplasia (as a result of either an • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. • Genetic counseling is recommended if both parents have a skeletal dysplasia. • If significant macrocephaly is noted, it is appropriate to consider delivery by cesarean section to reduce the risk of potential CNS complications associated with a vaginal delivery. ## Mode of Inheritance Hypochondroplasia is inherited in an autosomal dominant manner. ## Risk to Family Members The majority of individuals with hypochondroplasia have parents of average stature and have hypochondroplasia as the result of a There appears to be a paternal age effect in some simplex occurrences of hypochondroplasia [ In some instances, one or both parents have hypochondroplasia. Molecular genetic testing is recommended for the parents of a proband with an apparent If an The family history of some individuals diagnosed with hypochondroplasia may appear to be negative because of failure to recognize the disorder in family members (the height range in hypochondroplasia may overlap that of the average range; see Note: Because the skeletal features of hypochondroplasia are milder than those of achondroplasia and the incidence of disabilities is lower, the reproductive fitness of individuals with hypochondroplasia is most likely greater than that of individuals with achondroplasia. It is likely that the number of families with multiple affected members is higher for hypochondroplasia than for achondroplasia, and that the percentage of cases of hypochondroplasia attributable to If one parent of the proband is affected, the risk to the sibs is 50%. If both parents have hypochondroplasia or one has hypochondroplasia and the other has a different autosomal dominant skeletal dysplasia, the risk to sibs is more complex (see If the proband has a known An individual with hypochondroplasia who has a reproductive partner of average stature is at a 50% risk of having a child with hypochondroplasia. When the proband and the proband's reproductive partner have the same or different skeletal dysplasias, genetic counseling is more complicated. In general, if both members of a couple have a dominantly inherited skeletal dysplasia, each child has a 25% chance of having average stature, a 25% chance of having the same skeletal dysplasia as the father, a 25% chance of having the same skeletal dysplasia as the mother, and a 25% chance of inheriting a pathogenic variant from both parents and being at risk for a potentially poor pregnancy outcome. Individuals who are compound heterozygotes for Poor outcomes have been reported for individuals who are compound heterozygotes for achondroplasia and spondyloepiphyseal dysplasia congenita [ Compound heterozygotes for either achondroplasia and dyschondrosteosis or hypochondroplasia and dyschondrosteosis have phenotypes that do not appear to be more severe than that of either parent [ Genetic counseling of couples both of whom have hypochondroplasia is complicated by (1) genetic heterogeneity and (2) lack of information about the phenotypes and prognosis for offspring who inherit a pathogenic variant from both parents. No reports address the following phenotypes: Individuals with hypochondroplasia who are homozygous for Individuals who are compound heterozygotes for an Similarly, the following phenotypes have not been described: Individuals who are compound heterozygotes for a non- Individuals who are compound heterozygotes for hypochondroplasia (as a result of either an Therefore, it is not possible to provide information about prognosis for all at-risk offspring. • The majority of individuals with hypochondroplasia have parents of average stature and have hypochondroplasia as the result of a • There appears to be a paternal age effect in some simplex occurrences of hypochondroplasia [ • In some instances, one or both parents have hypochondroplasia. • Molecular genetic testing is recommended for the parents of a proband with an apparent • If an • The family history of some individuals diagnosed with hypochondroplasia may appear to be negative because of failure to recognize the disorder in family members (the height range in hypochondroplasia may overlap that of the average range; see • Note: Because the skeletal features of hypochondroplasia are milder than those of achondroplasia and the incidence of disabilities is lower, the reproductive fitness of individuals with hypochondroplasia is most likely greater than that of individuals with achondroplasia. It is likely that the number of families with multiple affected members is higher for hypochondroplasia than for achondroplasia, and that the percentage of cases of hypochondroplasia attributable to • If one parent of the proband is affected, the risk to the sibs is 50%. • If both parents have hypochondroplasia or one has hypochondroplasia and the other has a different autosomal dominant skeletal dysplasia, the risk to sibs is more complex (see • If the proband has a known • An individual with hypochondroplasia who has a reproductive partner of average stature is at a 50% risk of having a child with hypochondroplasia. • When the proband and the proband's reproductive partner have the same or different skeletal dysplasias, genetic counseling is more complicated. In general, if both members of a couple have a dominantly inherited skeletal dysplasia, each child has a 25% chance of having average stature, a 25% chance of having the same skeletal dysplasia as the father, a 25% chance of having the same skeletal dysplasia as the mother, and a 25% chance of inheriting a pathogenic variant from both parents and being at risk for a potentially poor pregnancy outcome. • Individuals who are compound heterozygotes for • Poor outcomes have been reported for individuals who are compound heterozygotes for achondroplasia and spondyloepiphyseal dysplasia congenita [ • Compound heterozygotes for either achondroplasia and dyschondrosteosis or hypochondroplasia and dyschondrosteosis have phenotypes that do not appear to be more severe than that of either parent [ • Individuals who are compound heterozygotes for • Poor outcomes have been reported for individuals who are compound heterozygotes for achondroplasia and spondyloepiphyseal dysplasia congenita [ • Compound heterozygotes for either achondroplasia and dyschondrosteosis or hypochondroplasia and dyschondrosteosis have phenotypes that do not appear to be more severe than that of either parent [ • Genetic counseling of couples both of whom have hypochondroplasia is complicated by (1) genetic heterogeneity and (2) lack of information about the phenotypes and prognosis for offspring who inherit a pathogenic variant from both parents. No reports address the following phenotypes: • Individuals with hypochondroplasia who are homozygous for • Individuals who are compound heterozygotes for an • Individuals with hypochondroplasia who are homozygous for • Individuals who are compound heterozygotes for an • Similarly, the following phenotypes have not been described: • Individuals who are compound heterozygotes for a non- • Individuals who are compound heterozygotes for hypochondroplasia (as a result of either an • Individuals who are compound heterozygotes for a non- • Individuals who are compound heterozygotes for hypochondroplasia (as a result of either an • Therefore, it is not possible to provide information about prognosis for all at-risk offspring. • Individuals who are compound heterozygotes for • Poor outcomes have been reported for individuals who are compound heterozygotes for achondroplasia and spondyloepiphyseal dysplasia congenita [ • Compound heterozygotes for either achondroplasia and dyschondrosteosis or hypochondroplasia and dyschondrosteosis have phenotypes that do not appear to be more severe than that of either parent [ • Individuals with hypochondroplasia who are homozygous for • Individuals who are compound heterozygotes for an • Individuals who are compound heterozygotes for a non- • Individuals who are compound heterozygotes for hypochondroplasia (as a result of either an ## Related Genetic Counseling Issues Genetic counseling for hypochondroplasia presents dilemmas relating to ethical and genetic issues. Hypochondroplasia is considered a mild disorder in which the chief physical disability is generally short stature. Many affected individuals do not think of themselves as disabled. However, some parents may consider short stature a significant physical, emotional, and/or social disability. Furthermore, a child with hypochondroplasia may have intellectual disability or a learning disability. An additional issue is genetic heterogeneity (i.e., pathogenic variants in more than one gene causing hypochondroplasia), which may result in an inability to predict phenotype or prognosis and/or make diagnosis difficult. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. Genetic counseling is recommended if both parents have a skeletal dysplasia. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. • Genetic counseling is recommended if both parents have a skeletal dysplasia. ## Prenatal Testing and Preimplantation Genetic Testing If significant macrocephaly is noted, it is appropriate to consider delivery by cesarean section to reduce the risk of potential CNS complications associated with a vaginal delivery. Guidelines for prenatal diagnosis of skeletal dysplasias are available [ Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • If significant macrocephaly is noted, it is appropriate to consider delivery by cesarean section to reduce the risk of potential CNS complications associated with a vaginal delivery. ## Resources United Kingdom • • • • • • United Kingdom • • • • • • • • • ## Molecular Genetics Hypochondroplasia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Hypochondroplasia ( Fibroblast growth factor receptor 3 is a receptor tyrosine kinase (FGFR3) and a member of the fibroblast growth factor receptor family. This family comprises four related genes in mammals ( The effects of the Notable Variants listed in the table have been provided by the authors. In the literature, two protein variants (p.Asn540Lys, p.Gly380Arg) may be cited without designating the precise underlying nucleotide substitution. ## Molecular Pathogenesis Fibroblast growth factor receptor 3 is a receptor tyrosine kinase (FGFR3) and a member of the fibroblast growth factor receptor family. This family comprises four related genes in mammals ( The effects of the Notable Variants listed in the table have been provided by the authors. In the literature, two protein variants (p.Asn540Lys, p.Gly380Arg) may be cited without designating the precise underlying nucleotide substitution. ## Chapter Notes Arthur S Aylsworth, MD, FACMG; University of North Carolina (1999-2005)Gary A Bellus, MD, PhD (1999-2005; 2013-present) Michael B Bober, MD, PhD (2013-present)Clair A Francomano, MD; National Institutes of Health (2005-2013) Thaddeus E Kelly, MD, PhD; University of Virginia Hospital (1999-2005) Sarah M Nikkel, MD (2013-present)George E Tiller, MD, PhD (2013-present) 7 May 2020 (sw) Comprehensive update posted live 26 September 2013 (me) Comprehensive update posted live 12 December 2005 (me) Comprehensive update posted live 13 February 2003 (me) Comprehensive update posted live 15 July 1999 (pb) Review posted live 27 April 1999 (gb) Original submission • 7 May 2020 (sw) Comprehensive update posted live • 26 September 2013 (me) Comprehensive update posted live • 12 December 2005 (me) Comprehensive update posted live • 13 February 2003 (me) Comprehensive update posted live • 15 July 1999 (pb) Review posted live • 27 April 1999 (gb) Original submission ## Author History Arthur S Aylsworth, MD, FACMG; University of North Carolina (1999-2005)Gary A Bellus, MD, PhD (1999-2005; 2013-present) Michael B Bober, MD, PhD (2013-present)Clair A Francomano, MD; National Institutes of Health (2005-2013) Thaddeus E Kelly, MD, PhD; University of Virginia Hospital (1999-2005) Sarah M Nikkel, MD (2013-present)George E Tiller, MD, PhD (2013-present) ## Revision History 7 May 2020 (sw) Comprehensive update posted live 26 September 2013 (me) Comprehensive update posted live 12 December 2005 (me) Comprehensive update posted live 13 February 2003 (me) Comprehensive update posted live 15 July 1999 (pb) Review posted live 27 April 1999 (gb) Original submission • 7 May 2020 (sw) Comprehensive update posted live • 26 September 2013 (me) Comprehensive update posted live • 12 December 2005 (me) Comprehensive update posted live • 13 February 2003 (me) Comprehensive update posted live • 15 July 1999 (pb) Review posted live • 27 April 1999 (gb) Original submission ## References Krakow D, Lachman RS, Rimoin DL. Guidelines for the prenatal diagnosis of fetal skeletal dysplasias. Available • Krakow D, Lachman RS, Rimoin DL. Guidelines for the prenatal diagnosis of fetal skeletal dysplasias. Available ## Published Guidelines / Consensus Statements Krakow D, Lachman RS, Rimoin DL. Guidelines for the prenatal diagnosis of fetal skeletal dysplasias. Available • Krakow D, Lachman RS, Rimoin DL. Guidelines for the prenatal diagnosis of fetal skeletal dysplasias. Available ## Literature Cited	[ "KS Alatzoglou, PC Hindmarsh, C Brain, J Torpiano, MT Dattani. Acanthosis nigricans and insulin sensitivity in patients with achondroplasia and hypochodroplasia due to FGFR3 mutations.. J Clin Endocrinol Metab. 2009;94:3959-63", "B Angle, JH Hersh, KM Christensen. Molecularly proven hypochondroplasia with cloverleaf skull deformity: a novel association.. Clin Genet. 1998;54:417-20", "MA Arenas, M Del Pino, V Fano. FGFR3-related hypochondroplasia: longitudinal growth in 57 children with the p.Asn540Lys mutation.. J Pediatr Endocrinol Metab. 2018;31:1279-84", "GA Bellus, MJ Bamshad, KA Przylepa, J Dorst, RR Lee, O Hurko, EW Jabs, CJ Curry, WR Wilcox, RS Lachman, DL Rimoin, CA Francomano. Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN): phenotypic analysis of a new skeletal dysplasia caused by a Lys650Met mutation in fibroblast growth factor receptor 3.. Am J Med Genet. 1999;85:53-65", "GA Bellus, I McIntosh, J Szabo, A Aylsworth, I Kaitila, CA Francomano. Hypochondroplasia: molecular analysis of the fibroblast growth factor receptor 3 gene.. Ann N Y Acad Sci. 1996;785:182-7", "GA Bellus, EB Spector, PW Speiser, CA Weaver, AT Garber, CR Bryke, J Israel, SS Rosengren, MK Webster, DJ Donoghue, CA Francomano. Distinct missense mutations of the FGFR3 lys650 codon modulate receptor kinase activation and the severity of the skeletal dysplasia phenotype.. Am J Hum Genet. 2000;67:1411-21", "FB Bengur, CG Ekmekci, E Karaarslan, H Gunoz, Y. p. Alanay. Ser348Cys mutation in FGFR3 gene leads to \"Mild ACH/Severe HCH\" phenotype.. Eur J Med Genet. 2020;63", "DR Berk, C Boente Mdel, D Montanari, MG Toloza, NB Primc, MI Prado, SJ Bayliss, LM Pique, I Schrijver. Acanthosis nigricans and hypochondroplasia in a child with a K650Q mutation in FGFR3.. Pediatr Dermatol. 2010;27:664-6", "M Blomberg, EM Jeppesen, F Skovby, E Benfeldt. FGFR3 mutations and the skin: report of a patient with a FGFR3 gene mutation,acanthosis nigricans, hypochondroplasia and hyperinsulinemia and review of the literature.. Dermatology. 2010;220:297-305", "MB Bober, M Taylor, R Heinle, W Mackenzie. Achondroplasia-hypochondroplasia complex and abnormal pulmonary anatomy.. Am J Med Genet A. 2012;158A:2336-41", "NA Bridges, CG Brook. Progress report: growth hormone in skeletal dysplasia.. Horm Res. 1994;42:231-4", "NA Bridges, PC Hindmarsh, CG Brook. Growth of children with hypochondroplasia treated with growth hormone for up to three years.. Horm Res. 1991;36:56-60", "T Çetin, Z Şıklar, P Kocaay, M Berberoğlu. Evaluation of efficacy of long-term growth hormone therapy in patients with hypochondroplasia.. J Clin Res Pediatr Endocrinol. 2018;10:373-6", "LS Chitty, DR Griffin, C Meaney, A Barrett, A Khalil, E Pajkrt, TJ Cole. New aids for the non-invasive prenatal diagnosis of achondroplasia: dysmorphic features, charts of fetal size and molecular confirmation using cell-free fetal DNA in maternal plasma.. Ultrasound Obstet Gynecol. 2011;37:283-9", "JS Colvin, BA Bohne, GW Harding, DG McEwen, DM Ornitz. Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3.. Nat Genet. 1996;12:390-7", "NL Couser, CK Pande, CM Turcott, EB Spector, AS Aylsworth, CM Powell. Mild achondroplasia/hypochondroplasia with acanthosis nigricans, normal development, and a p.Ser348Cys FGFR3 mutation.. Am J Med Genet A. 2017;173:1097-101", "C Deng, A Wynshaw-Boris, F Zhou, A Kuo, P Leder. Fibroblast growth factor receptor 3 is a negative regulator of bone growth.. Cell. 1996;84:911-21", "V Fano, LP Gravina, MD Pino, L Chertkoff, C Barreiro, H Lejarraga. High specificity of head circumference to recognize N540K mutation in hypochondroplasia.. Ann Hum Biol. 2005;32:782-8", "OV Fofanova, N Takamura, E Kinoshita, EM Meerson, VK Iljina, OL Nechvolodova, OV Evgrafov, VA Peterkova, S Yamashita. A missense mutation of C1659 in the fibroblast growth factor receptor 3 gene in Russian patients with hypochondroplasia.. Endocr J. 1998;45:791-5", "A González-Del Angel, R Rius, MA Alcántara-Ortigoza, E Spector, V Del Castillo, LE Mata-García. Further delineation of achondroplasia-hypochondroplasia complex with long-term survival.. Am J Med Genet A. 2018;176:1225-31", "J Günthard, C Fliegel, H Ohnacker, M Rutishauser, E Buhler. Lung hypoplasia and severe pulmonary hypertension in an infant with double heterozygosity for spondyloepiphyseal dysplasia congenita and achondroplasia.. Clin Genet. 1995;48:35-40", "BD Hall, J Spranger. Hypochondroplasia: clinical and radiological aspects in 39 cases.. Radiology. 1979;133:95-100", "K Hasegawa, R Fukuhara, T Moriwake, H Tanaka, Y Higuchi, M Yamashita, H. Tsukahara. A novel mutation p.Ser348Cys in FGFR3 causes achondroplasia.. Am J Med Genet A. 2016;170A:1370-2", "A Hatzaki, S Sifakis, D Apostolopoulou, D Bouzarelou, A Konstantinidou, D Kappou, A Sideris, E Tzortzis, A Athanassiadis, L Florentin, P Theodoropoulos, C Makatsoris, C Karadimas, V. Velissariou. FGFR3 related skeletal dysplasias diagnosed prenatally by ultrasonography and molecular analysis: presentation of 17 cases.. Am J Med Genet A. 2011;155A:2426-35", "NG Heselson, BJ Cremin, P Beighton. The radiographic manifestations of hypochondroplasia.. Clin Radiol. 1979;30:79-85", "S Heuertz, M Le Merrer, B Zabel, M Wright, L Legeai-Mallet, V Cormier-Daire, L Gibbs, J. Bonaventure. Novel FGFR3 mutations creating cysteine residues in the extracellular domain of the receptor cause achondroplasia or severe forms of hypochondroplasia.. Eur J Hum Genet. 2006;14:1240-7", "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", "MJ Huggins, JR Smith, K Chun, PN Ray, JK Shah, DT Whelan. Achondroplasia-hypochondroplasia complex in a newborn infant.. Am J Med Genet. 1999;84:396-400", "DE Johnson, LT Williams. Structural and functional diversity in the FGF receptor multigene family.. Adv Cancer Res. 1993;60:1-41", "SM Jones, LK Robinson, R Sperrazza. Prenatal diagnosis of skeletal dysplasia identified postnatally as hypochondroplasia.. Am J Med Genet. 1990;36:404-7", "D Krakow, RS Lachman, DL Rimoin. Guidelines for the prenatal diagnosis of fetal skeletal dysplasias.. Genet Med. 2009;11:127-33", "LO Langer, GB Schaefer, DT Wadsworth. Patient with double heterozygosity for achondroplasia and pseudoachondroplasia, with comments on these conditions and the relationship between pseudoachondroplasia and multiple epiphyseal dysplasia, Fairbank type.. Am J Med Genet. 1993;47:772-81", "CW Lie, W Chow. Limb lengthening in short-stature patients using monolateral and circular external fixators.. Hong Kong Med J. 2009;15:280-4", "T Linnankivi, O Mäkitie, L Valanne, S Toiviainen-Salo. Neuroimaging and neurological findings in patients with hypochondroplasia and FGFR3 N540K mutation.. Am J Med Genet A. 2012;158A:3119-25", "P Maroteaux, P. Falzon. Arch Fr Pediatr. 1988;45:105-9", "MF Meyer, KU Menken, S Zimny, B Hellmich, H Schatz. Pitfall in diagnosing growth hormone deficiency in a hypochondroplastic patient with a delayed puberty.. Exp Clin Endocrinol Diabetes. 2003;111:177-81", "DM Moloney, SF Slaney, M Oldridge, SA Wall, P Sahlin, G Stenman, AO Wilkie. Exclusive paternal origin of new mutations in Apert syndrome. Nat Genet. 1996;13:48-53", "L Muguet Guenot, H Aubert, B Isidor, A Toutain, J Mazereeuw-Hautier, C Collet, E Bourrat, M Denis Musquer, S Barbarot. Acanthosis nigricans, hypochondroplasia, and FGFR3 mutations: Findings with five new patients, and a review of the literature.. Pediatr Dermatol. 2019;36:242-6", "PE Mullis, MS Patel, PM Brickell, PC Hindmarsh, CG Brook. Growth characteristics and response to growth hormone therapy in patients with hypochondroplasia: genetic linkage of the insulin-like growth factor I gene at chromosome 12q23 to the disease in a subgroup of these patients.. Clin Endocrinol (Oxf) 1991;34:265-74", "MC Naski, Q Wang, J Xu, DM Ornitz. Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia.. Nat Genet. 1996;13:233-7", "F Oberklaid, DM Danks, F Jensen, L Stace, S Rosshandler. Achondroplasia and hypochondroplasia. Comments on frequency, mutation rate, and radiological features in skull and spine.. J Med Genet. 1979;16:140-6", "G Pinto, V Cormier, M Le Merrer, D Samara-Boustani, L Fresneau, M Viaud, JC Souberbielle, JC Pineau, M Polak. Efficacy and safety of growth hormone in the treatment of children with hypochondroplasia (HCH): comparison with a historical cohort of untreated children with HCH.. Hormone Res Paediatr. 2012;78:193", "P Prinos, T Costa, A Sommer, MW Kilpatrick, P Tsipouras. A common FGFR3 gene mutation in hypochondroplasia.. Hum Mol Genet. 1995;4:2097-101", "C Prinster, P Carrera, M Del Maschio, G Weber, M Maghnie, MC Vigone, S Mora, G Tonini, F Rigon, G Beluffi, F Severi, G Chiumello, M Ferrari. Comparison of clinical-radiological and molecular findings in hypochondroplasia.. Am J Med Genet. 1998;75:109-12", "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", "U Ramaswami, G Rumsby, PC Hindmarsh, CG Brook. Genotype and phenotype in hypochondroplasia.. J Pediatr. 1998;133:99-102", "JL Ross, G Bellus, CI Scott, J Abboudi, G Grigelioniene, AR Zinn. Mesomelic and rhizomelic short stature: the phenotype of combined Leri-Weill dyschondrosteosis and achondroplasia or hypochondroplasia.. Am J Med Genet. 2003;116A:61-5", "A Rothenbuhler, A Linglart, C Piquard, P. Bougnères. A pilot study of discontinuous, insulin-like growth factor 1-dosing growth hormone treatment in young children with FGFR3 N540K-mutated hypochondroplasia.. J Pediatr. 2012;160:849-53", "F Rousseau, J Bonaventure, L Legeai-Mallet, H Schmidt, J Weissenbach, P Maroteaux, A Munnich, M. Le Merrer. Clinical and genetic heterogeneity of hypochondroplasia.. J Med Genet. 1996;33:749-52", "SH Song, GC Balce, MV Agashe, H Lee, SJ Hong, YE Park, SG Kim, HR Song. New proposed clinico-radiologic and molecular criteria in hypochondroplasia: FGFR 3 gene mutations are not the only cause of hypochondroplasia.. Am J Med Genet A. 2012;158A:2456-62", "N Tanaka, N Katsumata, R Horikawa, T Tanaka. The comparison of the effects of short-term growth hormone treatment in patients with achondroplasia and with hypochondroplasia.. Endocr J. 2003;50:69-75", "PL Tavormina, GA Bellus, MK Webster, MJ Bamshad, AE Fraley, I McIntosh, J Szabo, W Jiang, EW Jabs, WR Wilcox, JJ Wasmuth, DJ Donoghue, LM Thompson, CA Francomano. A novel skeletal dysplasia with developmental delay and acanthosis nigricans is caused by a Lys650Met mutation in the fibroblast growth factor receptor 3 gene.. Am J Hum Genet. 1999;64:722-31", "RT Thomeer, JM van Dijk. Surgical treatment of lumbar stenosis in achondroplasia.. J Neurosurg. 2002;96:292-7", "LM Thompson, S Raffioni, JJ Wasmuth, RA Bradshaw. Chimeras of the native form or achondroplasia mutant (G375C) of human fibroblast growth factor receptor 3 induce ligand-dependent differentiation of PC12 cells.. Mol Cell Biol. 1997;17:4169-77", "TL Trotter, JG Hall. Health supervision for children with achondroplasia.. Pediatrics. 2005;116:771-83", "BA Walker, JL Murdoch, VA McKusick, LO Langer, RK Beals. Hypochondroplasia.. Am J Dis Child. 1971;122:95-104", "MK Webster, PY D'Avis, SC Robertson, DJ Donoghue. Profound ligand-independent kinase activation of fibroblast growth factor receptor 3 by the activation loop mutation responsible for a lethal skeletal dysplasia, thanatophoric dysplasia type II.. Mol Cell Biol. 1996;16:4081-7", "MK Webster, DJ Donoghue. Constitutive activation of fibroblast growth factor receptor 3 by the transmembrane domain point mutation found in achondroplasia.. EMBO J. 1996;15:520-7", "DJ Wilkin, JK Szabo, R Cameron, S Henderson, GA Bellus, ML Mack, I Kaitila, J Loughlin, A Munnich, B Sykes, J Bonaventure, CA Francomano. Mutations in fibroblast growth-factor receptor 3 in sporadic cases of achondroplasia occur exclusively on the paternally derived chromosome.. Am J Hum Genet. 1998;63:711-6", "R Wynne-Davies, MA Patton. The frequency of mental retardation in hypochondroplasia.. J Med Genet. 1991;28:644", "R Wynne-Davies, WK Walsh, J Gormley. Achondroplasia and hypochondroplasia. Clinical variation and spinal stenosis.. J Bone Joint Surg Br. 1981;63B:508-15", "Y Xue, A Sun, PB Mekikian, J Martin, DL Rimoin, RS Lachman, WR Wilcox. FGFR3 mutation frequency in 324 cases from the International Skeletal Dysplasia Registry.. Mol Genet Genomic Med. 2014;2:497-503", "N Yasui, H Kawabata, H Kojimoto, H Ohno, S Matsuda, N Araki, Y Shimomura, T Ochi. Lengthening of the lower limbs in patients with achondroplasia and hypochondroplasia.. Clin Orthop Relat Res. 1997:298-306", "ID Young, NR Ruggins, JM Somers, JM Zuccollo, N Rutter. Lethal skeletal dysplasia owing to double heterozygosity for achondroplasia and spondyloepiphyseal dysplasia congenita.. J Med Genet. 1992;29:831-3" ]	15/7/1999	7/5/2020		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
i-p	i-p	[ "Bloch-Sulzberger Syndrome", "Bloch-Sulzberger Syndrome", "NF-kappa-B essential modulator", "IKBKG", "Incontinentia Pigmenti" ]	Incontinentia Pigmenti	Angela E Scheuerle, Matilde Valeria Ursini	Summary Incontinentia pigmenti (IP) is a disorder that affects the skin, hair, teeth, nails, eyes, and central nervous system; it occurs primarily in females and on occasion in males. Characteristic skin lesions evolve through four stages: Blistering (birth to age ~4 months) Wart-like rash (for several months) Swirling macular hyperpigmentation (age ~6 months into adulthood) Linear hypopigmentation Alopecia, hypodontia, abnormal tooth shape, and dystrophic nails are observed. Neovascularization of the retina, present in some individuals, predisposes to retinal detachment. Neurologic findings including seizures, intellectual disability, and developmental delays are occasionally seen. The diagnosis of IP is established in a proband with at least one major criterion (characteristic skin lesion). Identification of a heterozygous IP is inherited in an X-linked manner. About 65% of affected individuals have IP as a result of a	## Diagnosis Incontinentia pigmenti (IP) Note: Though the lesions classically occur in the indicated stages, more than one type of lesion may be present at any time. The locations of the lesions can vary from stage to stage. Note: (1) The presence of minor criteria supports the clinical diagnosis. (2) The diagnosis of IP A heterozygous A hemizygous Mosaicism for an Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ The most efficacious molecular genetic testing approach is Note: Analysis of Note: In affected males, somatic mosaicism can result in failure to detect an For an introduction to multigene panels click Molecular Genetic Testing Used in Incontinentia Pigmenti See See Three of 18 males with IP with somatic mosaicism for the common 11.7-kb deletion [ Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small 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 locus-specific deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, and Southern blotting. Assay designs must account for presence of the Quantitative PCR analysis of Although no evidence of additional loci causing IP has been reported, there remain 4.7% of individuals with IP who have no pathogenic variant in the • A heterozygous • A hemizygous • Mosaicism for an ## Suggestive Findings Incontinentia pigmenti (IP) Note: Though the lesions classically occur in the indicated stages, more than one type of lesion may be present at any time. The locations of the lesions can vary from stage to stage. Note: (1) The presence of minor criteria supports the clinical diagnosis. (2) ## Establishing the Diagnosis The diagnosis of IP A heterozygous A hemizygous Mosaicism for an Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ The most efficacious molecular genetic testing approach is Note: Analysis of Note: In affected males, somatic mosaicism can result in failure to detect an For an introduction to multigene panels click Molecular Genetic Testing Used in Incontinentia Pigmenti See See Three of 18 males with IP with somatic mosaicism for the common 11.7-kb deletion [ Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small 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 locus-specific deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, and Southern blotting. Assay designs must account for presence of the Quantitative PCR analysis of Although no evidence of additional loci causing IP has been reported, there remain 4.7% of individuals with IP who have no pathogenic variant in the • A heterozygous • A hemizygous • Mosaicism for an ## Clinical Characteristics Incontinentia pigmenti (IP) is a disorder of the skin and its appendages, eye, and central nervous system (CNS) that occurs primarily in females and on occasion in males. The largest cohort of individuals with IP in whom the clinical and molecular diagnosis has been confirmed is reported in Evidence that Periventricular leukomalacia was identified on brain MRI in 27 of 43 individuals with IP who have neurocognitive disabilities, especially seizures, and subcortical white matter changes were also seen commonly. Some individuals have subsequent cystic changes. Myelination delays and ventricular dilatation have also been reported [ Survival in a male is mediated through one of two mechanisms: 47,XXY karyotype, estimated to be present in 7% of males with IP [ Somatic mosaicism Low-level mosaicism of 46,XY/47,XXY was demonstrated in one male only by interphase FISH using X and Y probes [ Low-level mosaicism for an Some males also exhibit "segmental" IP (lesions restricted to a single limb), a finding consistent with somatic mosaicism. The reasoning behind male lethality in IP is that male conceptuses that inherit an X chromosome with a mutated Pathogenic variants that produce a milder form of the condition are always associated with immunodeficiency, known as X-linked hypohidrotic ectodermal dysplasia and immunodeficiency (HED-ID), in males [ A group of pathogenic variants (mainly located in exon 10) that result in impaired but not absent NF-kappaB signaling [ Incontinentia pigmenti has high penetrance. Most persons with IP appear to express the phenotype within a few months after birth. Expressivity, however, is highly variable. In addition, the skin findings can resolve over time and may be indistinguishable from other skin conditions with age. Furthermore, the dental, hair, and nail abnormalities can be managed cosmetically such that an affected adult woman may not have clinically evident diagnostic findings on physical examination. Some individuals with structural abnormalities of the X chromosome manifest swirled hyperpigmentation even though their X-chromosome abnormalities do not involve the More than 2,000 females with IP have been reported [ • Evidence that • Periventricular leukomalacia was identified on brain MRI in 27 of 43 individuals with IP who have neurocognitive disabilities, especially seizures, and subcortical white matter changes were also seen commonly. Some individuals have subsequent cystic changes. Myelination delays and ventricular dilatation have also been reported [ • 47,XXY karyotype, estimated to be present in 7% of males with IP [ • Somatic mosaicism • Low-level mosaicism of 46,XY/47,XXY was demonstrated in one male only by interphase FISH using X and Y probes [ • Low-level mosaicism for an • Some males also exhibit "segmental" IP (lesions restricted to a single limb), a finding consistent with somatic mosaicism. • Low-level mosaicism of 46,XY/47,XXY was demonstrated in one male only by interphase FISH using X and Y probes [ • Low-level mosaicism for an • Some males also exhibit "segmental" IP (lesions restricted to a single limb), a finding consistent with somatic mosaicism. • Low-level mosaicism of 46,XY/47,XXY was demonstrated in one male only by interphase FISH using X and Y probes [ • Low-level mosaicism for an • Some males also exhibit "segmental" IP (lesions restricted to a single limb), a finding consistent with somatic mosaicism. ## Clinical Description Incontinentia pigmenti (IP) is a disorder of the skin and its appendages, eye, and central nervous system (CNS) that occurs primarily in females and on occasion in males. The largest cohort of individuals with IP in whom the clinical and molecular diagnosis has been confirmed is reported in Evidence that Periventricular leukomalacia was identified on brain MRI in 27 of 43 individuals with IP who have neurocognitive disabilities, especially seizures, and subcortical white matter changes were also seen commonly. Some individuals have subsequent cystic changes. Myelination delays and ventricular dilatation have also been reported [ Survival in a male is mediated through one of two mechanisms: 47,XXY karyotype, estimated to be present in 7% of males with IP [ Somatic mosaicism Low-level mosaicism of 46,XY/47,XXY was demonstrated in one male only by interphase FISH using X and Y probes [ Low-level mosaicism for an Some males also exhibit "segmental" IP (lesions restricted to a single limb), a finding consistent with somatic mosaicism. The reasoning behind male lethality in IP is that male conceptuses that inherit an X chromosome with a mutated Pathogenic variants that produce a milder form of the condition are always associated with immunodeficiency, known as X-linked hypohidrotic ectodermal dysplasia and immunodeficiency (HED-ID), in males [ • Evidence that • Periventricular leukomalacia was identified on brain MRI in 27 of 43 individuals with IP who have neurocognitive disabilities, especially seizures, and subcortical white matter changes were also seen commonly. Some individuals have subsequent cystic changes. Myelination delays and ventricular dilatation have also been reported [ • 47,XXY karyotype, estimated to be present in 7% of males with IP [ • Somatic mosaicism • Low-level mosaicism of 46,XY/47,XXY was demonstrated in one male only by interphase FISH using X and Y probes [ • Low-level mosaicism for an • Some males also exhibit "segmental" IP (lesions restricted to a single limb), a finding consistent with somatic mosaicism. • Low-level mosaicism of 46,XY/47,XXY was demonstrated in one male only by interphase FISH using X and Y probes [ • Low-level mosaicism for an • Some males also exhibit "segmental" IP (lesions restricted to a single limb), a finding consistent with somatic mosaicism. • Low-level mosaicism of 46,XY/47,XXY was demonstrated in one male only by interphase FISH using X and Y probes [ • Low-level mosaicism for an • Some males also exhibit "segmental" IP (lesions restricted to a single limb), a finding consistent with somatic mosaicism. ## Genotype-Phenotype Correlations A group of pathogenic variants (mainly located in exon 10) that result in impaired but not absent NF-kappaB signaling [ ## Penetrance Incontinentia pigmenti has high penetrance. Most persons with IP appear to express the phenotype within a few months after birth. Expressivity, however, is highly variable. In addition, the skin findings can resolve over time and may be indistinguishable from other skin conditions with age. Furthermore, the dental, hair, and nail abnormalities can be managed cosmetically such that an affected adult woman may not have clinically evident diagnostic findings on physical examination. ## Nomenclature Some individuals with structural abnormalities of the X chromosome manifest swirled hyperpigmentation even though their X-chromosome abnormalities do not involve the ## Prevalence More than 2,000 females with IP have been reported [ ## Genetically Related (Allelic) Disorders ## Differential Diagnosis A diagnosis other than incontinentia pigmenti (IP) should be considered when an individual has skeletal involvement (other than secondary to neurologic deficit), gross neurologic deficit, severe alopecia, atypical hyperpigmentation, or gross hypopigmentation. Body segment asymmetry is not usually associated with IP; however, one individual with IP and transverse terminal upper acromelia has been reported [ The differential diagnosis for the skin manifestations of IP varies by stage. Because a child with IP may have an infectious comorbidity, findings consistent with an infectious disease should be evaluated accordingly, regardless of the presence of IP. Linear and whorled pigmentation changes are a frequent finding in mosaic chromosome abnormalities. Individuals with chromosomal mosaicism often have intellectual disability and congenital malformations, including brain anomalies and the pigmentation abnormalities are present from birth without preceding rashes. Routine karyotyping on blood and/or skin (fibroblast) sample should be considered in these individuals. Hypomelanosis of Ito (OMIM The differential diagnosis of other manifestations of IP includes the following disorders: • Linear and whorled pigmentation changes are a frequent finding in mosaic chromosome abnormalities. Individuals with chromosomal mosaicism often have intellectual disability and congenital malformations, including brain anomalies and the pigmentation abnormalities are present from birth without preceding rashes. Routine karyotyping on blood and/or skin (fibroblast) sample should be considered in these individuals. Hypomelanosis of Ito (OMIM ## Management To establish the extent of disease and needs in an individual diagnosed with incontinentia pigmenti (IP), the following evaluations are recommended if they have not already been completed: Physical examination with particular emphasis on the skin, hair, nails, and neurologic system to establish the presence and extent of manifestations Consultation with a clinical geneticist and/or genetic counselor Involvement of a pediatric dermatologist for management of individuals with significant skin involvement Prompt examination by an ophthalmologist familiar with IP and/or diseases of the retina for evidence of retinal neovascularization Brain MRI examination and referral to a neurologist for an EEG if seizures, other neurologic abnormalities, or retinal hypervascularization are present Magnetic resonance angiography, potentially useful in identifying cerebrovascular lesions if the neurologic deficit is consistent with a stroke-like pattern Developmental evaluation if significant delays are identified Involvement of a pediatric cardiologist for management of neonates with pulmonary hypertension Treatment includes the following: Management of blisters in a standard manner (i.e., not opening them, avoiding trauma); topical treatment (e.g., medications, oatmeal baths) to relieve discomfort. Significant skin involvement may benefit from dermatology management. Treatment of infections as for any other cellulitis Referral to a pedodontist at age six months or when teeth erupt, whichever comes first. Dental implants have been performed as early as age seven years (as in children with ectodermal dysplasia, who have similar dental problems (see Referral to a speech pathologist and/or pediatric nutritionist if delayed or inadequate eruption of primary teeth interferes with chewing and/or speech development For retinal neovascularization that predisposes to retinal detachment, cryotherapy and laser photocoagulation Standard treatment for retinal detachment Referral to a pediatric neurologist for treatment of seizures and if spasticity, focal deficits, or retinal hypervascularization are present Brain MRI in any child with functional neurologic abnormalities or retinal neovascularization Appropriate developmental stimulation and special education as indicated for developmental delay Standard management of neonatal pulmonary hypertension Management in the newborn period is aimed at reducing the risk of infection of blisters using standard medical management: not rupturing sealed blisters, keeping the areas clean while they are healing, and careful monitoring for excessive inflammation and signs of systemic involvement. The parents should be instructed about the possibility of retinal detachment particularly in children younger than age seven years; any apparent changes in vision or any evidence of acquired strabismus should be evaluated promptly. Head trauma may precipitate retinal detachment; therefore, any evaluation for head trauma should include a thorough eye examination. There is currently no specific recommendation for avoidance of contact sports. No schedule for eye examinations has been established, but the following has been suggested: Monthly until age three to four months Every three months between ages four months and one year Every six months between ages one and three years Annually after age three years Neurologic function should be assessed at routine visits with a pediatrician, pediatric neurologist, or developmental pediatrician. Ongoing evaluation by a pedodontist or dentist is appropriate. It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures (routine eye examinations). Evaluations can include: Molecular genetic testing if the pathogenic variant in the family is known; Physical examination including examination of the skin, teeth, hair, nails, retina, and neurologic assessment if the pathogenic variant in the family is not known. See Overall pregnancy health and management usually does not vary from normal. The risk of spontaneous abortion related to fetal viability is higher than population rates, but management of pregnancy loss is done in the standard manner. For women with retinal problems, delivery management to minimize or eliminate labor should be considered to avoid retinal detachment. Search • Physical examination with particular emphasis on the skin, hair, nails, and neurologic system to establish the presence and extent of manifestations • Consultation with a clinical geneticist and/or genetic counselor • Involvement of a pediatric dermatologist for management of individuals with significant skin involvement • Prompt examination by an ophthalmologist familiar with IP and/or diseases of the retina for evidence of retinal neovascularization • Brain MRI examination and referral to a neurologist for an EEG if seizures, other neurologic abnormalities, or retinal hypervascularization are present • Magnetic resonance angiography, potentially useful in identifying cerebrovascular lesions if the neurologic deficit is consistent with a stroke-like pattern • Developmental evaluation if significant delays are identified • Involvement of a pediatric cardiologist for management of neonates with pulmonary hypertension • Management of blisters in a standard manner (i.e., not opening them, avoiding trauma); topical treatment (e.g., medications, oatmeal baths) to relieve discomfort. Significant skin involvement may benefit from dermatology management. • Treatment of infections as for any other cellulitis • Referral to a pedodontist at age six months or when teeth erupt, whichever comes first. Dental implants have been performed as early as age seven years (as in children with ectodermal dysplasia, who have similar dental problems (see • Referral to a speech pathologist and/or pediatric nutritionist if delayed or inadequate eruption of primary teeth interferes with chewing and/or speech development • For retinal neovascularization that predisposes to retinal detachment, cryotherapy and laser photocoagulation • Standard treatment for retinal detachment • Referral to a pediatric neurologist for treatment of seizures and if spasticity, focal deficits, or retinal hypervascularization are present • Brain MRI in any child with functional neurologic abnormalities or retinal neovascularization • Appropriate developmental stimulation and special education as indicated for developmental delay • Standard management of neonatal pulmonary hypertension • Monthly until age three to four months • Every three months between ages four months and one year • Every six months between ages one and three years • Annually after age three years • Molecular genetic testing if the pathogenic variant in the family is known; • Physical examination including examination of the skin, teeth, hair, nails, retina, and neurologic assessment 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 incontinentia pigmenti (IP), the following evaluations are recommended if they have not already been completed: Physical examination with particular emphasis on the skin, hair, nails, and neurologic system to establish the presence and extent of manifestations Consultation with a clinical geneticist and/or genetic counselor Involvement of a pediatric dermatologist for management of individuals with significant skin involvement Prompt examination by an ophthalmologist familiar with IP and/or diseases of the retina for evidence of retinal neovascularization Brain MRI examination and referral to a neurologist for an EEG if seizures, other neurologic abnormalities, or retinal hypervascularization are present Magnetic resonance angiography, potentially useful in identifying cerebrovascular lesions if the neurologic deficit is consistent with a stroke-like pattern Developmental evaluation if significant delays are identified Involvement of a pediatric cardiologist for management of neonates with pulmonary hypertension • Physical examination with particular emphasis on the skin, hair, nails, and neurologic system to establish the presence and extent of manifestations • Consultation with a clinical geneticist and/or genetic counselor • Involvement of a pediatric dermatologist for management of individuals with significant skin involvement • Prompt examination by an ophthalmologist familiar with IP and/or diseases of the retina for evidence of retinal neovascularization • Brain MRI examination and referral to a neurologist for an EEG if seizures, other neurologic abnormalities, or retinal hypervascularization are present • Magnetic resonance angiography, potentially useful in identifying cerebrovascular lesions if the neurologic deficit is consistent with a stroke-like pattern • Developmental evaluation if significant delays are identified • Involvement of a pediatric cardiologist for management of neonates with pulmonary hypertension ## Treatment of Manifestations Treatment includes the following: Management of blisters in a standard manner (i.e., not opening them, avoiding trauma); topical treatment (e.g., medications, oatmeal baths) to relieve discomfort. Significant skin involvement may benefit from dermatology management. Treatment of infections as for any other cellulitis Referral to a pedodontist at age six months or when teeth erupt, whichever comes first. Dental implants have been performed as early as age seven years (as in children with ectodermal dysplasia, who have similar dental problems (see Referral to a speech pathologist and/or pediatric nutritionist if delayed or inadequate eruption of primary teeth interferes with chewing and/or speech development For retinal neovascularization that predisposes to retinal detachment, cryotherapy and laser photocoagulation Standard treatment for retinal detachment Referral to a pediatric neurologist for treatment of seizures and if spasticity, focal deficits, or retinal hypervascularization are present Brain MRI in any child with functional neurologic abnormalities or retinal neovascularization Appropriate developmental stimulation and special education as indicated for developmental delay Standard management of neonatal pulmonary hypertension • Management of blisters in a standard manner (i.e., not opening them, avoiding trauma); topical treatment (e.g., medications, oatmeal baths) to relieve discomfort. Significant skin involvement may benefit from dermatology management. • Treatment of infections as for any other cellulitis • Referral to a pedodontist at age six months or when teeth erupt, whichever comes first. Dental implants have been performed as early as age seven years (as in children with ectodermal dysplasia, who have similar dental problems (see • Referral to a speech pathologist and/or pediatric nutritionist if delayed or inadequate eruption of primary teeth interferes with chewing and/or speech development • For retinal neovascularization that predisposes to retinal detachment, cryotherapy and laser photocoagulation • Standard treatment for retinal detachment • Referral to a pediatric neurologist for treatment of seizures and if spasticity, focal deficits, or retinal hypervascularization are present • Brain MRI in any child with functional neurologic abnormalities or retinal neovascularization • Appropriate developmental stimulation and special education as indicated for developmental delay • Standard management of neonatal pulmonary hypertension ## Prevention of Secondary Complications Management in the newborn period is aimed at reducing the risk of infection of blisters using standard medical management: not rupturing sealed blisters, keeping the areas clean while they are healing, and careful monitoring for excessive inflammation and signs of systemic involvement. The parents should be instructed about the possibility of retinal detachment particularly in children younger than age seven years; any apparent changes in vision or any evidence of acquired strabismus should be evaluated promptly. Head trauma may precipitate retinal detachment; therefore, any evaluation for head trauma should include a thorough eye examination. There is currently no specific recommendation for avoidance of contact sports. ## Surveillance No schedule for eye examinations has been established, but the following has been suggested: Monthly until age three to four months Every three months between ages four months and one year Every six months between ages one and three years Annually after age three years Neurologic function should be assessed at routine visits with a pediatrician, pediatric neurologist, or developmental pediatrician. Ongoing evaluation by a pedodontist or dentist is appropriate. • Monthly until age three to four months • Every three months between ages four months and one year • Every six months between ages one and three years • Annually after age three years ## Evaluation of Relatives at Risk It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures (routine eye examinations). Evaluations can include: Molecular genetic testing if the pathogenic variant in the family is known; Physical examination including examination of the skin, teeth, hair, nails, retina, and neurologic assessment if the pathogenic variant in the family is not known. See • Molecular genetic testing if the pathogenic variant in the family is known; • Physical examination including examination of the skin, teeth, hair, nails, retina, and neurologic assessment if the pathogenic variant in the family is not known. ## Pregnancy Management Overall pregnancy health and management usually does not vary from normal. The risk of spontaneous abortion related to fetal viability is higher than population rates, but management of pregnancy loss is done in the standard manner. For women with retinal problems, delivery management to minimize or eliminate labor should be considered to avoid retinal detachment. ## Therapies Under Investigation Search ## Genetic Counseling Incontinentia pigmenti (IP) is inherited in an X-linked manner. A female with IP may have inherited the When IP occurs as the result of a If the mother meets the diagnostic criteria for IP or if she has an additional affected first-degree relative, she has a pathogenic variant in If the pathogenic variant in If a male proband has IP as the result of mosaicism for a postzygotic If a male proband has a 47,XXY karyotype, his mother may be heterozygous for an If the mother of an affected female is also affected, the risk to sibs of inheriting the If the mother with IP has an If the proband represents a simplex case (i.e., a single occurrence in a family) and if the The risk to the offspring of females with IP must take into consideration the presumed lethality to affected males during gestation ( At conception, the risk that the When a mother with IP has an To date, all males with IP have had either an 47,XXY karyotype or somatic mosaicism for the An affected male with somatic mosaicism that includes the germline may transmit the If a parent of the proband has an X-chromosome inactivation studies to look for evidence of skewing can be helpful in identifying female relatives who have an See Management, As with many other genetic conditions, diagnosis of IP in a newborn may result in evaluation and diagnosis of the mother or other family members who were previously unaware of the presence of a genetic disorder in the family. The diagnosis of IP in a newborn can be difficult for the mother and her relatives because of implications for their health and because of a sense of "responsibility" for illness in their offspring. Efforts should be made to anticipate these 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, have an Once the Because the prognosis for affected females differs from that for affected males, the fetal karyotype must be determined for accurate genetic counseling. If the fetal karyotype is 46,XX, parents should be informed that 50% of fetuses are likely to be affected with IP. If the fetal karyotype is 46,XY, counseling should include discussion of the increased risk of miscarriage of affected males after the first trimester. If the fetal karyotype is 47,XXY, counseling should include a discussion of the more severe IP phenotype in males and a discussion of Klinefelter syndrome. Note: A group of pathogenic variants (mostly in exon 10) that result in a milder IP phenotype in females are associated with a lower risk for miscarriage (see • A female with IP may have inherited the • When IP occurs as the result of a • If the mother meets the diagnostic criteria for IP or if she has an additional affected first-degree relative, she has a pathogenic variant in • If the pathogenic variant in • If a male proband has IP as the result of mosaicism for a postzygotic • If a male proband has a 47,XXY karyotype, his mother may be heterozygous for an • • If the mother of an affected female is also affected, the risk to sibs of inheriting the • If the mother with IP has an • If the mother of an affected female is also affected, the risk to sibs of inheriting the • If the mother with IP has an • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the • If the mother of an affected female is also affected, the risk to sibs of inheriting the • If the mother with IP has an • The risk to the offspring of females with IP must take into consideration the presumed lethality to affected males during gestation ( • At conception, the risk that the • When a mother with IP has an • To date, all males with IP have had either an 47,XXY karyotype or somatic mosaicism for the • An affected male with somatic mosaicism that includes the germline may transmit the • If a parent of the proband has an • X-chromosome inactivation studies to look for evidence of skewing can be helpful in identifying female relatives who have an • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, have an • If the fetal karyotype is 46,XX, parents should be informed that 50% of fetuses are likely to be affected with IP. • If the fetal karyotype is 46,XY, counseling should include discussion of the increased risk of miscarriage of affected males after the first trimester. • If the fetal karyotype is 47,XXY, counseling should include a discussion of the more severe IP phenotype in males and a discussion of Klinefelter syndrome. ## Mode of Inheritance Incontinentia pigmenti (IP) is inherited in an X-linked manner. ## Risk to Family Members A female with IP may have inherited the When IP occurs as the result of a If the mother meets the diagnostic criteria for IP or if she has an additional affected first-degree relative, she has a pathogenic variant in If the pathogenic variant in If a male proband has IP as the result of mosaicism for a postzygotic If a male proband has a 47,XXY karyotype, his mother may be heterozygous for an If the mother of an affected female is also affected, the risk to sibs of inheriting the If the mother with IP has an If the proband represents a simplex case (i.e., a single occurrence in a family) and if the The risk to the offspring of females with IP must take into consideration the presumed lethality to affected males during gestation ( At conception, the risk that the When a mother with IP has an To date, all males with IP have had either an 47,XXY karyotype or somatic mosaicism for the An affected male with somatic mosaicism that includes the germline may transmit the If a parent of the proband has an X-chromosome inactivation studies to look for evidence of skewing can be helpful in identifying female relatives who have an • A female with IP may have inherited the • When IP occurs as the result of a • If the mother meets the diagnostic criteria for IP or if she has an additional affected first-degree relative, she has a pathogenic variant in • If the pathogenic variant in • If a male proband has IP as the result of mosaicism for a postzygotic • If a male proband has a 47,XXY karyotype, his mother may be heterozygous for an • • If the mother of an affected female is also affected, the risk to sibs of inheriting the • If the mother with IP has an • If the mother of an affected female is also affected, the risk to sibs of inheriting the • If the mother with IP has an • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the • If the mother of an affected female is also affected, the risk to sibs of inheriting the • If the mother with IP has an • The risk to the offspring of females with IP must take into consideration the presumed lethality to affected males during gestation ( • At conception, the risk that the • When a mother with IP has an • To date, all males with IP have had either an 47,XXY karyotype or somatic mosaicism for the • An affected male with somatic mosaicism that includes the germline may transmit the • If a parent of the proband has an • X-chromosome inactivation studies to look for evidence of skewing can be helpful in identifying female relatives who have an ## Related Genetic Counseling Issues See Management, As with many other genetic conditions, diagnosis of IP in a newborn may result in evaluation and diagnosis of the mother or other family members who were previously unaware of the presence of a genetic disorder in the family. The diagnosis of IP in a newborn can be difficult for the mother and her relatives because of implications for their health and because of a sense of "responsibility" for illness in their offspring. Efforts should be made to anticipate these 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, have an • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, have an ## Prenatal Testing and Preimplantation Genetic Testing Once the Because the prognosis for affected females differs from that for affected males, the fetal karyotype must be determined for accurate genetic counseling. If the fetal karyotype is 46,XX, parents should be informed that 50% of fetuses are likely to be affected with IP. If the fetal karyotype is 46,XY, counseling should include discussion of the increased risk of miscarriage of affected males after the first trimester. If the fetal karyotype is 47,XXY, counseling should include a discussion of the more severe IP phenotype in males and a discussion of Klinefelter syndrome. Note: A group of pathogenic variants (mostly in exon 10) that result in a milder IP phenotype in females are associated with a lower risk for miscarriage (see • If the fetal karyotype is 46,XX, parents should be informed that 50% of fetuses are likely to be affected with IP. • If the fetal karyotype is 46,XY, counseling should include discussion of the increased risk of miscarriage of affected males after the first trimester. • If the fetal karyotype is 47,XXY, counseling should include a discussion of the more severe IP phenotype in males and a discussion of Klinefelter syndrome. ## Resources Via Altair, 5 00012 Guidonia Montecelio Italy 30 East 72nd Street New York NY 10021 PO Box 5801 Bethesda MD 20824 IGB-CNR Via P. Castellino, 111 Naples 80131 Italy • • Via Altair, 5 • 00012 Guidonia Montecelio • Italy • • • 30 East 72nd Street • New York NY 10021 • • • PO Box 5801 • Bethesda MD 20824 • • • • • IGB-CNR • Via P. Castellino, 111 • Naples 80131 • Italy • ## Molecular Genetics Incontinentia Pigmenti: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Incontinentia Pigmenti ( The genomic organization around A 11.7-kb deletion of exons 4-10 in A duplication of MER67B (lower green chromosome schematic) that replicates the exon 4-10 region downstream of the normal Both variants were rare normal variants in a control population [ Small intragenic substitutions, deletions, and duplications are scattered throughout Smaller pathogenic variants in Selected Variants listed in the table have been provided by the authors. IKK-gamma is produced beginning in early embryogenesis and is expressed ubiquitously [ The 11.7-kb deletion results in a lack of NF-kappaB activation and extreme susceptibility to apoptosis, thus explaining the embryonic death in males and extremely skewed X-chromosome inactivation in females with IP [ • A 11.7-kb deletion of exons 4-10 in • A duplication of MER67B (lower green chromosome schematic) that replicates the exon 4-10 region downstream of the normal ## Molecular Pathogenesis The genomic organization around A 11.7-kb deletion of exons 4-10 in A duplication of MER67B (lower green chromosome schematic) that replicates the exon 4-10 region downstream of the normal Both variants were rare normal variants in a control population [ Small intragenic substitutions, deletions, and duplications are scattered throughout Smaller pathogenic variants in Selected Variants listed in the table have been provided by the authors. IKK-gamma is produced beginning in early embryogenesis and is expressed ubiquitously [ The 11.7-kb deletion results in a lack of NF-kappaB activation and extreme susceptibility to apoptosis, thus explaining the embryonic death in males and extremely skewed X-chromosome inactivation in females with IP [ • A 11.7-kb deletion of exons 4-10 in • A duplication of MER67B (lower green chromosome schematic) that replicates the exon 4-10 region downstream of the normal ## Chapter Notes David L Nelson, PhD; Baylor College of Medicine (1996-2010)Angela Scheuerle, MD, FAAP, FACMG (1996-present)Matilde Valeria Ursini, PhD (2010-present) Dr Scheuerle's research included above was done at Baylor College of Medicine in the laboratory of Dr David Nelson. Dr Ursini's work was supported by the Incontinentia Pigmenti International Foundation ( 3 April 2025 (ma) Revision: prevalence data updated 21 December 2017 (sw) Comprehensive update posted live 12 February 2015 (me) Comprehensive update posted live 28 October 2010 (me) Comprehensive update posted live 4 October 2007 (me) Comprehensive update posted live 31 March 2005 (me) Comprehensive update posted live 27 March 2003 (me) Comprehensive update posted live 19 December 2000 (me) Comprehensive update posted live 8 June 1999 (pb) Review posted live 22 December 1998 (as) Original submission • 3 April 2025 (ma) Revision: prevalence data updated • 21 December 2017 (sw) Comprehensive update posted live • 12 February 2015 (me) Comprehensive update posted live • 28 October 2010 (me) Comprehensive update posted live • 4 October 2007 (me) Comprehensive update posted live • 31 March 2005 (me) Comprehensive update posted live • 27 March 2003 (me) Comprehensive update posted live • 19 December 2000 (me) Comprehensive update posted live • 8 June 1999 (pb) Review posted live • 22 December 1998 (as) Original submission ## Author History David L Nelson, PhD; Baylor College of Medicine (1996-2010)Angela Scheuerle, MD, FAAP, FACMG (1996-present)Matilde Valeria Ursini, PhD (2010-present) ## Acknowledgments Dr Scheuerle's research included above was done at Baylor College of Medicine in the laboratory of Dr David Nelson. Dr Ursini's work was supported by the Incontinentia Pigmenti International Foundation ( ## Revision History 3 April 2025 (ma) Revision: prevalence data updated 21 December 2017 (sw) Comprehensive update posted live 12 February 2015 (me) Comprehensive update posted live 28 October 2010 (me) Comprehensive update posted live 4 October 2007 (me) Comprehensive update posted live 31 March 2005 (me) Comprehensive update posted live 27 March 2003 (me) Comprehensive update posted live 19 December 2000 (me) Comprehensive update posted live 8 June 1999 (pb) Review posted live 22 December 1998 (as) Original submission • 3 April 2025 (ma) Revision: prevalence data updated • 21 December 2017 (sw) Comprehensive update posted live • 12 February 2015 (me) Comprehensive update posted live • 28 October 2010 (me) Comprehensive update posted live • 4 October 2007 (me) Comprehensive update posted live • 31 March 2005 (me) Comprehensive update posted live • 27 March 2003 (me) Comprehensive update posted live • 19 December 2000 (me) Comprehensive update posted live • 8 June 1999 (pb) Review posted live • 22 December 1998 (as) Original submission ## References ## Literature Cited IP in an affected female; stage I: the bullous ("blistering") stage. Note that the blisters are not necessarily linear. IP in an affected female; stage II: the verrucous ("warty") stage. The lesions do not necessarily arise in the same place as those of stage I. IP in an affected female with stage III "rash" An adult with reticulated pigmentation patterns Genotype of conceptuses compared with genotype of live-born children Recurrent and non-recurrent rearrangements in IP locus. The inverted repeats are depicted on the top line by the two large regions outlined by inverted boxes and containing both MER67B repeats (red arrows). The location of real-time PCR amplicons assayed to delineate the deletions are labeled PF, P1, P2, etc. See text and	[]	8/6/1999	21/12/2017	3/4/2025	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
iahsp	iahsp	[ "Infantile-Onset Ascending Hereditary Spastic Paralysis (IAHSP)", "Juvenile Primary Lateral Sclerosis (JPLS)", "Juvenile Amyotrophic Lateral Sclerosis (JALS)", "Alsin", "ALS2", "ALS2-Related Disorder" ]		Richard W Orrell	Summary The diagnosis of	Infantile-onset ascending hereditary spastic paralysis (IAHSP) Juvenile primary lateral sclerosis (JPLS) Juvenile amyotrophic lateral sclerosis (JALS) For other genetic causes of these phenotypes see • Infantile-onset ascending hereditary spastic paralysis (IAHSP) • Juvenile primary lateral sclerosis (JPLS) • Juvenile amyotrophic lateral sclerosis (JALS) ## Diagnosis No consensus clinical diagnostic criteria for Childhood onset of progressive upper motor neuron involvement (spasticity affecting the legs and upper limbs) Variably lower motor neuron involvement (muscle atrophy and sensory disturbances) Later pseudobulbar involvement including speech Preservation of cognitive function Electrophysiologic Studies in EMG = electromyography; IAHSP = infantile-onset ascending hereditary spastic paralysis; JALS = juvenile amyotrophic lateral sclerosis; JPLS = juvenile primary lateral sclerosis; MEP = motor evoked potentials; NA = not available; SSEP = somatosensory evoked potentials; TCMS = transcranial magnetic stimulation Primitive, pure degeneration of the upper motor neurons Older individuals have: Brain cortical atrophy predominant in the motor areas; T In addition, it is common to find T 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: Identification of biallelic Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in 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 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; however, loss of • Childhood onset of progressive upper motor neuron involvement (spasticity affecting the legs and upper limbs) • Variably lower motor neuron involvement (muscle atrophy and sensory disturbances) • Later pseudobulbar involvement including speech • Preservation of cognitive function • Brain cortical atrophy predominant in the motor areas; • T ## Suggestive Findings Childhood onset of progressive upper motor neuron involvement (spasticity affecting the legs and upper limbs) Variably lower motor neuron involvement (muscle atrophy and sensory disturbances) Later pseudobulbar involvement including speech Preservation of cognitive function Electrophysiologic Studies in EMG = electromyography; IAHSP = infantile-onset ascending hereditary spastic paralysis; JALS = juvenile amyotrophic lateral sclerosis; JPLS = juvenile primary lateral sclerosis; MEP = motor evoked potentials; NA = not available; SSEP = somatosensory evoked potentials; TCMS = transcranial magnetic stimulation Primitive, pure degeneration of the upper motor neurons Older individuals have: Brain cortical atrophy predominant in the motor areas; T In addition, it is common to find T 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. • Childhood onset of progressive upper motor neuron involvement (spasticity affecting the legs and upper limbs) • Variably lower motor neuron involvement (muscle atrophy and sensory disturbances) • Later pseudobulbar involvement including speech • Preservation of cognitive function • Brain cortical atrophy predominant in the motor areas; • T ## Clinical Findings Childhood onset of progressive upper motor neuron involvement (spasticity affecting the legs and upper limbs) Variably lower motor neuron involvement (muscle atrophy and sensory disturbances) Later pseudobulbar involvement including speech Preservation of cognitive function • Childhood onset of progressive upper motor neuron involvement (spasticity affecting the legs and upper limbs) • Variably lower motor neuron involvement (muscle atrophy and sensory disturbances) • Later pseudobulbar involvement including speech • Preservation of cognitive function ## Electrophysiologic Findings Electrophysiologic Studies in EMG = electromyography; IAHSP = infantile-onset ascending hereditary spastic paralysis; JALS = juvenile amyotrophic lateral sclerosis; JPLS = juvenile primary lateral sclerosis; MEP = motor evoked potentials; NA = not available; SSEP = somatosensory evoked potentials; TCMS = transcranial magnetic stimulation Primitive, pure degeneration of the upper motor neurons ## Neuroimaging Findings Older individuals have: Brain cortical atrophy predominant in the motor areas; T In addition, it is common to find T • Brain cortical atrophy predominant in the motor areas; • T ## 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: Identification of biallelic Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in 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 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; however, loss 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 Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and 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. No data on detection rate of gene-targeted deletion/duplication analysis are available; however, loss of ## Clinical Characteristics Pathogenic variants in An increasing number of individuals have been identified with biallelic pathogenic variants in Feeding difficulties, especially in swallowing liquids, may manifest in the second decade; however, those few individuals with long-term follow up who have reached their 30s have neither experienced recurrent bronchopneumonia nor required feeding gastrostomy. Some individuals in the advanced stage of disease are reported to require feeding by gastrostomy tube and to lose bladder and sphincter functions [ Overall, IAHSP is compatible with long survival. Cognitive function is preserved. Intrafamilial variability can be considerable: in one family with two affected sibs with onset in early childhood, one began using a wheelchair at age two years (and was alive at age 42 years); the other began using a wheelchair at age 50 years (and was alive at age 55 years) [ In some instances, the same entity may be referred to as either juvenile primary lateral sclerosis (JPLS) or infantile ascending hereditary spastic paraplegia (IAHSP). JALS may also be referred to as JALS/ALS2. No data on prevalence are available; however, ## Clinical Description Pathogenic variants in An increasing number of individuals have been identified with biallelic pathogenic variants in Feeding difficulties, especially in swallowing liquids, may manifest in the second decade; however, those few individuals with long-term follow up who have reached their 30s have neither experienced recurrent bronchopneumonia nor required feeding gastrostomy. Some individuals in the advanced stage of disease are reported to require feeding by gastrostomy tube and to lose bladder and sphincter functions [ Overall, IAHSP is compatible with long survival. Cognitive function is preserved. Intrafamilial variability can be considerable: in one family with two affected sibs with onset in early childhood, one began using a wheelchair at age two years (and was alive at age 42 years); the other began using a wheelchair at age 50 years (and was alive at age 55 years) [ ## Genotype-Phenotype Correlations ## Nomenclature In some instances, the same entity may be referred to as either juvenile primary lateral sclerosis (JPLS) or infantile ascending hereditary spastic paraplegia (IAHSP). JALS may also be referred to as JALS/ALS2. ## Prevalence No data on prevalence are available; however, ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis For a detailed discussion of HSP and the differential diagnosis of HSP, see the The hereditary spastic paraplegias are clinically and genetically heterogeneous disorders characterized by insidiously progressive lower-extremity weakness and spasticity. Hereditary spastic paraplegia may be transmitted in an autosomal dominant, autosomal recessive, X-linked, or maternally inherited (mitochondrial) manner. Children with autosomal dominant HSP and with congenital onset of spasticity ( ARHSP caused by pathogenic variants in Metabolic causes of progressive HSP include Note: PLS, defined as the presence of slowly progressive, uncomplicated signs of upper motor neuron disease in persons in whom all other known causes of spasticity have been eliminated, has been reported in adults with an isolated degenerative process of the upper motor neurons. Phenotypic overlap has not been described between PLS and For a detailed discussion of ALS and the differential diagnosis of ALS, see ## Hereditary Spastic Paraplegia (HSP) For a detailed discussion of HSP and the differential diagnosis of HSP, see the The hereditary spastic paraplegias are clinically and genetically heterogeneous disorders characterized by insidiously progressive lower-extremity weakness and spasticity. Hereditary spastic paraplegia may be transmitted in an autosomal dominant, autosomal recessive, X-linked, or maternally inherited (mitochondrial) manner. Children with autosomal dominant HSP and with congenital onset of spasticity ( ARHSP caused by pathogenic variants in Metabolic causes of progressive HSP include Note: PLS, defined as the presence of slowly progressive, uncomplicated signs of upper motor neuron disease in persons in whom all other known causes of spasticity have been eliminated, has been reported in adults with an isolated degenerative process of the upper motor neurons. Phenotypic overlap has not been described between PLS and ## Amyotrophic Lateral Sclerosis (ALS) For a detailed discussion of ALS and the differential diagnosis of ALS, see ## Management No clinical practice guidelines specifically for To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with Motor, adaptive, cognitive, & speech/language eval Eval for early intervention / special education Gross motor & fine motor skills Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) To incl eval of aspiration risk & nutritional status Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk. Use of community resources, Need for social work involvement for parental support; Need for home nursing referral. ADL = activities of daily living; LMN = lower motor neuron; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; UMN = upper motor neuron Medical geneticist, certified genetic counselor, certified advanced genetic nurse Management by multidisciplinary specialists, including neurology, orthopedics, physical therapy, occupational therapy, speech and language therapy, and feeding specialists (gastroenterology, nutrition) is recommended. Treatment of Manifestations in Individuals with Stretching to help avoid contractures & fractures Consider need for orthotics, positioning & mobility devices (e.g., motorized chairs), & disability parking placard. Ensure appropriate social work involvement to connect families with local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ADL = activities of daily living; LMN = lower motor neuron; OT = occupational therapy; PT = physical therapy; UMN = upper motor neuron The following information represents typical management recommendations for individuals with developmental / intellectual educational issues 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, and modified assignments. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated 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 ADL = activities of daily living; OT = occupational therapy; PT = physical therapy See Search • Motor, adaptive, cognitive, & speech/language eval • Eval for early intervention / special education • Gross motor & fine motor skills • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • To incl eval of aspiration risk & nutritional status • Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk. • Use of community resources, • Need for social work involvement for parental support; • Need for home nursing referral. • Stretching to help avoid contractures & fractures • Consider need for orthotics, positioning & mobility devices (e.g., motorized chairs), & disability parking placard. • Ensure appropriate social work involvement to connect families with 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. • Special education law requires that children participating in 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, and modified assignments. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated 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. ## 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 Motor, adaptive, cognitive, & speech/language eval Eval for early intervention / special education Gross motor & fine motor skills Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) To incl eval of aspiration risk & nutritional status Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk. Use of community resources, Need for social work involvement for parental support; Need for home nursing referral. ADL = activities of daily living; LMN = lower motor neuron; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; UMN = upper motor neuron Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Motor, adaptive, cognitive, & speech/language eval • Eval for early intervention / special education • Gross motor & fine motor skills • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • To incl eval of aspiration risk & nutritional status • Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk. • Use of community resources, • Need for social work involvement for parental support; • Need for home nursing referral. ## Treatment of Manifestations Management by multidisciplinary specialists, including neurology, orthopedics, physical therapy, occupational therapy, speech and language therapy, and feeding specialists (gastroenterology, nutrition) is recommended. Treatment of Manifestations in Individuals with Stretching to help avoid contractures & fractures Consider need for orthotics, positioning & mobility devices (e.g., motorized chairs), & disability parking placard. Ensure appropriate social work involvement to connect families with local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ADL = activities of daily living; LMN = lower motor neuron; OT = occupational therapy; PT = physical therapy; UMN = upper motor neuron The following information represents typical management recommendations for individuals with developmental / intellectual educational issues 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, and modified assignments. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • Stretching to help avoid contractures & fractures • Consider need for orthotics, positioning & mobility devices (e.g., motorized chairs), & disability parking placard. • Ensure appropriate social work involvement to connect families with 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. • Special education law requires that children participating in 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, and modified assignments. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated 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/Educational Management Issues The following information represents typical management recommendations for individuals with developmental / intellectual educational issues 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, and modified assignments. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated 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, and modified assignments. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated 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 ADL = activities of daily living; OT = occupational therapy; PT = physical therapy ## 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 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 Intrafamilial variability is recognized. For example, 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 obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • 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 • Intrafamilial variability is recognized. For example, • 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 obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. 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 is recognized. For example, 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 • 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 • Intrafamilial variability is recognized. For example, • 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 United Kingdom • • • • • • • • Canada • • • • • United Kingdom • • • • • ## Molecular Genetics ALS2-Related Disorder: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for ALS2-Related Disorder ( Biallelic pathogenic variants of ## Molecular Pathogenesis Biallelic pathogenic variants of ## Chapter Notes Dr Orrell is Associate Professor in Clinical Neurosciences at UCL Queen Square Institute of Neurology, and Consultant Neurologist at Royal Free London Hospital and National Hospital for Neurology and Neurosurgery, London. He has longstanding research and clinical interests in the genetics, pathogenesis, experimental therapeutics, and management of patients with motor neuron diseases, including ALS. Dr Orrell acknowledges support from the Motor Neurone Disease Association. Enrico S Bertini, MD; Ospedale Bambino Gesu, Rome (2005-2016)Odile Boespflug-Tanguy, MD, PhD; Institut National de la Santé et de la Recherche Médicale, Clermont-Ferrand (2005-2016)Don W Cleveland, PhD, University of California San Diego (2005-2016)Eleonore Eymard-Pierre, PhD; Institut National de la Santé et de la Recherche Médicale, Clermont-Ferrand (2005-2016)Richard W Orrell, BSc, MD, FRCP (2016-present)Koji Yamanaka, MD, PhD; RIKEN Brain Science Institute, Wako (2005-2016) 13 May 2021 (bp) Comprehensive update posted live 28 January 2016 (me) Comprehensive update posted live 18 April 2013 (tb) Revision: information on mutations in 10 February 2011 (me) Comprehensive update posted live 21 October 2005 (me) Review posted live 16 December 2004 (esb) Original submission • 13 May 2021 (bp) Comprehensive update posted live • 28 January 2016 (me) Comprehensive update posted live • 18 April 2013 (tb) Revision: information on mutations in • 10 February 2011 (me) Comprehensive update posted live • 21 October 2005 (me) Review posted live • 16 December 2004 (esb) Original submission ## Author Notes Dr Orrell is Associate Professor in Clinical Neurosciences at UCL Queen Square Institute of Neurology, and Consultant Neurologist at Royal Free London Hospital and National Hospital for Neurology and Neurosurgery, London. He has longstanding research and clinical interests in the genetics, pathogenesis, experimental therapeutics, and management of patients with motor neuron diseases, including ALS. ## Acknowledgments Dr Orrell acknowledges support from the Motor Neurone Disease Association. ## Author History Enrico S Bertini, MD; Ospedale Bambino Gesu, Rome (2005-2016)Odile Boespflug-Tanguy, MD, PhD; Institut National de la Santé et de la Recherche Médicale, Clermont-Ferrand (2005-2016)Don W Cleveland, PhD, University of California San Diego (2005-2016)Eleonore Eymard-Pierre, PhD; Institut National de la Santé et de la Recherche Médicale, Clermont-Ferrand (2005-2016)Richard W Orrell, BSc, MD, FRCP (2016-present)Koji Yamanaka, MD, PhD; RIKEN Brain Science Institute, Wako (2005-2016) ## Revision History 13 May 2021 (bp) Comprehensive update posted live 28 January 2016 (me) Comprehensive update posted live 18 April 2013 (tb) Revision: information on mutations in 10 February 2011 (me) Comprehensive update posted live 21 October 2005 (me) Review posted live 16 December 2004 (esb) Original submission • 13 May 2021 (bp) Comprehensive update posted live • 28 January 2016 (me) Comprehensive update posted live • 18 April 2013 (tb) Revision: information on mutations in • 10 February 2011 (me) Comprehensive update posted live • 21 October 2005 (me) Review posted live • 16 December 2004 (esb) Original submission ## References ## Literature Cited	[ "M Ben Hamida, F Hentati, C Ben Hamida. Hereditary motor system diseases (chronic juvenile amyotrophic lateral sclerosis). Conditions combining a bilateral pyramidal syndrome with limb and bulbar amyotrophy.. Brain 1990;113:347-63", "R Borg, MF Wismayer, K Bonavia, AF Wismayer, M Vella, JJFA Vugt, BJ Kenna, KP Kenna, N Vassallo, JH Veldink, RJ Cauchi. Genetic analysis of ALS cases in the isolated island population of Malta.. Eur J Hum Genet. 2021;29:604-14", "F Brugman, E Eymard-Pierre, LH van den Berg, JH Wokke, F Gauthier-Barichard, O Boespflug-Tanguy. Adult-onset primary lateral sclerosis is not associated with mutations in the ALS2 gene.. Neurology 2007;69:702-4", "RS Devon, JR Helm, GA Rouleau, Y Leitner, T Lerman-Sagie, D Lev, MR Hayden. The first nonsense mutation in alsin results in a homogeneous phenotype of infantile-onset ascending spastic paralysis with bulbar involvement in two siblings.. Clin Genet 2003;64:210-5", "E Eymard-Pierre, G Lesca, S Dollet, FM Santorelli, M di Capua, E Bertini, O Boespflug-Tanguy. Infantile-onset ascending hereditary spastic paralysis is associated with mutations in the alsin gene.. Am J Hum Genet 2002;71:518-27", "E Eymard-Pierre, K Yamanaka, M Haeussler, W Kress, F Gauthier-Barichard, P Combes, DW Cleveland, O Boespflug-Tanguy. Novel missense mutation in ALS2 gene results in infantile ascending hereditary spastic paralysis.. Ann Neurol. 2006;59:976-80", "F Gros-Louis, IA Meijer, CK Hand, MP Dube, DL MacGregor, MH Seni, RS Devon, MR Hayden, F Andermann, E Andermann, GA Rouleau. An ALS2 gene mutation causes hereditary spastic paraplegia in a Pakistani kindred.. Ann Neurol 2003;53:144-5", "S Hadano, CK Hand, H Osuga, Y Yanagisawa, A Otomo, RS Devon, N Miyamoto, J Showguchi-Miyata, Y Okada, R Singaraja, DA Figlewicz, T Kwiatkowski, BA Hosler, T Sagie, J Skaug, J Nasir, RH Brown, SW Scherer, GA Rouleau, MR Hayden, JE Ikeda. A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2.. Nat Genet 2001;29:166-73", "A Hentati, K Bejaoui, MA Pericak-Vance, F Hentati, MC Speer, WY Hung, DA Figlewicz, J Haines, J Rimmler, C Ben Hamida. Linkage of recessive familial amyotrophic lateral sclerosis to chromosome 2q33-q35.. Nat Genet. 1994;7:425-8", "T Herzfeld, N Wolf, P Winter, H Hackstein, D Vater, U Müller. Maternal uniparental heterodisomy with partial isodisomy of a chromosome 2 carrying a splice acceptor site mutation (IVS9-2A>T) in ALS2 causes infantile-onset ascending spastic paralysis (IAHSP). Neurogenetics 2009;10:59-64", "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 Kress, P Kühnlein, P Winter, AC Ludolph, J Kassubek, U Müller, AD Sperfeld. Novel mutation in the ALS2 gene in juvenile amyotrophic lateral sclerosis.. Ann Neurol. 2005;58:800-3", "G Lesca, E Eymard-Pierre, FM Santorelli, R Cusmai, M Di Capua, EM Valente, J Attia-Sobol, H Plauchu, V Leuzzi, A Ponzone, O Boespflug-Tanguy, E Bertini. Infantile ascending hereditary spastic paralysis (IAHSP): clinical features in 11 families.. Neurology 2003;60:674-82", "J Lin, W Chen, P Huang, Y Xie, M Zheng, X Yao. The distinct manifestation of young-onset amyotrophic lateral sclerosis in China.. Amyotroph Lateral Scler Frontotemporal Degener. 2021;22:30-7", "N Mintchev, E Zamba-Papanicolaou, KA Kleopa, K Christodoulou. A novel ALS2 splice-site mutation in a Cypriot juvenile-onset primary lateral sclerosis family.. Neurology 2009;72:28-32", "E Nogueira, J Alarcon, C Garma, C. Paredes. ALS2-related disorders in Spanish children.. Neurol Sci. 2021;42:2091-4", "C Panzeri, C De Palma, A Martinuzzi, A Daga, G De Polo, N Bresolin, CC Miller, EL Tudor, E Clementi, MT Bassi. The first ALS2 missense mutation associated with JPLS reveals new aspects of alsin biological function.. Brain. 2006;129:1710-9", "U-M Sheerin, SA Schneider, L Carr, G Deuschl, F Hopfner, M Stamelou, NW Wood, KP Bhatia. ALS2 mutations. Juvenile amyotrophic lateral sclerosis and generalized dystonia.. Neurology 2014;82:1065-7", "SR Shepheard, MD Parker, J Cooper-Knock, NS Verber, L Tuddenham, P Heath, N Beauchamp, E Place, ESA Sollars, MR Turner, A Malaspina, P Fratta, C Hewamadduma, TM Jenkins, CJ McDermott, D Wang, J Kirby, PJ Shaw. Value of systematic genetic screening of patients with amyotrophic lateral sclerosis.. J Neurol Neurosurg Psychiatry. 2021;92:510-8", "K Shirakawa, H Suzuki, M Ito, S Kono, T Uchiyama, T Ohashi, H Miyajima. Novel compound heterozygous ALS2 mutations cause juvenile amyotrophic lateral sclerosis in Japan.. Neurology. 2009;73:2124-6", "M Simone, A Trabacca, E Panzeri, L Losito, A Citterio, MT Bassi. KIF5A and ALS2 variants in a family with hereditary spastic paraplegia and amyotrophic lateral sclerosis.. Front Neurol 2018;9:1078", "R Sprute, H Jergas, A Olmez, S Alawbathani, H Karasoy, HS Dafsari, K Becker, H-S Daimaguler, P Nurnberg, F Muntoni, H Topaloglu, G Uyanik, S Cirak. Genotype-phenotype correlation in seven motor neuron disease families with novel ALS2 mutations.. Am J Med Genet A. 2021;185:344-54", "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", "L Sztriha, C Panzeri, R Kálmánchey, N Szabó, E Endreffy, S Túri, C Baschirotto, N Bresolin, Z Vekerdy, MT Bassi. First case of compound heterozygosity in ALS2 gene in infantile-onset ascending spastic paralysis with bulbar involvement.. Clin Genet. 2008;73:591-3", "CC Verschuuren-Bemelmans, P Winter, DA Sival, JW Elting, OF Brouwer, U Müller. Novel homozygous ALS2 nonsense mutation (p.Gln715X) in sibs with infantile-onset ascending spastic paralysis: the first cases from northwestern Europe. Eur J Hum Genet. 2008;16:1407-11", "Y Yang, A Hentati, HX Deng, O Dabbagh, T Sasaki, M Hirano, WY Hung, K Ouahchi, J Yan, AC Azim, N Cole, G Gascon, A Yagmour, M Ben-Hamida, M Pericak-Vance, F Hentati, T Siddique. The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis.. Nat Genet 2001;29:160-5" ]	21/10/2005	13/5/2021	18/4/2013	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
ibm	ibm	[ "Distal Myopathy with Rimmed Vacuoles (DMRV)", "Hereditary Inclusion Body Myopathy (HIBM)", "Inclusion Body Myopathy Type 2 (IBM2)", "Nonaka Myopathy", "Quadriceps-Sparing Myopathy", "Distal Myopathy with Rimmed Vacuoles (DMRV)", "Hereditary Inclusion Body Myopathy (HIBM)", "Inclusion Body Myopathy Type 2 (IBM2)", "Nonaka Myopathy", "Quadriceps-Sparing Myopathy", "Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase", "GNE", "GNE Myopathy" ]		Nuria Carrillo, May Christine Malicdan, Marjan Huizing	Summary The diagnosis of	## Diagnosis Myopathy presenting in young adults with bilateral foot drop caused by anterior tibialis weakness, followed by slowly progressive skeletal muscle weakness. Although there is relative sparing of the quadriceps, they may become affected at late stages of the disease. The clinical picture varies depending on the stage of disease progression at which individuals are evaluated (see Serum CK may be normal or up to four times the upper limit of normal. Cryosections of affected muscles show atrophy, variation of fiber size, rimmed vacuoles, and no inflammation. The most prominent finding, the presence of rimmed vacuoles, is best identified in cryosections using modified Gomori trichrome stain and may be missed in paraffin-embedded tissue or hematoxylin and eosin staining. The "rimmed vacuoles" observed on electron microscopy that correspond to autophagic vacuoles are seen in a variety of myopathies with other etiologies that lead to autophagic degeneration (see Note: (1) Because histopathologic findings may be difficult to identify in biopsies of muscles that are unaffected or that have been replaced by fibro-fatty tissue, muscle strength or muscle MRI may aid in the identification of suitable muscles to biopsy. (2) Muscle biopsy and histopathologic examination may not be required to suspect or establish the diagnosis of 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 biallelic Molecular genetic testing approaches can include Note: Targeted analysis for founder pathogenic variants identified in several populations may be appropriate in some circumstances (for more details see 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 Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • Myopathy presenting in young adults with bilateral foot drop caused by anterior tibialis weakness, followed by slowly progressive skeletal muscle weakness. Although there is relative sparing of the quadriceps, they may become affected at late stages of the disease. The clinical picture varies depending on the stage of disease progression at which individuals are evaluated (see • Serum CK may be normal or up to four times the upper limit of normal. • Cryosections of affected muscles show atrophy, variation of fiber size, rimmed vacuoles, and no inflammation. The most prominent finding, the presence of rimmed vacuoles, is best identified in cryosections using modified Gomori trichrome stain and may be missed in paraffin-embedded tissue or hematoxylin and eosin staining. The "rimmed vacuoles" observed on electron microscopy that correspond to autophagic vacuoles are seen in a variety of myopathies with other etiologies that lead to autophagic degeneration (see • Note: (1) Because histopathologic findings may be difficult to identify in biopsies of muscles that are unaffected or that have been replaced by fibro-fatty tissue, muscle strength or muscle MRI may aid in the identification of suitable muscles to biopsy. (2) Muscle biopsy and histopathologic examination may not be required to suspect or establish the diagnosis of ## Suggestive Findings Myopathy presenting in young adults with bilateral foot drop caused by anterior tibialis weakness, followed by slowly progressive skeletal muscle weakness. Although there is relative sparing of the quadriceps, they may become affected at late stages of the disease. The clinical picture varies depending on the stage of disease progression at which individuals are evaluated (see Serum CK may be normal or up to four times the upper limit of normal. Cryosections of affected muscles show atrophy, variation of fiber size, rimmed vacuoles, and no inflammation. The most prominent finding, the presence of rimmed vacuoles, is best identified in cryosections using modified Gomori trichrome stain and may be missed in paraffin-embedded tissue or hematoxylin and eosin staining. The "rimmed vacuoles" observed on electron microscopy that correspond to autophagic vacuoles are seen in a variety of myopathies with other etiologies that lead to autophagic degeneration (see Note: (1) Because histopathologic findings may be difficult to identify in biopsies of muscles that are unaffected or that have been replaced by fibro-fatty tissue, muscle strength or muscle MRI may aid in the identification of suitable muscles to biopsy. (2) Muscle biopsy and histopathologic examination may not be required to suspect or establish the diagnosis of • Myopathy presenting in young adults with bilateral foot drop caused by anterior tibialis weakness, followed by slowly progressive skeletal muscle weakness. Although there is relative sparing of the quadriceps, they may become affected at late stages of the disease. The clinical picture varies depending on the stage of disease progression at which individuals are evaluated (see • Serum CK may be normal or up to four times the upper limit of normal. • Cryosections of affected muscles show atrophy, variation of fiber size, rimmed vacuoles, and no inflammation. The most prominent finding, the presence of rimmed vacuoles, is best identified in cryosections using modified Gomori trichrome stain and may be missed in paraffin-embedded tissue or hematoxylin and eosin staining. The "rimmed vacuoles" observed on electron microscopy that correspond to autophagic vacuoles are seen in a variety of myopathies with other etiologies that lead to autophagic degeneration (see • Note: (1) Because histopathologic findings may be difficult to identify in biopsies of muscles that are unaffected or that have been replaced by fibro-fatty tissue, muscle strength or muscle MRI may aid in the identification of suitable muscles to biopsy. (2) Muscle biopsy and histopathologic examination may not be required to suspect or establish the diagnosis of ## 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 biallelic Molecular genetic testing approaches can include Note: Targeted analysis for founder pathogenic variants identified in several populations may be appropriate in some circumstances (for more details see 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 Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 Note: Targeted analysis for founder pathogenic variants identified in several populations may be appropriate in some circumstances (for more details see 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 Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 the upper extremities, shoulder abduction may be affected early in the disease course before grip and hand muscles are affected. Clinical findings depend on the stage of disease progression at the time of evaluation [ Ultimately, disease progression may result in complete loss of skeletal muscle function and dependence on caregivers. Life span is not reduced. Respiratory muscle involvement resulting in decreased forced vital capacity has been described in the late stages of the disease; however, clinically significant involvement is rare and typically limited to individuals who are wheelchair dependent [ Cardiac muscle is typically not affected. While cardiac involvement has been reported in persons with Serum creatine kinase (CK) activity may be normal or elevated; it typically does not exceed four times the normal value. Creatinine values decrease over time due to decreased muscle mass; hence, cystatin C should be used instead of creatinine to evaluate renal function. Mild elevation of alanine aminotransferase and aspartate aminotransferase is seen in some individuals, especially those with elevated CK. Because reports of Penetrance of biallelic In order to unify the nomenclature and avoid confusion with unrelated but similarly named disorders, an international consortium proposed the term " The phenotype was first described by The terms "quadriceps-sparing myopathy" and "hereditary rimmed vacuole myopathy (HIBM)" were used by With the identification of the causative gene, The prevalence of To date, more than 1,000 individuals with The worldwide carrier rate of a pathogenic • Respiratory muscle involvement resulting in decreased forced vital capacity has been described in the late stages of the disease; however, clinically significant involvement is rare and typically limited to individuals who are wheelchair dependent [ • Cardiac muscle is typically not affected. While cardiac involvement has been reported in persons with • Serum creatine kinase (CK) activity may be normal or elevated; it typically does not exceed four times the normal value. • Creatinine values decrease over time due to decreased muscle mass; hence, cystatin C should be used instead of creatinine to evaluate renal function. • Mild elevation of alanine aminotransferase and aspartate aminotransferase is seen in some individuals, especially those with elevated CK. • The phenotype was first described by • The terms "quadriceps-sparing myopathy" and "hereditary rimmed vacuole myopathy (HIBM)" were used by ## Clinical Description In the upper extremities, shoulder abduction may be affected early in the disease course before grip and hand muscles are affected. Clinical findings depend on the stage of disease progression at the time of evaluation [ Ultimately, disease progression may result in complete loss of skeletal muscle function and dependence on caregivers. Life span is not reduced. Respiratory muscle involvement resulting in decreased forced vital capacity has been described in the late stages of the disease; however, clinically significant involvement is rare and typically limited to individuals who are wheelchair dependent [ Cardiac muscle is typically not affected. While cardiac involvement has been reported in persons with Serum creatine kinase (CK) activity may be normal or elevated; it typically does not exceed four times the normal value. Creatinine values decrease over time due to decreased muscle mass; hence, cystatin C should be used instead of creatinine to evaluate renal function. Mild elevation of alanine aminotransferase and aspartate aminotransferase is seen in some individuals, especially those with elevated CK. • Respiratory muscle involvement resulting in decreased forced vital capacity has been described in the late stages of the disease; however, clinically significant involvement is rare and typically limited to individuals who are wheelchair dependent [ • Cardiac muscle is typically not affected. While cardiac involvement has been reported in persons with • Serum creatine kinase (CK) activity may be normal or elevated; it typically does not exceed four times the normal value. • Creatinine values decrease over time due to decreased muscle mass; hence, cystatin C should be used instead of creatinine to evaluate renal function. • Mild elevation of alanine aminotransferase and aspartate aminotransferase is seen in some individuals, especially those with elevated CK. ## Genotype-Phenotype Correlations Because reports of ## Penetrance Penetrance of biallelic ## Nomenclature In order to unify the nomenclature and avoid confusion with unrelated but similarly named disorders, an international consortium proposed the term " The phenotype was first described by The terms "quadriceps-sparing myopathy" and "hereditary rimmed vacuole myopathy (HIBM)" were used by With the identification of the causative gene, • The phenotype was first described by • The terms "quadriceps-sparing myopathy" and "hereditary rimmed vacuole myopathy (HIBM)" were used by ## Prevalence The prevalence of To date, more than 1,000 individuals with The worldwide carrier rate of a pathogenic ## Genetically Related (Allelic) Disorders ## Differential Diagnosis The differential diagnosis includes adult-onset distal myopathies and myopathies with rimmed vacuoles (see Genes of Interest in the Differential Diagnosis of Modified from AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; ULN = upper limit of normal; XL = X-linked Histopathologic characteristics of myofibrillar myopathies include variation in fiber size, amorphous granular or hyaline deposits on trichrome-stained sections, and decrease of oxidative enzyme activities leading to abnormal fibers. ## Management Individuals with To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with Muscle strength Balance Function Fine motor skills Impact on activities of daily living Need for ongoing PT/OT Need for AFOs, & assistive ambulatory devices Need for adaptive devices Need for handicapped parking Community or online Social work involvement for caregiver support. AFOs = ankle-foot orthoses; MEP = maximal expiratory pressure; MIP = maximal inspiratory pressure; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse There is no approved therapy for Treatment of Manifestations in Individuals with Transfers (e.g., from bed to wheelchair, wheelchair to car) Medical alert system for those unable to stand after a fall Techniques & devices to accomplish tasks incl mobility, washing, dressing, eating, cooking, grooming To assist w/household modifications to meet special needs OT = occupational therapy; PT = physical therapy All affected individuals should consult their physician before beginning an exercise program. Routine follow up with the multidisciplinary team is recommended annually, or more frequently as determined by managing physician (see Recommended Multidisciplinary Team Surveillance for Individuals with Muscle strength testing using a quantitative scale, e.g., MMT, hand-held dynamometry, or QMA Physical function, e.g., 6-min walk test, AMAT Activities of daily living AFOs = ankle-foot orthoses; AMAT = Adult Myopathy Assessment Tool; MEP = maximal expiratory pressure; MIP = maximal inspiratory pressure; MMT= manual muscle testing; PFTs = pulmonary function tests; QMA = Quantitative Muscle Assessment It may be prudent to use medications/drugs with potential myotoxicity (e.g., colchicine, statins) with caution. It is strongly recommended that affected individuals have a healthy diet and exercise to avoid developing hypercholesterolemia, in an effort to reduce the risk associated with taking statins. Individuals with See N-acetylmanossamine (ManNAc) is the only therapy currently in clinical development for Ultragenyx discontinued the clinical development of extended-release sialic acid (Ace-ER) in 2017 following a Phase III trial that failed to detect clinical efficacy [ Preclinical studies are ongoing to advance gene therapy as a potential therapy for Search • Muscle strength • Balance • Function • Fine motor skills • Impact on activities of daily living • Need for ongoing PT/OT • Need for AFOs, & assistive ambulatory devices • Need for adaptive devices • Need for handicapped parking • Community or online • Social work involvement for caregiver support. • Transfers (e.g., from bed to wheelchair, wheelchair to car) • Medical alert system for those unable to stand after a fall • Techniques & devices to accomplish tasks incl mobility, washing, dressing, eating, cooking, grooming • To assist w/household modifications to meet special needs • Muscle strength testing using a quantitative scale, e.g., MMT, hand-held dynamometry, or QMA • Physical function, e.g., 6-min walk test, AMAT • Activities of daily living ## 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 Muscle strength Balance Function Fine motor skills Impact on activities of daily living Need for ongoing PT/OT Need for AFOs, & assistive ambulatory devices Need for adaptive devices Need for handicapped parking Community or online Social work involvement for caregiver support. AFOs = ankle-foot orthoses; MEP = maximal expiratory pressure; MIP = maximal inspiratory pressure; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Muscle strength • Balance • Function • Fine motor skills • Impact on activities of daily living • Need for ongoing PT/OT • Need for AFOs, & assistive ambulatory devices • Need for adaptive devices • Need for handicapped parking • Community or online • Social work involvement for caregiver support. ## Treatment of Manifestations There is no approved therapy for Treatment of Manifestations in Individuals with Transfers (e.g., from bed to wheelchair, wheelchair to car) Medical alert system for those unable to stand after a fall Techniques & devices to accomplish tasks incl mobility, washing, dressing, eating, cooking, grooming To assist w/household modifications to meet special needs OT = occupational therapy; PT = physical therapy All affected individuals should consult their physician before beginning an exercise program. • Transfers (e.g., from bed to wheelchair, wheelchair to car) • Medical alert system for those unable to stand after a fall • Techniques & devices to accomplish tasks incl mobility, washing, dressing, eating, cooking, grooming • To assist w/household modifications to meet special needs ## Surveillance Routine follow up with the multidisciplinary team is recommended annually, or more frequently as determined by managing physician (see Recommended Multidisciplinary Team Surveillance for Individuals with Muscle strength testing using a quantitative scale, e.g., MMT, hand-held dynamometry, or QMA Physical function, e.g., 6-min walk test, AMAT Activities of daily living AFOs = ankle-foot orthoses; AMAT = Adult Myopathy Assessment Tool; MEP = maximal expiratory pressure; MIP = maximal inspiratory pressure; MMT= manual muscle testing; PFTs = pulmonary function tests; QMA = Quantitative Muscle Assessment • Muscle strength testing using a quantitative scale, e.g., MMT, hand-held dynamometry, or QMA • Physical function, e.g., 6-min walk test, AMAT • Activities of daily living ## Agents/Circumstances to Avoid It may be prudent to use medications/drugs with potential myotoxicity (e.g., colchicine, statins) with caution. It is strongly recommended that affected individuals have a healthy diet and exercise to avoid developing hypercholesterolemia, in an effort to reduce the risk associated with taking statins. Individuals with ## Evaluation of Relatives at Risk See ## Therapies Under Investigation N-acetylmanossamine (ManNAc) is the only therapy currently in clinical development for Ultragenyx discontinued the clinical development of extended-release sialic acid (Ace-ER) in 2017 following a Phase III trial that failed to detect clinical efficacy [ Preclinical studies are ongoing to advance gene therapy as a potential therapy for Search ## Genetic Counseling Parents of an affected individual are obligate heterozygotes (i.e., carriers for one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a Heterozygotes (carriers) are asymptomatic and are not at risk for If both parents are known to be heterozygous for a Heterozygotes (carriers) are asymptomatic and are not at risk for 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. • Parents of an affected individual are obligate heterozygotes (i.e., carriers for one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • Heterozygotes (carriers) are asymptomatic and are not at risk for • If both parents are known to be heterozygous for a • Heterozygotes (carriers) are asymptomatic and are not at risk for • 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 Parents of an affected individual are obligate heterozygotes (i.e., carriers for one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a Heterozygotes (carriers) are asymptomatic and are not at risk for If both parents are known to be heterozygous for a Heterozygotes (carriers) are asymptomatic and are not at risk for • Parents of an affected individual are obligate heterozygotes (i.e., carriers for one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • Heterozygotes (carriers) are asymptomatic and are not at risk for • If both parents are known to be heterozygous for a • Heterozygotes (carriers) are asymptomatic and are not at risk for ## Carrier (Heterozygote) Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources P.O. Box 261926 Encino 91426-1926 Neuromuscular Network United Kingdom Japan • • P.O. Box 261926 • Encino 91426-1926 • • • • • • • Neuromuscular Network • • • • • United Kingdom • • • • Japan • ## Molecular Genetics GNE Myopathy: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for GNE Myopathy ( Heterozygous pathogenic variants in the allosteric site of The mechanism by which disruption of GNE enzyme function causes muscle atrophy in Notable Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis Heterozygous pathogenic variants in the allosteric site of The mechanism by which disruption of GNE enzyme function causes muscle atrophy in Notable Variants listed in the table have been provided by the authors. ## Chapter Notes George Karpati, MD, one of the original authors of this This study was supported Intramural Program of the National Human Genome Research Institute of the National Institutes of Health, Bethesda, Maryland, USA. Nuria Carrillo, MD (2020-present)Marjan Huizing, PhD (2020-present)George Karpati, MD, FRCP(C), FRS(C), OC; McGill University (2004-2009)May Christine Malicdan, MD, PhD (2020-present)Erin K O'Ferrall, MD, MSc, FRCPC; Montreal Neurological Institute (2009-2020)Michael Sinnreich, MD, PhD; University Hospital Basel (2004-2020) 9 April 2020 (bp) Comprehensive update posted live 7 March 2013 (me) Comprehensive update posted live 6 August 2009 (me) Comprehensive update posted live 24 May 2006 (me) Comprehensive update posted live 26 March 2004 (me) Review posted live 17 November 2003 (gk) Original submission Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the • 9 April 2020 (bp) Comprehensive update posted live • 7 March 2013 (me) Comprehensive update posted live • 6 August 2009 (me) Comprehensive update posted live • 24 May 2006 (me) Comprehensive update posted live • 26 March 2004 (me) Review posted live • 17 November 2003 (gk) Original submission ## Author Notes George Karpati, MD, one of the original authors of this ## Acknowledgments This study was supported Intramural Program of the National Human Genome Research Institute of the National Institutes of Health, Bethesda, Maryland, USA. ## Author History Nuria Carrillo, MD (2020-present)Marjan Huizing, PhD (2020-present)George Karpati, MD, FRCP(C), FRS(C), OC; McGill University (2004-2009)May Christine Malicdan, MD, PhD (2020-present)Erin K O'Ferrall, MD, MSc, FRCPC; Montreal Neurological Institute (2009-2020)Michael Sinnreich, MD, PhD; University Hospital Basel (2004-2020) ## Revision History 9 April 2020 (bp) Comprehensive update posted live 7 March 2013 (me) Comprehensive update posted live 6 August 2009 (me) Comprehensive update posted live 24 May 2006 (me) Comprehensive update posted live 26 March 2004 (me) Review posted live 17 November 2003 (gk) Original submission Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the • 9 April 2020 (bp) Comprehensive update posted live • 7 March 2013 (me) Comprehensive update posted live • 6 August 2009 (me) Comprehensive update posted live • 24 May 2006 (me) Comprehensive update posted live • 26 March 2004 (me) Review posted live • 17 November 2003 (gk) Original submission ## References ## Literature Cited The biosynthesis of sialic acid (Neu5Ac) is an intracellular process with enzymes shown in	[ "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", "A Arai, K Tanaka, T Ikeuchi, S Igarashi, H Kobayashi, T Asaka, H Date, M Saito, H Tanaka, S Kawasaki, E Uyama, H Mizusawa, N Fukuhara, S. Tsuji. A novel mutation in the GNE gene and a linkage disequilibrium in Japanese pedigrees.. Ann Neurol. 2002;52:516-9", "Z Argov, I Eisenberg, G Grabov-Nardini, M Sadeh, I Wirguin, D Soffer, S Mitrani-Rosenbaum. Hereditary inclusion body myopathy: the Middle Eastern genetic cluster.. Neurology. 2003;60:1519-23", "Z Argov, R Yarom. \"Rimmed vacuole myopathy\" sparing the quadriceps: a unique disorder in Iranian Jews.. J Neurol Sci. 1984;64:33-43", "S Bhattacharya, SV Khadilkar, A Nalini, A Ganapathy, AU Mannan, PP Majumder, A Bhattacharya. Mutation spectrum of GNE myopathy in the Indian sub-continent.. J Neuromuscul Dis. 2018;5:85-92", "A Broccolini, T Gidaro, R De Cristofaro, R Morosetti, C Gliubizzi, E Ricci, PA Tonali, M Mirabella. Hyposialylation of neprilysin possibly affects its expression and enzymatic activity in hereditary inclusion-body myopathy muscle.. J Neurochem. 2008;105:971-81", "A Broccolini, E Ricci, D Cassandrini, C Gliubizzi, C Bruno, E Tonoli, G Silvestri, M Pescatori, C Rodolico, S Sinicropi, S Servidei, F Zara, C Minetti, PA Tonali, M Mirabella. Novel GNE mutations in Italian families with autosomal recessive hereditary inclusion-body myopathy.. Hum Mutat. 2004;23:632", "N Carrillo, MC Malicdan, M Huizing. GNE myopathy: etiology, diagnosis, and therapeutic challenges.. Neurotherapeutics. 2018;15:900-14", "FV Celeste, T Vilboux, C Ciccone, JK de Dios, MC Malicdan, P Leoyklang, JC McKew, WA Gahl, N Carrillo-Carrasco, M Huizing. Mutation update for GNE gene variants associated with GNE myopathy.. Hum Mutat. 2014;35:915-26", "M Cerino, S Gorokhova, A Béhin, JA Urtizberea, V Kergourlay, E Salvo, R Bernard, N Lévy, M Bartoli, M Krahn. Novel pathogenic variants in a French cohort widen the mutational spectrum of GNE myopathy.. J Neuromuscul Dis. 2015;2:131-6", "Y Chai, TE Bertorini, FA McGrew. Hereditary inclusion-body myopathy associated with cardiomyopathy: report of two siblings.. Muscle Nerve. 2011;43:133-6", "T Chamova, V Guergueltcheva, M Gospodinova, S Krause, S Cirak, A Kaprelyan, L Angelova, V Mihaylova, S Bichev, D Chandler, E Naydenov, M Grudkova, P Djukmedzhiev, T Voit, O Pogoryelova, H Lochmüller, HH Goebel, M Bahlo, L Kalaydjieva, I Tournev. GNE myopathy in Roma patients homozygous for the p.I618T founder mutation.. Neuromuscul Disord. 2015;25:713-8", "A Chaouch, KM Brennan, J Hudson, C Longman, J McConville, PJ Morrison, ME Farrugia, R Petty, W Stewart, F Norwood, R Horvath, PF Chinnery, D Costigan, J Winer, T Polvikoski, E Healy, A Sarkozy, T Evangelista, O Pogoryelova, M Eagle, K Bushby, V Straub, H Lochmüller. Two recurrent mutations are associated with GNE myopathy in the North of Britain.. J Neurol Neurosurg Psychiatry. 2014;85:1359-65", "Y Chen, J Xi, W Zhu, J Lin, S Luo, D Yue, S Cai, C Sun, C Zhao, S Mitsuhashi, I Nishino, M Xu, J. Lu. GNE myopathy in Chinese population: hotspot and novel mutations.. J Hum Genet. 2019;64:11-16", "A Cho, YK Hayashi, K Monma, Y Oya, S Noguchi, I Nonaka, I Nishino. Mutation profile of the GNE gene in Japanese patients with distal myopathy with rimmed vacuoles (GNE myopathy).. J Neurol Neurosurg Psychiatry. 2014;85:914-7", "M Cohen, A. Varki. The sialome--far more than the sum of its parts.. OMICS 2010;14:455-64", "JK de Dios, JA Shrader, GO Joe, JC McClean, K Williams, R Evers, MC Malicdan, C Ciccone, A Mankodi, M Huizing, JC McKew, DA Bluemke, WA Gahl, N Carrillo-Carrasco. Atypical presentation of GNE myopathy with asymmetric hand weakness.. Neuromuscul Disord. 2014;24:1063-7", "R Del Bo, P Baron, A Prelle, M Serafini, M Moggio, AD Fonzo, M Castagni, N Bresolin, GP Comi. Novel missense mutation and large deletion of GNE gene in autosomal-recessive inclusion-body myopathy.. Muscle Nerve. 2003;28:113-7", "K Effertz, S Hinderlich, W Reutter. Selective loss of either the epimerase or kinase activity of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase due to site-directed mutagenesis based on sequence alignments.. J Biol Chem. 1999;274:28771-8", "I Eisenberg, N Avidan, T Potikha, H Hochner, M Chen, T Olender, M Barash, M Shemesh, M Sadeh, G Grabov-Nardini, I Shmilevich, A Friedmann, G Karpati, WG Bradley, L Baumbach, D Lancet, EB Asher, JS Beckmann, Z Argov, S Mitrani-Rosenbaum. The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy.. Nat Genet. 2001;29:83-7", "J Futterer, A Dalby, GC Lowe, B Johnson, MA Simpson, J Motwani, M Williams, SP Watson, NV Morgan. Mutation in GNE is associated with severe congenital thrombocytopenia.. Blood. 2018;132:1855-8", "D Gagiannis, A Orthmann, I Danssmann, M Schwarzkopf, W Weidemann, R Horstkorte. Reduced sialylation status in UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE)-deficient mice.. Glycoconj J. 2007;24:125-30", "B Galeano, R Klootwijk, I Manoli, M Sun, C Ciccone, D Darvish, MF Starost, PM Zerfas, VJ Hoffmann, S Hoogstraten-Miller, DM Krasnewich, WA Gahl, M Huizing. Mutation in the key enzyme of sialic acid biosynthesis causes severe glomerular proteinuria and is rescued by N-acetylmannosamine.. J Clin Invest. 2007;117:1585-94", "J Garland, J Stephen, B Class, A Gruber, C Ciccone, A Poliak, CP Hayes, V Singhal, C Slota, J Perreault, R Gavrilova, JA Shrader, P Chittiboina, G Joe, J Heiss, WA Gahl, M Huizing, N Carrillo, MCV Malicdan. Identification of an. Mol Genet Genomic Med. 2017;5:410-7", "P Hackman, J Sarparanta, S Lehtinen, A Vihola, A Evilä, PH Jonson, H Luque, J Kere, M Screen, PF Chinnery, G Åhlberg, L Edström, B Udd. Welander distal myopathy is caused by a mutation in the RNA-binding protein TIA1.. Ann Neurol. 2013;73:500-9", "MO Harris-Love, G Joe, TE Davenport, D Koziol, K Abbett Rose, JA Shrader, OM Vasconcelos, B McElroy, MC Dalakas. Reliability of the adult myopathy assessment tool in individuals with myositis.. Arthritis Care Res. 2015;67:563-70", "M Huizing, N Carrillo-Carrasco, MC Malicdan, S Noguchi, WA Gahl, S Mitrani-Rosenbaum, Z Argov, I Nishino. GNE myopathy: new name and new mutation nomenclature.. Neuromuscul Disord. 2014;24:387-9", "M Huizing, G Rakocevic, SE Sparks, I Mamali, A Shatunov, L Goldfarb, D Krasnewich, WA Gahl, MC Dalakas. Hypoglycosylation of alpha-dystroglycan in patients with hereditary IBM due to GNE mutations.. Mol Genet Metab. 2004;81:196-202", "RH Jebsen, N Taylor, RB Trieschmann, MJ Trotter, LA Howard. An objective and standardized test of hand function.. Arch Phys Med Rehabil. 1969;50:311-9", "OT Keppler. UDP-GlcNAc 2-epimerase: a regulator of cell surface sialylation.. Science. 1999;284:1372-6", "VE Kimonis, E Fulchiero, J Vesa, G Watts. VCP disease associated with myopathy, Paget disease of bone and frontotemporal dementia: review of a unique disorder.. Biochim Biophys Acta. 2008;1782:744-8", "SV Khadilkar, BR Nallamilli, A Bhutada, M Hegde, K Gandhi, HD Faldu, SB Patil. A report on GNE myopathy: individuals of Rajasthan ancestry share the Roma gene.. J Neurol Sci. 2017;375:239-40", "N Kurochkina, T Yardeni, M Huizing. Molecular modeling of the bifunctional enzyme UDP-GlcNAc 2-epimerase/ManNAc kinase and predictions of structural effects of mutations associated with HIBM and sialuria.. Glycobiology. 2010;20:322-37", "P Leoyklang, B Class, S Noguchi, WA Gahl, N Carrillo, I Nishino, M Huizing, MC Malicdan. Quantification of lectin fluorescence in GNE myopathy muscle biopsies.. Muscle Nerve. 2018;58:286-92", "H Lochmüller, A Behin, Y Caraco, H Lau, M Mirabella, I Tournev, M Tarnopolsky, O Pogoryelova, C Woods, A Lai, J Shah, T Koutsoukos, A Skrinar, H Mansbach, E Kakkis, T. Mozaffar. A phase 3 randomized study evaluating sialic acid extended-release for GNE myopathy.. Neurology. 2019;92:e2109-e2117", "MC Malicdan, S Noguchi, YK Hayashi, I Nonaka, I Nishino. Prophylactic treatment with sialic acid metabolites precludes the development of the myopathic phenotype in the DMRV-hIBM mouse model.. Nat Med. 2009;15:690-5", "M Mori-Yoshimura, Y Oya, YK Hayashi, S Noguchi, I Nishino, M Murata. Respiratory dysfunction in patients severely affected by GNE myopathy (distal myopathy with rimmed vacuoles).. Neuromuscul Disord. 2013;23:84-8", "N Muelas, P Hackman, H Luque, M Garcés-Sánchez, I Azorín, T Suominen, T Sevilla, F Mayordomo, L Gómez, P Martí, J María Millán, B Udd, JJ Vílchez. MYH7 gene tail mutation causing myopathic profiles beyond Laing distal myopathy.. Neurology. 2010;75:732-41", "TK Niethamer, T Yardeni, P Leoyklang, C Ciccone, A Astiz-Martinez, K Jacobs, HM Dorward, PM Zerfas, WA Gahl, M Huizing. Oral monosaccharide therapies to reverse renal and muscle hyposialylation in a mouse model of GNE myopathy.. Mol Genet Metab. 2012;107:748-55", "I Nishino, S Noguchi, K Murayama, A Driss, K Sugie, Y Oya, T Nagata, K Chida, T Takahashi, Y Takusa, T Ohi, J Nishimiya, N Sunohara, E Ciafaloni, M Kawai, M Aoki, I. Nonaka. Distal myopathy with rimmed vacuoles is allelic to hereditary inclusion body myopathy.. Neurology. 2002;59:1689-93", "S Noguchi, Y Keira, K Murayama, M Ogawa, M Fujita, G Kawahara, Y Oya, M Imazawa, Y Goto, YK Hayashi, I Nonaka, I Nishino. Reduction of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase activity and sialylation in distal myopathy with rimmed vacuoles.. J Biol Chem. 2004;279:11402-7", "I Nonaka, N Sunohara, S Ishiura, E Satoyoshi. Familial distal myopathy with rimmed vacuole and lamellar (myeloid) body formation.. J Neurol Sci. 1981;51:141-55", "M Olivé, LG Goldfarb, A Shatunov, D Fischer, I Ferrer. Myotilinopathy: refining the clinical and myopathological phenotype.. Brain. 2005;128:2315-26", "YE Park, DS Kim, YC Choi, JH Shin. Progression of GNE myopathy based on the patient-reported outcome.. J Clin Neurol. 2019;15:275-84", "J Penner, LR Mantey, S Elgavish, D Ghaderi, S Cirak, M Berger, S Krause, L Lucka, T Voit, S Mitrani-Rosenbaum, S Hinderlich. Influence of UDP-GlcNAc 2-epimerase/ManNAc kinase mutant proteins on hereditary inclusion body myopathy.. Biochemistry. 2006;45:2968-77", "M Quintana, J Shrader, C Slota, G Joe, JC McKew, M Fitzgerald, WA Gahl, S Berry, N Carrillo. Bayesian model of disease progression in GNE myopathy.. Stat Med. 2019;38:1459-74", "E Ricci, A Broccolini, T Gidaro, R Morosetti, C Gliubizzi, R Frusciante, GM Di Lella, PA Tonali, M Mirabella. NCAM is hyposialylated in hereditary inclusion body myopathy due to GNE mutations.. Neurology. 2006;66:755-8", "M Sadeh, N Gadoth, H Hadar, E Ben-David. Vacuolar myopathy sparing the quadriceps.. Brain. 1993;116:217-32", "M Savarese, J Sarparanta, A Vihola, B Udd, P Hackman. Increasing role of titin mutations in neuromuscular disorders.. J Neuromuscul Dis. 2016;3:293-308", "M Schwarzkopf, KP Knobeloch, E Rohde, S Hinderlich, N Wiechens, L Lucka, I Horak, W Reutter, R Horstkorte. Sialylation is essential for early development in mice.. Proc Natl Acad Sci U S A. 2002;99:5267-70", "D Selcen, AG Engel. Mutations in ZASP define a novel form of muscular dystrophy in humans.. Ann Neurol. 2005;57:269-76", "J Senderek, SM Garvey, M Krieger, V Guergueltcheva, A Urtizberea, A Roos, M Elbracht, C Stendel, I Tournev, V Mihailova, H Feit, J Tramonte, P Hedera, K Crooks, C Bergmann, S Rudnik-Schöneborn, K Zerres, H Lochmüller, E Seboun, J Weis, JS Beckmann, MA Hauser, CE Jackson. Autosomal-dominant distal myopathy associated with a recurrent missense mutation in the gene encoding the nuclear matrix protein, matrin 3.. Am J Hum Genet. 2009;84:511-8", "R Seppala, VP Lehto, WA Gahl. Mutations in the human UDP-N-acetylglucosamine 2-epimerase gene define the disease sialuria and the allosteric site of the enzyme.. Am J Hum Genet. 1999;64:1563-9", "SE Sparks, C Ciccone, M Lalor, E Orvisky, R Klootwijk, PJ Savelkoul, MC Dalakas, DM Krasnewich, WA Gahl, M Huizing. Use of a cell-free system to determine UDPN-acetylglucosamine 2-epimerase and N-acetylmannosamine kinase activities in human hereditary inclusion body myopathy.. Glycobiology. 2005;15:1102-10", "Y Tajima, E Uyama, S Go, C Sato, N Tao, M Kotani, H Hino, A Suzuki, Y Sanai, K Kitajima, H Sakuraba. Distal myopathy with rimmed vacuoles: impaired O-glycan formation in muscular glycoproteins.. Am J Pathol. 2005;166:1121-30", "G Tasca, E Ricci, M Monforte, F Laschena, P Ottaviani, C Rodolico, E Barca, G Silvestri, E Iannaccone, M Mirabella, A. Broccolini. Muscle imaging findings in GNE myopathy.. J Neurol. 2012;259:1358-65", "B Udd, R. Griggs. Distal myopathies.. Curr Opin Neurol. 2001;14:561-6", "J Visser, E Mans, M de Visser, RM van den Berg-Vos, H Franssen, JM de Jong, LH van den Berg, JH Wokke, RJ de Haan. Comparison of maximal voluntary isometric contraction and hand-held dynamometry in measuring muscle strength of patients with progressive lower motor neuron syndrome.. Neuromuscul Disord. 2003;13:744-50", "S Wopereis, DJ. Lefeber, E Morava, RA Wevers. Mechanisms in protein O-glycan biosynthesis and clinical and molecular aspects of protein O-glycan biosynthesis defects: a review.. Clin Chem. 2006;52:574-600", "X Xu, AQ Wang, LL Latham, F Celeste, C Ciccone, MC Malicdan, B Goldspiel, P Terse, J Cradock, N Yang, S Yorke, JC McKew, WA Gahl, M Huizing, N Carrillo. Safety, pharmacokinetics and sialic acid production after oral administration of N-acetylmannosamine (ManNAc) to subjects with GNE myopathy.. Mol Genet Metab. 2017;122:126-34", "J Zhao, Z Wang, D Hong, H Lv, W Zhang, J Chen, Y Yuan. Mutational spectrum and clinical features in 35 unrelated mainland Chinese patients with GNE myopathy.. J Neurol Sci 2015;354:21-26", "W Zhu, S Mitsuhashi, T Yonekawa, S Noguchi, JC Huei, A Nalini, V Preethish-Kumar, M Yamamoto, K Murakata, M Mori-Yoshimura, S Kamada, H Yahikozawa. Missing genetic variations in GNE myopathy: rearrangement hotspots encompassing 5'UTR and founder allele.. J Hum Genet. 2017;62:159-66" ]	26/3/2004	9/4/2020		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
ibmpfd	ibmpfd	[ "IBMPFD", "Inclusion Body Myopathy with Early-Onset Paget Disease of Bone and/or Frontotemporal Dementia", "Multisystem Proteinopathy", "Inclusion Body Myopathy with Early-Onset Paget Disease of Bone and/or Frontotemporal Dementia", "IBMPFD", "Heterogeneous nuclear ribonucleoprotein A1", "Heterogeneous nuclear ribonucleoproteins A2/B1", "Transitional endoplasmic reticulum ATPase", "HNRNPA1", "HNRNPA2B1", "VCP", "Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia" ]	Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia	Virginia Kimonis	Summary Inclusion body myopathy associated with Paget disease of bone (PDB) and/or frontotemporal dementia (IBMPFD) is characterized by adult-onset proximal and distal muscle weakness (clinically resembling a limb-girdle muscular dystrophy syndrome), early-onset PDB, and premature frontotemporal dementia (FTD). Muscle weakness progresses to involve other limb and respiratory muscles. PDB involves focal areas of increased bone turnover that typically lead to spine and/or hip pain and localized enlargement and deformity of the long bones; pathologic fractures occur on occasion. Early stages of FTD are characterized by dysnomia, dyscalculia, comprehension deficits, and paraphasic errors, with minimal impairment of episodic memory; later stages are characterized by inability to speak, auditory comprehension deficits for even one-step commands, alexia, and agraphia. Mean age at diagnosis for muscle disease and PDB is 42 years; for FTD, 56 years. Dilated cardiomyopathy, amyotrophic lateral sclerosis, and Parkinson disease are now known to be part of the spectrum of findings associated with IBMPFD. The diagnosis of IBMPFD is established in a proband with typical clinical findings and a heterozygous pathogenic variant in IBMPFD is inherited in an autosomal dominant manner. An estimated 80% of affected individuals have an affected parent; approximately 20% have the disorder as a result of a	## Diagnosis Inclusion body or nonspecific myopathy associated with Paget disease of bone with or without frontotemporal dementia (IBMPFD) Serum CK concentration is normal to mildly elevated (mean: 195 U/L; range: 40-1145 U/L; normal range: 20-222 U/L). EMG (electromyogram) shows myopathic changes, and neuropathic changes including acute and chronic denervation. Skeletal muscle pathology is typically nonspecific (both light microscopy and electron microscopy). On light microscopy, findings characteristic of inclusion body myopathy consisting of rimmed vacuoles and cytoplasmic TAR DNA-binding protein 43 (TDP-43) and ubiquitin-positive inclusions may be visible in some fibers; the inclusions appear with time and can be observed at a later stage of the disease in some individuals. Elevated serum alkaline phosphatase concentration (mean: 359 U/L; range: 58-1724 U/L; normal range: 30-130 U/L) Elevated urine concentrations of pyridinoline (PYD) and deoxypyridinoline (DPD): Mean PYD: 153 IU/L (normal: 31.1 IU/L) Mean DPD: 40 IU/L (normal: 6.8 IU/L) Note: The DPD/PYD ratio is not significantly different between affected persons (0.291) and normal controls (0.214). Bone findings – Skeletal radiographs reveal diagnostic changes of coarse trabeculation; cortical thickening; and spotty sclerosis in the skull, pelvis, spine, and scapula that later becomes widespread. Radiographic findings of PDB are typically present ten to 15 years before the diagnosis of PDB can be made based on clinical findings. Radionuclide scan shows focally increased bony uptake (a more sensitive indicator of PDB than skeletal radiographs). The diagnosis of IBMPFD 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 IBMPFD is broad, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of IBMPFD molecular genetic testing approaches can include use of a For an introduction to multigene panels click If no pathogenic variant is found in When the diagnosis of IBMPFD is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia (IBMPFD) 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. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used 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 data on detection rate of gene-targeted deletion/duplication analysis are available. • Serum CK concentration is normal to mildly elevated (mean: 195 U/L; range: 40-1145 U/L; normal range: 20-222 U/L). • EMG (electromyogram) shows myopathic changes, and neuropathic changes including acute and chronic denervation. • Elevated serum alkaline phosphatase concentration (mean: 359 U/L; range: 58-1724 U/L; normal range: 30-130 U/L) • Elevated urine concentrations of pyridinoline (PYD) and deoxypyridinoline (DPD): • Mean PYD: 153 IU/L (normal: 31.1 IU/L) • Mean DPD: 40 IU/L (normal: 6.8 IU/L) • Note: The DPD/PYD ratio is not significantly different between affected persons (0.291) and normal controls (0.214). • Mean PYD: 153 IU/L (normal: 31.1 IU/L) • Mean DPD: 40 IU/L (normal: 6.8 IU/L) • Bone findings – • Skeletal radiographs reveal diagnostic changes of coarse trabeculation; cortical thickening; and spotty sclerosis in the skull, pelvis, spine, and scapula that later becomes widespread. Radiographic findings of PDB are typically present ten to 15 years before the diagnosis of PDB can be made based on clinical findings. • Radionuclide scan shows focally increased bony uptake (a more sensitive indicator of PDB than skeletal radiographs). • Skeletal radiographs reveal diagnostic changes of coarse trabeculation; cortical thickening; and spotty sclerosis in the skull, pelvis, spine, and scapula that later becomes widespread. Radiographic findings of PDB are typically present ten to 15 years before the diagnosis of PDB can be made based on clinical findings. • Radionuclide scan shows focally increased bony uptake (a more sensitive indicator of PDB than skeletal radiographs). • Mean PYD: 153 IU/L (normal: 31.1 IU/L) • Mean DPD: 40 IU/L (normal: 6.8 IU/L) • Skeletal radiographs reveal diagnostic changes of coarse trabeculation; cortical thickening; and spotty sclerosis in the skull, pelvis, spine, and scapula that later becomes widespread. Radiographic findings of PDB are typically present ten to 15 years before the diagnosis of PDB can be made based on clinical findings. • Radionuclide scan shows focally increased bony uptake (a more sensitive indicator of PDB than skeletal radiographs). • For an introduction to multigene panels click • If no pathogenic variant is found in ## Suggestive Findings Inclusion body or nonspecific myopathy associated with Paget disease of bone with or without frontotemporal dementia (IBMPFD) Serum CK concentration is normal to mildly elevated (mean: 195 U/L; range: 40-1145 U/L; normal range: 20-222 U/L). EMG (electromyogram) shows myopathic changes, and neuropathic changes including acute and chronic denervation. Skeletal muscle pathology is typically nonspecific (both light microscopy and electron microscopy). On light microscopy, findings characteristic of inclusion body myopathy consisting of rimmed vacuoles and cytoplasmic TAR DNA-binding protein 43 (TDP-43) and ubiquitin-positive inclusions may be visible in some fibers; the inclusions appear with time and can be observed at a later stage of the disease in some individuals. Elevated serum alkaline phosphatase concentration (mean: 359 U/L; range: 58-1724 U/L; normal range: 30-130 U/L) Elevated urine concentrations of pyridinoline (PYD) and deoxypyridinoline (DPD): Mean PYD: 153 IU/L (normal: 31.1 IU/L) Mean DPD: 40 IU/L (normal: 6.8 IU/L) Note: The DPD/PYD ratio is not significantly different between affected persons (0.291) and normal controls (0.214). Bone findings – Skeletal radiographs reveal diagnostic changes of coarse trabeculation; cortical thickening; and spotty sclerosis in the skull, pelvis, spine, and scapula that later becomes widespread. Radiographic findings of PDB are typically present ten to 15 years before the diagnosis of PDB can be made based on clinical findings. Radionuclide scan shows focally increased bony uptake (a more sensitive indicator of PDB than skeletal radiographs). • Serum CK concentration is normal to mildly elevated (mean: 195 U/L; range: 40-1145 U/L; normal range: 20-222 U/L). • EMG (electromyogram) shows myopathic changes, and neuropathic changes including acute and chronic denervation. • Elevated serum alkaline phosphatase concentration (mean: 359 U/L; range: 58-1724 U/L; normal range: 30-130 U/L) • Elevated urine concentrations of pyridinoline (PYD) and deoxypyridinoline (DPD): • Mean PYD: 153 IU/L (normal: 31.1 IU/L) • Mean DPD: 40 IU/L (normal: 6.8 IU/L) • Note: The DPD/PYD ratio is not significantly different between affected persons (0.291) and normal controls (0.214). • Mean PYD: 153 IU/L (normal: 31.1 IU/L) • Mean DPD: 40 IU/L (normal: 6.8 IU/L) • Bone findings – • Skeletal radiographs reveal diagnostic changes of coarse trabeculation; cortical thickening; and spotty sclerosis in the skull, pelvis, spine, and scapula that later becomes widespread. Radiographic findings of PDB are typically present ten to 15 years before the diagnosis of PDB can be made based on clinical findings. • Radionuclide scan shows focally increased bony uptake (a more sensitive indicator of PDB than skeletal radiographs). • Skeletal radiographs reveal diagnostic changes of coarse trabeculation; cortical thickening; and spotty sclerosis in the skull, pelvis, spine, and scapula that later becomes widespread. Radiographic findings of PDB are typically present ten to 15 years before the diagnosis of PDB can be made based on clinical findings. • Radionuclide scan shows focally increased bony uptake (a more sensitive indicator of PDB than skeletal radiographs). • Mean PYD: 153 IU/L (normal: 31.1 IU/L) • Mean DPD: 40 IU/L (normal: 6.8 IU/L) • Skeletal radiographs reveal diagnostic changes of coarse trabeculation; cortical thickening; and spotty sclerosis in the skull, pelvis, spine, and scapula that later becomes widespread. Radiographic findings of PDB are typically present ten to 15 years before the diagnosis of PDB can be made based on clinical findings. • Radionuclide scan shows focally increased bony uptake (a more sensitive indicator of PDB than skeletal radiographs). ## Establishing the Diagnosis The diagnosis of IBMPFD 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 IBMPFD is broad, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of IBMPFD molecular genetic testing approaches can include use of a For an introduction to multigene panels click If no pathogenic variant is found in When the diagnosis of IBMPFD is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia (IBMPFD) 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. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used 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 data on detection rate of gene-targeted deletion/duplication analysis are available. • For an introduction to multigene panels click • If no pathogenic variant is found in ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of IBMPFD molecular genetic testing approaches can include use of a For an introduction to multigene panels click If no pathogenic variant is found in • For an introduction to multigene panels click • If no pathogenic variant is found in ## Option 2 When the diagnosis of IBMPFD is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia (IBMPFD) 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. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used 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 data on detection rate of gene-targeted deletion/duplication analysis are available. ## Clinical Characteristics Inclusion body myopathy associated with Paget disease of bone and/or frontotemporal dementia (IBMPFD) is characterized by adult-onset proximal and distal muscle weakness (clinically resembling a limb-girdle muscular dystrophy syndrome), early-onset Paget disease of bone (PDB), and premature frontotemporal dementia (FTD). Death typically occurs in the sixth or seventh decade from progressive respiratory failure. Recently Diagnosis was at a mean age of 43 years (range: 3-61 years; typically 20s-40s). Muscle weakness is usually proximal, involving the hip and shoulder girdle muscles; however, several individuals have had initial weakness of the muscles of the hands and feet. Affected individuals experience difficulty walking upstairs and raising the arms above the shoulders. The gait is typically waddling and the stance lordotic. Weakness progresses and other limb and respiratory muscle groups become involved over time. Many affected individuals become wheelchair bound. Muscle biopsy findings: Light microscopy of muscle biopsy reveals nonspecific changes: variability in fiber size, type I fiber predominance, and atrophic and hypertrophic fibers. Fibers may contain single or multiple vacuoles. Rimmed vacuoles and cytoplasmic ubiquitin and TAR DNA-binding protein 43 (TDP-43) positive inclusions visible in some fibers are characteristic of inclusion body myopathy [ Electron microscopy may show nonspecific cytoplasmic changes. The characteristic inclusions, composed of randomly oriented tubulofilaments roughly 15-21 nm in diameter, are seen in muscle nuclei and in cytoplasm. In one family, atrophic and vacuolated muscle fibers containing abundant cytoplasmic-paired helical filaments with epitopes of phosphorylated tau, congophilia, abnormal accumulation of β-amyloid precursor protein (βAPP) epitopes, and accumulation of apolipoprotein E (ApoE) were observed [ PDB involves focal areas of increased bone turnover that lead to complications such as bone pain, localized painful enlargement and deformity of the long bones, pathologic fractures (rare), and deafness. PDB typically manifests as spine and/or hip pain. Among those studied, features were consistent with frontotemporal dementia. In the early stages, dysnomia, dyscalculia, comprehension deficits, and paraphasic errors were evident. Adjusting for aphasia, episodic memory is minimally impaired in the early stages. Progressive aphasia with inability to speak, auditory comprehension deficits for even one-step commands, alexia, and agraphia are noted. In families studied by An earlier study by IBMPFD associated with pathogenic variants in either No major differences are noted in the IBMPFD phenotype associated with pathogenic variants in either Penetrance is almost complete; however, it is age related. Presence of all three major manifestations: 10% of affected individuals Presence of only two major manifestations in any combination: 50% of affected individuals Each of the three major manifestations as an apparently isolated finding: Inclusion body myopathy: 37% Paget disease of bone: 5% Frontotemporal dementia: 3% IBMPFD is rare; the true prevalence is unknown. A study from the UK estimated a prevalence of approximately 1:300,000, although this was not a population ascertainment and the true incidence may be higher. Because previous studies have shown that individuals receive a diagnosis after a diagnostic odyssey of several years and are typically seen by numerous specialists in a number of disciplines (neurology, rheumatology, endocrinology, pain management, genetics), this disorder is considered to be significantly underdiagnosed. As the spectrum of disorders associated with pathogenic variants in Very few families have been reported with IBMPFD associated with a pathogenic variant in either • Diagnosis was at a mean age of 43 years (range: 3-61 years; typically 20s-40s). • Muscle weakness is usually proximal, involving the hip and shoulder girdle muscles; however, several individuals have had initial weakness of the muscles of the hands and feet. • Affected individuals experience difficulty walking upstairs and raising the arms above the shoulders. • The gait is typically waddling and the stance lordotic. • Weakness progresses and other limb and respiratory muscle groups become involved over time. Many affected individuals become wheelchair bound. • Muscle biopsy findings: • Light microscopy of muscle biopsy reveals nonspecific changes: variability in fiber size, type I fiber predominance, and atrophic and hypertrophic fibers. Fibers may contain single or multiple vacuoles. Rimmed vacuoles and cytoplasmic ubiquitin and TAR DNA-binding protein 43 (TDP-43) positive inclusions visible in some fibers are characteristic of inclusion body myopathy [ • Electron microscopy may show nonspecific cytoplasmic changes. The characteristic inclusions, composed of randomly oriented tubulofilaments roughly 15-21 nm in diameter, are seen in muscle nuclei and in cytoplasm. In one family, atrophic and vacuolated muscle fibers containing abundant cytoplasmic-paired helical filaments with epitopes of phosphorylated tau, congophilia, abnormal accumulation of β-amyloid precursor protein (βAPP) epitopes, and accumulation of apolipoprotein E (ApoE) were observed [ • Light microscopy of muscle biopsy reveals nonspecific changes: variability in fiber size, type I fiber predominance, and atrophic and hypertrophic fibers. Fibers may contain single or multiple vacuoles. Rimmed vacuoles and cytoplasmic ubiquitin and TAR DNA-binding protein 43 (TDP-43) positive inclusions visible in some fibers are characteristic of inclusion body myopathy [ • Electron microscopy may show nonspecific cytoplasmic changes. The characteristic inclusions, composed of randomly oriented tubulofilaments roughly 15-21 nm in diameter, are seen in muscle nuclei and in cytoplasm. In one family, atrophic and vacuolated muscle fibers containing abundant cytoplasmic-paired helical filaments with epitopes of phosphorylated tau, congophilia, abnormal accumulation of β-amyloid precursor protein (βAPP) epitopes, and accumulation of apolipoprotein E (ApoE) were observed [ • Light microscopy of muscle biopsy reveals nonspecific changes: variability in fiber size, type I fiber predominance, and atrophic and hypertrophic fibers. Fibers may contain single or multiple vacuoles. Rimmed vacuoles and cytoplasmic ubiquitin and TAR DNA-binding protein 43 (TDP-43) positive inclusions visible in some fibers are characteristic of inclusion body myopathy [ • Electron microscopy may show nonspecific cytoplasmic changes. The characteristic inclusions, composed of randomly oriented tubulofilaments roughly 15-21 nm in diameter, are seen in muscle nuclei and in cytoplasm. In one family, atrophic and vacuolated muscle fibers containing abundant cytoplasmic-paired helical filaments with epitopes of phosphorylated tau, congophilia, abnormal accumulation of β-amyloid precursor protein (βAPP) epitopes, and accumulation of apolipoprotein E (ApoE) were observed [ • Presence of all three major manifestations: 10% of affected individuals • Presence of only two major manifestations in any combination: 50% of affected individuals • Each of the three major manifestations as an apparently isolated finding: • Inclusion body myopathy: 37% • Paget disease of bone: 5% • Frontotemporal dementia: 3% • Inclusion body myopathy: 37% • Paget disease of bone: 5% • Frontotemporal dementia: 3% • Inclusion body myopathy: 37% • Paget disease of bone: 5% • Frontotemporal dementia: 3% ## Clinical Description Inclusion body myopathy associated with Paget disease of bone and/or frontotemporal dementia (IBMPFD) is characterized by adult-onset proximal and distal muscle weakness (clinically resembling a limb-girdle muscular dystrophy syndrome), early-onset Paget disease of bone (PDB), and premature frontotemporal dementia (FTD). Death typically occurs in the sixth or seventh decade from progressive respiratory failure. Recently Diagnosis was at a mean age of 43 years (range: 3-61 years; typically 20s-40s). Muscle weakness is usually proximal, involving the hip and shoulder girdle muscles; however, several individuals have had initial weakness of the muscles of the hands and feet. Affected individuals experience difficulty walking upstairs and raising the arms above the shoulders. The gait is typically waddling and the stance lordotic. Weakness progresses and other limb and respiratory muscle groups become involved over time. Many affected individuals become wheelchair bound. Muscle biopsy findings: Light microscopy of muscle biopsy reveals nonspecific changes: variability in fiber size, type I fiber predominance, and atrophic and hypertrophic fibers. Fibers may contain single or multiple vacuoles. Rimmed vacuoles and cytoplasmic ubiquitin and TAR DNA-binding protein 43 (TDP-43) positive inclusions visible in some fibers are characteristic of inclusion body myopathy [ Electron microscopy may show nonspecific cytoplasmic changes. The characteristic inclusions, composed of randomly oriented tubulofilaments roughly 15-21 nm in diameter, are seen in muscle nuclei and in cytoplasm. In one family, atrophic and vacuolated muscle fibers containing abundant cytoplasmic-paired helical filaments with epitopes of phosphorylated tau, congophilia, abnormal accumulation of β-amyloid precursor protein (βAPP) epitopes, and accumulation of apolipoprotein E (ApoE) were observed [ PDB involves focal areas of increased bone turnover that lead to complications such as bone pain, localized painful enlargement and deformity of the long bones, pathologic fractures (rare), and deafness. PDB typically manifests as spine and/or hip pain. Among those studied, features were consistent with frontotemporal dementia. In the early stages, dysnomia, dyscalculia, comprehension deficits, and paraphasic errors were evident. Adjusting for aphasia, episodic memory is minimally impaired in the early stages. Progressive aphasia with inability to speak, auditory comprehension deficits for even one-step commands, alexia, and agraphia are noted. In families studied by An earlier study by IBMPFD associated with pathogenic variants in either • Diagnosis was at a mean age of 43 years (range: 3-61 years; typically 20s-40s). • Muscle weakness is usually proximal, involving the hip and shoulder girdle muscles; however, several individuals have had initial weakness of the muscles of the hands and feet. • Affected individuals experience difficulty walking upstairs and raising the arms above the shoulders. • The gait is typically waddling and the stance lordotic. • Weakness progresses and other limb and respiratory muscle groups become involved over time. Many affected individuals become wheelchair bound. • Muscle biopsy findings: • Light microscopy of muscle biopsy reveals nonspecific changes: variability in fiber size, type I fiber predominance, and atrophic and hypertrophic fibers. Fibers may contain single or multiple vacuoles. Rimmed vacuoles and cytoplasmic ubiquitin and TAR DNA-binding protein 43 (TDP-43) positive inclusions visible in some fibers are characteristic of inclusion body myopathy [ • Electron microscopy may show nonspecific cytoplasmic changes. The characteristic inclusions, composed of randomly oriented tubulofilaments roughly 15-21 nm in diameter, are seen in muscle nuclei and in cytoplasm. In one family, atrophic and vacuolated muscle fibers containing abundant cytoplasmic-paired helical filaments with epitopes of phosphorylated tau, congophilia, abnormal accumulation of β-amyloid precursor protein (βAPP) epitopes, and accumulation of apolipoprotein E (ApoE) were observed [ • Light microscopy of muscle biopsy reveals nonspecific changes: variability in fiber size, type I fiber predominance, and atrophic and hypertrophic fibers. Fibers may contain single or multiple vacuoles. Rimmed vacuoles and cytoplasmic ubiquitin and TAR DNA-binding protein 43 (TDP-43) positive inclusions visible in some fibers are characteristic of inclusion body myopathy [ • Electron microscopy may show nonspecific cytoplasmic changes. The characteristic inclusions, composed of randomly oriented tubulofilaments roughly 15-21 nm in diameter, are seen in muscle nuclei and in cytoplasm. In one family, atrophic and vacuolated muscle fibers containing abundant cytoplasmic-paired helical filaments with epitopes of phosphorylated tau, congophilia, abnormal accumulation of β-amyloid precursor protein (βAPP) epitopes, and accumulation of apolipoprotein E (ApoE) were observed [ • Light microscopy of muscle biopsy reveals nonspecific changes: variability in fiber size, type I fiber predominance, and atrophic and hypertrophic fibers. Fibers may contain single or multiple vacuoles. Rimmed vacuoles and cytoplasmic ubiquitin and TAR DNA-binding protein 43 (TDP-43) positive inclusions visible in some fibers are characteristic of inclusion body myopathy [ • Electron microscopy may show nonspecific cytoplasmic changes. The characteristic inclusions, composed of randomly oriented tubulofilaments roughly 15-21 nm in diameter, are seen in muscle nuclei and in cytoplasm. In one family, atrophic and vacuolated muscle fibers containing abundant cytoplasmic-paired helical filaments with epitopes of phosphorylated tau, congophilia, abnormal accumulation of β-amyloid precursor protein (βAPP) epitopes, and accumulation of apolipoprotein E (ApoE) were observed [ ## Genotype-Phenotype Correlations No major differences are noted in the IBMPFD phenotype associated with pathogenic variants in either ## Penetrance Penetrance is almost complete; however, it is age related. Presence of all three major manifestations: 10% of affected individuals Presence of only two major manifestations in any combination: 50% of affected individuals Each of the three major manifestations as an apparently isolated finding: Inclusion body myopathy: 37% Paget disease of bone: 5% Frontotemporal dementia: 3% • Presence of all three major manifestations: 10% of affected individuals • Presence of only two major manifestations in any combination: 50% of affected individuals • Each of the three major manifestations as an apparently isolated finding: • Inclusion body myopathy: 37% • Paget disease of bone: 5% • Frontotemporal dementia: 3% • Inclusion body myopathy: 37% • Paget disease of bone: 5% • Frontotemporal dementia: 3% • Inclusion body myopathy: 37% • Paget disease of bone: 5% • Frontotemporal dementia: 3% ## Prevalence IBMPFD is rare; the true prevalence is unknown. A study from the UK estimated a prevalence of approximately 1:300,000, although this was not a population ascertainment and the true incidence may be higher. Because previous studies have shown that individuals receive a diagnosis after a diagnostic odyssey of several years and are typically seen by numerous specialists in a number of disciplines (neurology, rheumatology, endocrinology, pain management, genetics), this disorder is considered to be significantly underdiagnosed. As the spectrum of disorders associated with pathogenic variants in Very few families have been reported with IBMPFD associated with a pathogenic variant in either ## Genetically Related (Allelic) Disorders Isolated proximal limb-girdle myopathy Isolated dementia Isolated familial amyotrophic lateral sclerosis Hereditary spastic paraplegia Charcot-Marie-Tooth disease type 2 Individuals with pathogenic variants in No phenotype other than IBMPFD is known to be associated with pathogenic variants in • Isolated proximal limb-girdle myopathy • Isolated dementia • Isolated familial amyotrophic lateral sclerosis • Hereditary spastic paraplegia • Charcot-Marie-Tooth disease type 2 ## Differential Diagnosis The differential diagnosis of inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFD) includes the following disorders. Limb-girdle myopathy with bone fragility (also referred to as diaphyseal medullary stenosis with malignant fibrous histiocytoma [DMSMFH]) (OMIM Nasu Hakola disease (also known as • Limb-girdle myopathy with bone fragility (also referred to as diaphyseal medullary stenosis with malignant fibrous histiocytoma [DMSMFH]) (OMIM • Nasu Hakola disease (also known as ## Management To establish the extent of disease in an individual diagnosed with inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFD), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with IBMPFD Individuals benefit from care by a multidisciplinary team including: a neuromuscular specialist, endocrinologist with expertise in Paget disease, specially trained nurses, pulmonologist, speech therapist, physical therapist, occupational therapist, respiratory therapist, nutritionist, psychologist, social worker, and medical geneticist/genetic counselor. Treatment of Manifestations in Individuals with IBMPFD OT = occupational therapy; PT = physical therapy Recommended Surveillance for Individuals with IBMFD Obtain baseline studies. If normal, reevaluate at 2-3-yr intervals or if symptomatic. Annual alkaline phosphatase Bone scan only when alkaline phosphatase ↑ or symptoms of pain or bony deformity observed Individuals and their families should be educated about safety precautions and environmental modification in the home and at work. See Search • Obtain baseline studies. • If normal, reevaluate at 2-3-yr intervals or if symptomatic. • Annual alkaline phosphatase • Bone scan only when alkaline phosphatase ↑ or symptoms of pain or bony deformity observed ## Evaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFD), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with IBMPFD ## Treatment of Manifestations Individuals benefit from care by a multidisciplinary team including: a neuromuscular specialist, endocrinologist with expertise in Paget disease, specially trained nurses, pulmonologist, speech therapist, physical therapist, occupational therapist, respiratory therapist, nutritionist, psychologist, social worker, and medical geneticist/genetic counselor. Treatment of Manifestations in Individuals with IBMPFD OT = occupational therapy; PT = physical therapy ## Surveillance Recommended Surveillance for Individuals with IBMFD Obtain baseline studies. If normal, reevaluate at 2-3-yr intervals or if symptomatic. Annual alkaline phosphatase Bone scan only when alkaline phosphatase ↑ or symptoms of pain or bony deformity observed • Obtain baseline studies. • If normal, reevaluate at 2-3-yr intervals or if symptomatic. • Annual alkaline phosphatase • Bone scan only when alkaline phosphatase ↑ or symptoms of pain or bony deformity observed ## Agents/Circumstances to Avoid Individuals and their families should be educated about safety precautions and environmental modification in the home and at work. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFD) is inherited in an autosomal dominant manner. Approximately 80% of individuals diagnosed with IBMPFD have an affected parent. A proband with IBMPFD may have the disorder as the result of a Molecular genetic testing is recommended for the parents of a proband with an apparent If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a The family history of some individuals diagnosed with IBMPFD 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 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 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 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 increased risk for IBMPFD because of the possibility of late onset in a heterozygous parent or the theoretic possibility of parental germline mosaicism. Predictive testing for at-risk relatives is possible once the pathogenic variant has been identified in an affected family member. Because of the individualized nature of predictive testing, consultation with a genetic counselor or clinical geneticist prior to and following testing is recommended. A testing protocol similar to that used for other genetic disorders (e.g., breast cancer, Huntington disease, familial Alzheimer disease) has been developed [ 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 IBMPFD, it is appropriate to consider testing of symptomatic individuals regardless of age. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Once the IBMPFD-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • Approximately 80% of individuals diagnosed with IBMPFD have an affected parent. • A proband with IBMPFD may have the disorder as the result of a • Molecular genetic testing is recommended for the parents of a proband with an apparent • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a • The family history of some individuals diagnosed with IBMPFD 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 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 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 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 increased risk for IBMPFD because of the possibility of late onset in a heterozygous parent or the theoretic possibility of parental germline mosaicism. • Predictive testing for at-risk relatives is possible once the pathogenic variant has been identified in an affected family member. • Because of the individualized nature of predictive testing, consultation with a genetic counselor or clinical geneticist prior to and following testing is recommended. A testing protocol similar to that used for other genetic disorders (e.g., breast cancer, Huntington disease, familial Alzheimer disease) has been developed [ • 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 Inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFD) is inherited in an autosomal dominant manner. ## Risk to Family Members Approximately 80% of individuals diagnosed with IBMPFD have an affected parent. A proband with IBMPFD may have the disorder as the result of a Molecular genetic testing is recommended for the parents of a proband with an apparent If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a The family history of some individuals diagnosed with IBMPFD 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 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 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 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 increased risk for IBMPFD because of the possibility of late onset in a heterozygous parent or the theoretic possibility of parental germline mosaicism. • Approximately 80% of individuals diagnosed with IBMPFD have an affected parent. • A proband with IBMPFD may have the disorder as the result of a • Molecular genetic testing is recommended for the parents of a proband with an apparent • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a • The family history of some individuals diagnosed with IBMPFD 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 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 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 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 increased risk for IBMPFD because of the possibility of late onset in a heterozygous parent or the theoretic possibility of parental germline mosaicism. ## Related Genetic Counseling Issues Predictive testing for at-risk relatives is possible once the pathogenic variant has been identified in an affected family member. Because of the individualized nature of predictive testing, consultation with a genetic counselor or clinical geneticist prior to and following testing is recommended. A testing protocol similar to that used for other genetic disorders (e.g., breast cancer, Huntington disease, familial Alzheimer disease) has been developed [ 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 IBMPFD, it is appropriate to consider testing of symptomatic individuals regardless of age. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • Predictive testing for at-risk relatives is possible once the pathogenic variant has been identified in an affected family member. • Because of the individualized nature of predictive testing, consultation with a genetic counselor or clinical geneticist prior to and following testing is recommended. A testing protocol similar to that used for other genetic disorders (e.g., breast cancer, Huntington disease, familial Alzheimer disease) has been developed [ • 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 IBMPFD-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources PO Box 6533 Americus GA 31709 United Kingdom 1737 King Street Suite 600 Alexandria VA 22314 • • PO Box 6533 • Americus GA 31709 • • • • • • • • • United Kingdom • • • 1737 King Street • Suite 600 • Alexandria VA 22314 • • • ## Molecular Genetics Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia ( Cell cycle control homotypic membrane fusion Nuclear envelope reconstruction Postmitotic organelle reassembly Ubiquitin-dependent protein degradation. VCP forms a homohexamer in which the double ψ barrel D1/D2 domains bind in a head-to-tail ring [ Growing evidence implicates VCP in neuronal degeneration. Pathogenic variants in the D2 domain are associated with accumulation of abnormal polyubiquitinated proteins. VCP also binds to expanded polyglutamine (poly-Q) protein aggregates via poly-Q binding (amino acids 142-200). Single disease-associated variants, one in The double ψ barrel (amino acids 25-106) The four-stranded β barrel (amino acids 112-186) A short linker region (amino acids 107-111) Examples of recurrent pathogenic variants in the CDC48 domain are given in Studies in yeast suggest that the IBMPFD: Gene-Specific Laboratory Considerations Genes from IBMPFD: Notable Pathogenic Variants by Gene Variants listed in the table have been provided by the author. Genes from See comment for p.Ala232Glu. • Cell cycle control homotypic membrane fusion • Nuclear envelope reconstruction • Postmitotic organelle reassembly • Ubiquitin-dependent protein degradation. • The double ψ barrel (amino acids 25-106) • The four-stranded β barrel (amino acids 112-186) • A short linker region (amino acids 107-111) ## Molecular Pathogenesis Cell cycle control homotypic membrane fusion Nuclear envelope reconstruction Postmitotic organelle reassembly Ubiquitin-dependent protein degradation. VCP forms a homohexamer in which the double ψ barrel D1/D2 domains bind in a head-to-tail ring [ Growing evidence implicates VCP in neuronal degeneration. Pathogenic variants in the D2 domain are associated with accumulation of abnormal polyubiquitinated proteins. VCP also binds to expanded polyglutamine (poly-Q) protein aggregates via poly-Q binding (amino acids 142-200). Single disease-associated variants, one in The double ψ barrel (amino acids 25-106) The four-stranded β barrel (amino acids 112-186) A short linker region (amino acids 107-111) Examples of recurrent pathogenic variants in the CDC48 domain are given in Studies in yeast suggest that the IBMPFD: Gene-Specific Laboratory Considerations Genes from IBMPFD: Notable Pathogenic Variants by Gene Variants listed in the table have been provided by the author. Genes from See comment for p.Ala232Glu. • Cell cycle control homotypic membrane fusion • Nuclear envelope reconstruction • Postmitotic organelle reassembly • Ubiquitin-dependent protein degradation. • The double ψ barrel (amino acids 25-106) • The four-stranded β barrel (amino acids 112-186) • A short linker region (amino acids 107-111) ## Chapter Notes Dr Kimonis' University of California, Irvine We acknowledge the support of the NIH, MDA and the contribution of collaborators and families. Funding of this study was from the NINDS, NIAMS, National Institutes of Health (RO1, R03, R21, R56), Muscular Dystrophy Association, and Paget Foundation. Sandra Donkervoort, MS, CGC; National Institute of Neurological Disorders and Stroke (2011-2019)Virginia Kimonis, MD (2007-present)Giles Watts, PhD; University of East Anglia (2007-2019) 12 September 2019 (ha) Comprehensive update posted live 28 July 2011 (me) Comprehensive update posted live 19 May 2009 (cd) Revision: prenatal testing available clinically 5 March 2008 (cd) Revision: sequence analysis available clinically 25 May 2007 (me) Review posted live 18 November 2004 (vk, gw) Original submission • 12 September 2019 (ha) Comprehensive update posted live • 28 July 2011 (me) Comprehensive update posted live • 19 May 2009 (cd) Revision: prenatal testing available clinically • 5 March 2008 (cd) Revision: sequence analysis available clinically • 25 May 2007 (me) Review posted live • 18 November 2004 (vk, gw) Original submission ## Author Notes Dr Kimonis' University of California, Irvine ## Acknowledgments We acknowledge the support of the NIH, MDA and the contribution of collaborators and families. Funding of this study was from the NINDS, NIAMS, National Institutes of Health (RO1, R03, R21, R56), Muscular Dystrophy Association, and Paget Foundation. ## Author History Sandra Donkervoort, MS, CGC; National Institute of Neurological Disorders and Stroke (2011-2019)Virginia Kimonis, MD (2007-present)Giles Watts, PhD; University of East Anglia (2007-2019) ## Revision History 12 September 2019 (ha) Comprehensive update posted live 28 July 2011 (me) Comprehensive update posted live 19 May 2009 (cd) Revision: prenatal testing available clinically 5 March 2008 (cd) Revision: sequence analysis available clinically 25 May 2007 (me) Review posted live 18 November 2004 (vk, gw) Original submission • 12 September 2019 (ha) Comprehensive update posted live • 28 July 2011 (me) Comprehensive update posted live • 19 May 2009 (cd) Revision: prenatal testing available clinically • 5 March 2008 (cd) Revision: sequence analysis available clinically • 25 May 2007 (me) Review posted live • 18 November 2004 (vk, gw) Original submission ## References Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available • Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available ## Published Guidelines / Consensus Statements Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available • Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available ## Literature Cited IBMPFD phenotypes FTD = frontotemporal dementia; IBM = inclusion body myopathy; IBMPFD = inclusion body myopathy with Paget disease of bone and/or frontotemporal dementia; PDB = Paget disease of bone From	[ "E Al-Obeidi, S Al-Tahan, A Surampalli, N Goyal, AK Wang, A Hermann, M Omizo, C Smith, T Mozaffar, V Kimonis. Genotype-phenotype study in patients with valosin-containing protein mutations associated with multisystem proteinopathy.. Clin Genet. 2018;93:119-25", "A Alvarez, Z Simmons, WK Engel, V Askanas. New autosomal dominant inclusion body myopathy (AD-IBM) with many congophilic muscle nuclei that contain paired-helical filaments (PHFs) composed of phosphorylated tau.. Neurology 1998;50:A204", "V Askanas, WK Engel. Inclusion-body myositis and myopathies: different etiologies, possibly similar pathogenic mechanisms.. Curr Opin Neurol 2002;15:525-31", "M Benatar, J Wuu, C Fernandez, CC Weihl, H Katzen, J Steele, B Oskarsson, JP Taylor. Motor neuron involvement in multisystem proteinopathy: Implications for ALS.. Neurology. 2013;80:1874-80", "N Chan, C Le, P Shieh, T Mozaffar, M Khare, J Bronstein, V Kimonis. Valosin-containing protein mutation and Parkinson's disease.. Parkinsonism Relat Disord. 2012;18:107-9", "RM Dai, CC Li. Valosin-containing protein is a multi-ubiquitin chain-targeting factor required in ubiquitin-proteasome degradation.. Nat Cell Biol 2001;3:740-4", "A Djamshidian, J Schaefer, D Haubenberger, E Stogmann, F Zimprich, E Auff, A Zimprich. A novel mutation in the VCP gene (G157R) in a German family with inclusion-body myopathy with Paget disease of bone and frontotemporal dementia.. Muscle Nerve. 2009;39:389-91", "V Fernández-Sáiz, A. Buchberger. Imbalances in p97 co-factor interactions in human proteinopathy.. EMBO reports. 2010;11:479-85", "MS Forman, IR Mackenzie, NJ Cairns, E Swanson, PJ Boyer, DA Drachman, BS Jhaveri, JH Karlawish, A Pestronk, TW Smith, PH Tu, GD Watts, WR Markesbery, CD Smith, VE Kimonis. Novel ubiquitin neuropathology in frontotemporal dementia with valosin-containing protein gene mutations.. J Neuropathol Exp Neurol 2006;65:571-81", "L Guyant-Maréchal, A Laquerrière, C Duyckaerts, C Dumanchin, J Bou, F Dugny, I Le Ber, T Frébourg, D Hannequin, D Campion. Valosin-containing protein gene mutations: clinical and neuropathologic features.. Neurology 2006;67:644-51", "D Halawani, AC LeBlanc, I Rouiller, SW Michnick, MJ Servant, M Latterich. Hereditary inclusion body myopathy-linked p97/VCP mutations in the NH2 domain and the D1 ring modulate p97/VCP ATPase activity and D2 ring conformation.. Mol Cell Biol. 2009;29:4484-94", "D Haubenberger, RE Bittner, S Rauch-Shorny, F Zimprich, C Mannhalter, L Wagner, I Mineva, K Vass, E Auff, A Zimprich. Inclusion body myopathy and Paget disease is linked to a novel mutation in the VCP gene.. Neurology 2005;65:1304-5", "M Hetzer, HH Meyer, TC Walther, D Bilbao-Cortes, G Warren, IW Mattaj. Distinct AAA-ATPase p97 complexes function in discrete steps of nuclear assembly.. Nat Cell Biol 2001;3:1086-91", "CU Hübbers, CS Clemen, K Kesper, A Böddrich, A Hofmann, O Kämäräinen, K Tolksdorf, M Stumpf, J Reichelt, U Roth, S Krause, G Watts, V Kimonis, MP Wattjes, J Reimann, DR Thal, K Biermann, BO Evert, H Lochmüller, EE Wanker, BG Schoser, AA Noegel, R Schröder. Pathological consequences of VCP mutations on human striated muscle.. Brain 2007;130:381-93", "E Jarosch, R Geiss-Friedlander, B Meusser, J Walter, T Sommer. Protein dislocation from the endoplasmic reticulum--pulling out the suspect.. Traffic 2002;3:530-6", "JO Johnson, J Mandrioli, M Benatar, Y Abramzon, VM Van Deerlin, JQ Trojanowski, JR Gibbs, M Brunetti, S Gronka, J Wuu, J Ding, L McCluskey, M Martinez-Lage, D Falcone, DG Hernandez, S Arepalli, S Chong, JC Schymick, J Rothstein, F Landi, YD Wang, A Calvo, G Mora, M Sabatelli, MR Monsurrò, S Battistini, F Salvi, R Spataro, P Sola, G Borghero. Galassi G, Scholz SW, Taylor JP, Restagno G, Chiò A, Traynor BJ. Exome sequencing reveals VCP mutations as a cause of familial ALS.. Neuron. 2010;68:857-64", "JS Ju, CC Weihl. Inclusion body myopathy, Paget's disease of the bone and fronto-temporal dementia: a disorder of autophagy.. Hum Mol Genet. 2010;19:R38-45", "HJ Kim, NC Kim, YD Wang, EA Scarborough, J Moore, Z Diaz, KS MacLea, B Freibaum, S Li, A Molliex, AP Kanagaraj, R Carter, KB Boylan, AM Wojtas, R Rademakers, JL Pinkus, SA Greenberg, JQ Trojanowski, BJ Traynor, BN Smith, S Topp, AS Gkazi, J Miller, CE Shaw, M Kottlors, J Kirschner, A Pestronk, YR Li, AF Ford, AD Gitler, M Benatar, OD King, VE Kimonis, ED Ross, CC Weihl, J Shorter, JP Taylor. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS.. Nature. 2013;495:467-73", "VE Kimonis, MJ Kovach, B Waggoner, S Leal, A Salam, L Rimer, K Davis, R Khardori, D Gelber. Clinical and molecular studies in a unique family with autosomal dominant limb-girdle muscular dystrophy and Paget disease of bone.. Genet Med 2000;2:232-41", "VE Kimonis, SG Mehta, EC Fulchiero, D Thomasova, M Pasquali, K Boycott, EG Neilan, A Kartashov, MS Forman, S Tucker, K Kimonis, S Mumm, MP Whyte, CD Smith, GD Watts. Clinical studies in familial VCP myopathy associated with Paget disease of bone and frontotemporal dementia.. Am J Med Genet 2008;146A:745-57", "H Kondo, C Rabouille, R Newman, TP Levine, D Pappin, P Freemont, G Warren. p47 is a cofactor for p97-mediated membrane fusion.. Nature 1997;388:75-8", "KR Kumar, M Needham, K Mina, M Davis, J Brewer, C Staples, K Ng, CM Sue, FL Mastaglia. Two Australian families with inclusion-body myopathy, Paget's disease of bone and frontotemporal dementia: novel clinical and genetic findings.. Neuromuscul Disord. 2010;20:330-4", "E Majounie, BJ Traynor, A Chio, G Restagno, J Mandrioli, M Benatar, JP Taylor, AB Singleton. Mutational analysis of the VCP gene in Parkinson’s disease.. Neurobiol Aging 2012;33:209.e1-2", "HH Meyer, JG Shorter, J Seemann, D Pappin, G Warren. A complex of mammalian ufd1 and npl4 links the AAA-ATPase, p97, to ubiquitin and nuclear transport pathways.. EMBO J 2000;19:2181-92", "BL Miller, C Ikonte, M Ponton, M Levy, K Boone, A Darby, N Berman, I Mena, JL Cummings. A study of the Lund-Manchester research criteria for frontotemporal dementia: clinical and single-photon emission CT correlations.. Neurology 1997;48:937-42", "TD Miller, AP Jackson, R Barresi, CM Smart, M Eugenicos, D Summers, S Clegg, V Straub, J Stone. Inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFD): clinical features including sphincter disturbance in a large pedigree.. J Neurol Neurosurg Psychiatry. 2009;80:583-4", "M Neumann, IR Mackenzie, NJ Cairns, PJ Boyer, WR Markesbery, CD Smith, JP Taylor, HA Kretzschmar, VE Kimonis, MS Forman. TDP-43 in the ubiquitin pathology of frontotemporal dementia with VCP gene mutations.. J Neuropathol Exp Neurol 2007;66:152-7", "H Niwa, CA Ewens, C Tsang, HO Yeung, X Zhang, PS Freemont. The role of the N-domain in the ATPase activity of the mammalian AAA ATPase p97/VCP.. The Journal of biological chemistry. 2012;287:8561-70", "E Rabinovich, A Kerem, KU Frohlich, N Diamant, S Bar-Nun. AAA-ATPase p97/Cdc48p, a cytosolic chaperone required for endoplasmic reticulum-associated protein degradation.. Mol Cell Biol 2002;22:626-34", "C Rabouille, H Kondo, R Newman, N Hui, P Freemont, G Warren. Syntaxin 5 is a common component of the NSF- and p97-mediated reassembly pathways of Golgi cisternae from mitotic Golgi fragments in vitro.. Cell 1998;92:603-10", "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", "M Rape, T Hoppe, I Gorr, M Kalocay, H Richly, S Jentsch. Mobilization of processed, membrane-tethered SPT23 transcription factor by CDC48(UFD1/NPL4), a ubiquitin-selective chaperone.. Cell 2001;107:667-77", "M Regensburger, M Türk, A Pagenstecher, R Schröder, J. Winkler. VCP-related multisystem proteinopathy presenting as early-onset Parkinson disease.. Neurology. 2017;89:746-8", "S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24", "S Spina, AD Van Laar, JR Murrell, RL Hamilton, JK Kofler, F Epperson, MR Farlow, OL Lopez, J Quinlan, ST DeKosky, B Ghetti. Phenotypic variability in three families with valosin-containing protein mutation.. Eur J Neurol. 2013;20:251-8", "A Surampalli, M Khare, G Kubrussi, M Wencel, J Tanaja, S Donkervoort, K Osann, M Simon, D Wallace, C Smith, A McInerney-Leo, V Kimonis. Psychological impact of predictive genetic testing in vcp inclusion body myopathy, Paget disease of bone and frontotemporal dementia.. J Genet Couns. 2015;24:842-50", "J van der Zee, D Pirici, T Van Langenhove, S Engelborghs, R Vandenberghe, M Hoffmann, G Pusswald, M Van den Broeck, K Peeters, M Mattheijssens, JJ Martin, PP De Deyn, M Cruts, D Haubenberger, S Kumar-Singh, A Zimprich, C Van Broeckhoven. Clinical heterogeneity in 3 unrelated families linked to VCP p.Arg159His.. Neurology. 2009;73:626-32", "B Waggoner, MJ Kovach, M Winkelman, D Cai, R Khardori, D Gelber, VE Kimonis. Heterogeneity in familial dominant Paget disease of bone and muscular dystrophy.. Am J Med Genet 2002;108:187-91", "CC Weihl, P Temiz, SE Miller, G Watts, C Smith, M Forman, PI Hanson, V Kimonis, A Pestronk. TDP-43 accumulation in inclusion body myopathy muscle suggests a common pathogenic mechanism with frontotemporal dementia.. J Neurol Neurosurg Psychiatry 2008;79:1186-9", "T Zhang, P Mishra, BA Hay, D Chan, M Guo. Valosin-containing protein (VCP/p97) inhibitors relieve Mitofusin-dependent mitochondrial defects due to VCP disease mutants.. eLife. 2017:6", "X Zhang, A Shaw, PA Bates, RH Newman, B Gowen, E Orlova, MA Gorman, H Kondo, P Dokurno, J Lally, G Leonard, H Meyer, M van Heel, PS Freemont. Structure of the AAA ATPase p97.. Mol Cell 2000;6:1473-84" ]	25/5/2007	12/9/2019	19/5/2009	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
idednik	idednik	[ "Intellectual Disability, Enteropathy, Deafness, Peripheral Neuropathy, Ichthyosis, and Keratoderma Syndrome", "Keratitis-Ichthyosis-Deafness, Autosomal Recessive (KIDAR) Syndrome", "MEDNIK Syndrome", "MEDNIK-like Syndrome", "Intellectual Disability, Enteropathy, Deafness, Peripheral Neuropathy, Ichthyosis, and Keratoderma Syndrome", "Keratitis-Ichthyosis-Deafness, Autosomal Recessive (KIDAR) Syndrome", "MEDNIK Syndrome", "MEDNIK-like Syndrome", "AP-1 complex subunit beta-1", "AP-1 complex subunit sigma-1A", "AP1B1", "AP1S1", "IDEDNIK Syndrome" ]	IDEDNIK Syndrome	Hessa S Alsaif, Fowzan S Alkuraya	Summary IDEDNIK syndrome is characterized by enteropathy, poor weight gain, growth deficiency, skin manifestations (ichthyosis, erythroderma, and keratoderma), sparse hair, global developmental delay, mild-to-severe intellectual disability, and deafness. Additional manifestations can include liver disease, recurrent infections, and hematologic and ocular manifestations (photophobia, corneal scarring, and keratitis). Reduced serum ceruloplasmin and total copper levels are common. Some individuals have findings on brain MRI (cerebral atrophy, basal ganglia abnormalities, and thin corpus callosum). Death prior to age two years occurs in some individuals due to severe enteropathy or sepsis; in others survival into adulthood is reported. The diagnosis of IDEDNIK syndrome is established in a proband by identification of biallelic pathogenic variants in IDEDNIK syndrome is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an	## Diagnosis No consensus clinical diagnostic criteria for IDEDNIK syndrome have been published. IDEDNIK syndrome Infantile-onset diarrhea Poor weight gain and growth deficiency Skin and hair manifestations: ichthyosis, erythroderma, hyperkeratosis, sparse hair, and alopecia Global developmental delay Hypotonia Sensorineural hearing loss Intellectual disability (mild to severe) Hepatomegaly Recurrent infections Ocular manifestations: photophobia, corneal scarring, and keratitis Characteristic facial features: high anterior hairline, frontal bossing, low-set ears, and depressed nasal bridge Reduced ceruloplasmin and total serum copper levels Increased serum free copper level Elevated transaminases Elevated plasma total bile acid levels Elevated very long-chain fatty acids Anemia and/or thrombocytopenia Increased urinary copper excretion (2 individuals) Duodenal biopsy: mild villous blunting Liver biopsy: increased copper content (1 individual), liver fibrosis (3 individuals), cirrhosis (2 individuals) Cerebral atrophy (8 of 11 individuals) Basal ganglia abnormalities (3 of 9 individuals) Thin corpus callosum (3 of 5 individuals) The diagnosis of IDEDNIK syndrome Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click When the diagnosis of IDEDNIK 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 IDEDNIK Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Data derived from the subscription-based professional view of Human Gene Mutation Database [ To date, two large To date, no large intragenic • Infantile-onset diarrhea • Poor weight gain and growth deficiency • Skin and hair manifestations: ichthyosis, erythroderma, hyperkeratosis, sparse hair, and alopecia • Global developmental delay • Hypotonia • Sensorineural hearing loss • Intellectual disability (mild to severe) • Hepatomegaly • Recurrent infections • Ocular manifestations: photophobia, corneal scarring, and keratitis • Characteristic facial features: high anterior hairline, frontal bossing, low-set ears, and depressed nasal bridge • Reduced ceruloplasmin and total serum copper levels • Increased serum free copper level • Elevated transaminases • Elevated plasma total bile acid levels • Elevated very long-chain fatty acids • Anemia and/or thrombocytopenia • Increased urinary copper excretion (2 individuals) • Duodenal biopsy: mild villous blunting • Liver biopsy: increased copper content (1 individual), liver fibrosis (3 individuals), cirrhosis (2 individuals) • Cerebral atrophy (8 of 11 individuals) • Basal ganglia abnormalities (3 of 9 individuals) • Thin corpus callosum (3 of 5 individuals) ## Suggestive Findings IDEDNIK syndrome Infantile-onset diarrhea Poor weight gain and growth deficiency Skin and hair manifestations: ichthyosis, erythroderma, hyperkeratosis, sparse hair, and alopecia Global developmental delay Hypotonia Sensorineural hearing loss Intellectual disability (mild to severe) Hepatomegaly Recurrent infections Ocular manifestations: photophobia, corneal scarring, and keratitis Characteristic facial features: high anterior hairline, frontal bossing, low-set ears, and depressed nasal bridge Reduced ceruloplasmin and total serum copper levels Increased serum free copper level Elevated transaminases Elevated plasma total bile acid levels Elevated very long-chain fatty acids Anemia and/or thrombocytopenia Increased urinary copper excretion (2 individuals) Duodenal biopsy: mild villous blunting Liver biopsy: increased copper content (1 individual), liver fibrosis (3 individuals), cirrhosis (2 individuals) Cerebral atrophy (8 of 11 individuals) Basal ganglia abnormalities (3 of 9 individuals) Thin corpus callosum (3 of 5 individuals) • Infantile-onset diarrhea • Poor weight gain and growth deficiency • Skin and hair manifestations: ichthyosis, erythroderma, hyperkeratosis, sparse hair, and alopecia • Global developmental delay • Hypotonia • Sensorineural hearing loss • Intellectual disability (mild to severe) • Hepatomegaly • Recurrent infections • Ocular manifestations: photophobia, corneal scarring, and keratitis • Characteristic facial features: high anterior hairline, frontal bossing, low-set ears, and depressed nasal bridge • Reduced ceruloplasmin and total serum copper levels • Increased serum free copper level • Elevated transaminases • Elevated plasma total bile acid levels • Elevated very long-chain fatty acids • Anemia and/or thrombocytopenia • Increased urinary copper excretion (2 individuals) • Duodenal biopsy: mild villous blunting • Liver biopsy: increased copper content (1 individual), liver fibrosis (3 individuals), cirrhosis (2 individuals) • Cerebral atrophy (8 of 11 individuals) • Basal ganglia abnormalities (3 of 9 individuals) • Thin corpus callosum (3 of 5 individuals) ## Establishing the Diagnosis The diagnosis of IDEDNIK syndrome Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click When the diagnosis of IDEDNIK 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 IDEDNIK Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Data derived from the subscription-based professional view of Human Gene Mutation Database [ To date, two large To date, no large intragenic ## Option 1 For an introduction to multigene panels click ## Option 2 When the diagnosis of IDEDNIK 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 IDEDNIK Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Data derived from the subscription-based professional view of Human Gene Mutation Database [ To date, two large To date, no large intragenic ## Clinical Characteristics IDEDNIK syndrome is characterized by enteropathy, growth deficiency, skin manifestations (ichthyosis, erythroderma, and keratoderma), sparse hair, global developmental delay, mild-to-severe intellectual disability, and deafness. Additional manifestations can include liver disease, recurrent infections, and hematologic and ocular manifestations. To date, 24 individuals have been diagnosed with IDEDNIK syndrome – ten individuals with IDEDNIK Syndrome: Frequency of Select Features NR = not reported 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. Some reports describe liver disease as hepatopathy without providing additional information. Birth length can also vary from normal to three SD below the mean. Growth deficiency varies but can be progressive, with a height range of 2-3 SD below the mean to 4.7 SD below the mean (reported in 1 child, age 3 years) [ Head circumference is often normal at birth. Head circumference reported in children with IDEDNIK syndrome varies from one to two SD below the mean [ Speech development is also frequently delayed. Of note, factors such as sensorineural hearing loss contribute to speech delay as well as specific delays in nonverbal communication [ Thrombocytopenia was reported in four individuals. One individual had platelet counts with range 223-843 K/µL [ Intermittent peripheral eosinophilia was reported in one individual (range 0.15-1.21 K/µL) [ Hypoplastic scrotum with cryptorchidism (1 individual) Testicular atrophy (1 individual) Primary hypothyroidism and growth hormone deficiency (1 individual) Dilated cardiomyopathy identified on echocardiogram resolved in the first year of life (1 individual) Recurrent venous thromboses (1 individual) Severe osteoporosis (1 individual) Prominent abdomen (2 individuals) Individuals with Individuals with IDEDNIK syndrome was initially referred to as The IDEDNIK syndrome is rare, with only 24 affected individuals reported to date. A founder variant ( • Hypoplastic scrotum with cryptorchidism (1 individual) • Testicular atrophy (1 individual) • Primary hypothyroidism and growth hormone deficiency (1 individual) • Dilated cardiomyopathy identified on echocardiogram resolved in the first year of life (1 individual) • Recurrent venous thromboses (1 individual) • Severe osteoporosis (1 individual) • Prominent abdomen (2 individuals) ## Clinical Description IDEDNIK syndrome is characterized by enteropathy, growth deficiency, skin manifestations (ichthyosis, erythroderma, and keratoderma), sparse hair, global developmental delay, mild-to-severe intellectual disability, and deafness. Additional manifestations can include liver disease, recurrent infections, and hematologic and ocular manifestations. To date, 24 individuals have been diagnosed with IDEDNIK syndrome – ten individuals with IDEDNIK Syndrome: Frequency of Select Features NR = not reported 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. Some reports describe liver disease as hepatopathy without providing additional information. Birth length can also vary from normal to three SD below the mean. Growth deficiency varies but can be progressive, with a height range of 2-3 SD below the mean to 4.7 SD below the mean (reported in 1 child, age 3 years) [ Head circumference is often normal at birth. Head circumference reported in children with IDEDNIK syndrome varies from one to two SD below the mean [ Speech development is also frequently delayed. Of note, factors such as sensorineural hearing loss contribute to speech delay as well as specific delays in nonverbal communication [ Thrombocytopenia was reported in four individuals. One individual had platelet counts with range 223-843 K/µL [ Intermittent peripheral eosinophilia was reported in one individual (range 0.15-1.21 K/µL) [ Hypoplastic scrotum with cryptorchidism (1 individual) Testicular atrophy (1 individual) Primary hypothyroidism and growth hormone deficiency (1 individual) Dilated cardiomyopathy identified on echocardiogram resolved in the first year of life (1 individual) Recurrent venous thromboses (1 individual) Severe osteoporosis (1 individual) Prominent abdomen (2 individuals) • Hypoplastic scrotum with cryptorchidism (1 individual) • Testicular atrophy (1 individual) • Primary hypothyroidism and growth hormone deficiency (1 individual) • Dilated cardiomyopathy identified on echocardiogram resolved in the first year of life (1 individual) • Recurrent venous thromboses (1 individual) • Severe osteoporosis (1 individual) • Prominent abdomen (2 individuals) ## Phenotype Correlations by Gene Individuals with Individuals with ## Nomenclature IDEDNIK syndrome was initially referred to as The ## Prevalence IDEDNIK syndrome is rare, with only 24 affected individuals reported to date. A founder variant ( ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis IDEDNIK syndrome presents a combination of clinical and biochemical signs overlapping several disorders, including Menkes disease and Wilson disease (see Genes of Interest in the Differential Diagnosis of IDEDNIK Syndrome AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; GI = gastrointestinal; MOI = mode of inheritance; XL = X-linked ## Management No clinical practice guidelines for IDEDNIK syndrome have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder. To establish the extent of disease and needs in an individual diagnosed with IDEDNIK syndrome, the evaluations summarized in IDEDNIK Syndrome: Recommended Evaluations Following Initial Diagnosis Consultation w/ gastroenterologist & dietitian Assessment for aspiration risk To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Gross motor & fine motor skills Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) To incl brain MRI Consider EEG if seizures are a concern. Assess for peripheral neuropathy esp in older persons. Assess for recurrent mastoiditis, sinusitis, & otitis media. ENT consultation as needed Immunology or infectious disease consultation as needed CBC to assess for anemia, thrombocytopenia, neutropenia, & peripheral eosinophilia Referral to hematology w/bone marrow biopsy if indicated If severe short stature: assess thyroid function (thyroxine, TSH). Assess for growth hormone deficiency. Community or Social work involvement for parental support Home nursing referral ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ALP = alkaline phosphatase; ALT = alanine transaminase; ASD = autism spectrum disorder; AST = aspartate transaminase; CBC = complete blood count; GGT = gamma-glutamyl transferase; GI = gastrointestinal; INR = international normalized ratio; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; TSH = thyroid-stimulating hormone Medical geneticist, certified genetic counselor, certified advanced genetic nurse IDEDNIK syndrome presents a unique combination of clinical and biochemical signs that overlap Menkes disease and Wilson disease. Treatment with zinc acetate, a drug shown to reduce intestinal copper absorption in Wilson disease, has been found to significantly improve clinical manifestations in individuals with IDEDNIK syndrome, including reducing liver copper and plasma total bile acid levels and improving behavioral disturbances, cognitive function, and itching. This finding suggests a new approach to treating individuals with IDEDNIK syndrome as a copper metabolism defect [ Treatment with oral zinc acetate therapy (50 mg/day) to reduce liver copper overload results in marked improvement of behavioral disturbances and clear relief from itching Note: Zinc sulfate has also been used as an alternative, less expensive treatment option [ 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 IDEDNIK Syndrome: Treatment of Manifestations Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Low-dose oral acitretin Skin emollients & topical lactic acid (2%) Frequent emollient applications & short courses of topical corticosteroids or pimecrolimus ointment 50% urea ointments on palmoplantar skin can result in modest benefit. Many ASMs may be effective; phenobarbital has been demonstrated effective in 2 persons w/this disorder. Education of parents/caregivers Supportive treatment as indicated Occasionally, transfusion may be necessary. 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; RCF = Ross carbohydrate free Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the US; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (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 IDEDNIK Syndrome: Recommended Surveillance Measurement of growth parameters Eval of nutritional status & safety of oral intake Assessment of diarrhea Monitor those w/seizures as clinically indicated. Assess for new manifestations such as seizures & peripheral neuropathy. Assess thyroid function (thyroxine, TSH). Assess for growth hormone deficiency. ALP = alkaline phosphatase; ALT = alanine transaminase; ASD = autism spectrum disorder; AST = aspartate transaminase; CBC = complete blood count; GGT = gamma-glutamyl transferase; INR = international normalized ratio; OT = occupational therapy; PT = physical therapy; TSH = thyroid-stimulating hormone Although it is expected that sibs of a proband who have inherited biallelic See Search • Consultation w/ gastroenterologist & dietitian • Assessment for aspiration risk • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Gross motor & fine motor skills • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • To incl brain MRI • Consider EEG if seizures are a concern. • Assess for peripheral neuropathy esp in older persons. • Assess for recurrent mastoiditis, sinusitis, & otitis media. • ENT consultation as needed • Immunology or infectious disease consultation as needed • CBC to assess for anemia, thrombocytopenia, neutropenia, & peripheral eosinophilia • Referral to hematology w/bone marrow biopsy if indicated • If severe short stature: assess thyroid function (thyroxine, TSH). • Assess for growth hormone deficiency. • Community or • Social work involvement for parental support • Home nursing referral • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Low-dose oral acitretin • Skin emollients & topical lactic acid (2%) • Frequent emollient applications & short courses of topical corticosteroids or pimecrolimus ointment • 50% urea ointments on palmoplantar skin can result in modest benefit. • Many ASMs may be effective; phenobarbital has been demonstrated effective in 2 persons w/this disorder. • Education of parents/caregivers • Supportive treatment as indicated • Occasionally, transfusion may be necessary. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Assessment of diarrhea • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as seizures & peripheral neuropathy. • Assess thyroid function (thyroxine, TSH). • Assess for growth hormone deficiency. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with IDEDNIK syndrome, the evaluations summarized in IDEDNIK Syndrome: Recommended Evaluations Following Initial Diagnosis Consultation w/ gastroenterologist & dietitian Assessment for aspiration risk To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Gross motor & fine motor skills Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) To incl brain MRI Consider EEG if seizures are a concern. Assess for peripheral neuropathy esp in older persons. Assess for recurrent mastoiditis, sinusitis, & otitis media. ENT consultation as needed Immunology or infectious disease consultation as needed CBC to assess for anemia, thrombocytopenia, neutropenia, & peripheral eosinophilia Referral to hematology w/bone marrow biopsy if indicated If severe short stature: assess thyroid function (thyroxine, TSH). Assess for growth hormone deficiency. Community or Social work involvement for parental support Home nursing referral ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ALP = alkaline phosphatase; ALT = alanine transaminase; ASD = autism spectrum disorder; AST = aspartate transaminase; CBC = complete blood count; GGT = gamma-glutamyl transferase; GI = gastrointestinal; INR = international normalized ratio; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; TSH = thyroid-stimulating hormone Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Consultation w/ gastroenterologist & dietitian • Assessment for aspiration risk • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Gross motor & fine motor skills • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • To incl brain MRI • Consider EEG if seizures are a concern. • Assess for peripheral neuropathy esp in older persons. • Assess for recurrent mastoiditis, sinusitis, & otitis media. • ENT consultation as needed • Immunology or infectious disease consultation as needed • CBC to assess for anemia, thrombocytopenia, neutropenia, & peripheral eosinophilia • Referral to hematology w/bone marrow biopsy if indicated • If severe short stature: assess thyroid function (thyroxine, TSH). • Assess for growth hormone deficiency. • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations IDEDNIK syndrome presents a unique combination of clinical and biochemical signs that overlap Menkes disease and Wilson disease. Treatment with zinc acetate, a drug shown to reduce intestinal copper absorption in Wilson disease, has been found to significantly improve clinical manifestations in individuals with IDEDNIK syndrome, including reducing liver copper and plasma total bile acid levels and improving behavioral disturbances, cognitive function, and itching. This finding suggests a new approach to treating individuals with IDEDNIK syndrome as a copper metabolism defect [ Treatment with oral zinc acetate therapy (50 mg/day) to reduce liver copper overload results in marked improvement of behavioral disturbances and clear relief from itching Note: Zinc sulfate has also been used as an alternative, less expensive treatment option [ 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 IDEDNIK Syndrome: Treatment of Manifestations Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Low-dose oral acitretin Skin emollients & topical lactic acid (2%) Frequent emollient applications & short courses of topical corticosteroids or pimecrolimus ointment 50% urea ointments on palmoplantar skin can result in modest benefit. Many ASMs may be effective; phenobarbital has been demonstrated effective in 2 persons w/this disorder. Education of parents/caregivers Supportive treatment as indicated Occasionally, transfusion may be necessary. 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; RCF = Ross carbohydrate free Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the US; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (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. • Low-dose oral acitretin • Skin emollients & topical lactic acid (2%) • Frequent emollient applications & short courses of topical corticosteroids or pimecrolimus ointment • 50% urea ointments on palmoplantar skin can result in modest benefit. • Many ASMs may be effective; phenobarbital has been demonstrated effective in 2 persons w/this disorder. • Education of parents/caregivers • Supportive treatment as indicated • Occasionally, transfusion may be necessary. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## Targeted Therapy Treatment with oral zinc acetate therapy (50 mg/day) to reduce liver copper overload results in marked improvement of behavioral disturbances and clear relief from itching Note: Zinc sulfate has also been used as an alternative, less expensive treatment option [ ## 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 IDEDNIK Syndrome: Treatment of Manifestations Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Low-dose oral acitretin Skin emollients & topical lactic acid (2%) Frequent emollient applications & short courses of topical corticosteroids or pimecrolimus ointment 50% urea ointments on palmoplantar skin can result in modest benefit. Many ASMs may be effective; phenobarbital has been demonstrated effective in 2 persons w/this disorder. Education of parents/caregivers Supportive treatment as indicated Occasionally, transfusion may be necessary. 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; RCF = Ross carbohydrate free Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the US; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (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. • Low-dose oral acitretin • Skin emollients & topical lactic acid (2%) • Frequent emollient applications & short courses of topical corticosteroids or pimecrolimus ointment • 50% urea ointments on palmoplantar skin can result in modest benefit. • Many ASMs may be effective; phenobarbital has been demonstrated effective in 2 persons w/this disorder. • Education of parents/caregivers • Supportive treatment as indicated • Occasionally, transfusion may be necessary. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the US; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in IDEDNIK Syndrome: Recommended Surveillance Measurement of growth parameters Eval of nutritional status & safety of oral intake Assessment of diarrhea Monitor those w/seizures as clinically indicated. Assess for new manifestations such as seizures & peripheral neuropathy. Assess thyroid function (thyroxine, TSH). Assess for growth hormone deficiency. ALP = alkaline phosphatase; ALT = alanine transaminase; ASD = autism spectrum disorder; AST = aspartate transaminase; CBC = complete blood count; GGT = gamma-glutamyl transferase; INR = international normalized ratio; OT = occupational therapy; PT = physical therapy; TSH = thyroid-stimulating hormone • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Assessment of diarrhea • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as seizures & peripheral neuropathy. • Assess thyroid function (thyroxine, TSH). • Assess for growth hormone deficiency. ## Evaluation of Relatives at Risk Although it is expected that sibs of a proband who have inherited biallelic See ## Therapies Under Investigation Search ## Genetic Counseling IDEDNIK syndrome 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 the proband to confirm that both parents 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. 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 carriers or are at risk of being carriers. Carrier testing should be considered for the reproductive partners of individuals known to have an Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected child are presumed to be heterozygous for an • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents 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. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual 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. • Carrier testing should be considered for the reproductive partners of individuals known to have an ## Mode of Inheritance IDEDNIK syndrome 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 the proband to confirm that both parents 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. 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 • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. Carrier testing should be considered for the reproductive partners of individuals known to have an • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. • Carrier testing should be considered for the reproductive partners of individuals known to have an ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • • • • • ## Molecular Genetics IDEDNIK Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for IDEDNIK Syndrome ( Pathogenic Variants Referenced in This Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis Pathogenic Variants Referenced in This Variants listed in the table have been provided by the authors. ## Chapter Notes Dr Fowzan Alkuraya ( Our heartfelt thanks to the participating affected individuals and their families. Your invaluable contribution has been the cornerstone of a better understanding of IDEDNIK syndrome. 14 November 2024 (sw) Review posted live 2 April 2024 (ha) Original submission • 14 November 2024 (sw) Review posted live • 2 April 2024 (ha) Original submission ## Author Notes Dr Fowzan Alkuraya ( ## Acknowledgments Our heartfelt thanks to the participating affected individuals and their families. Your invaluable contribution has been the cornerstone of a better understanding of IDEDNIK syndrome. ## Revision History 14 November 2024 (sw) Review posted live 2 April 2024 (ha) Original submission • 14 November 2024 (sw) Review posted live • 2 April 2024 (ha) Original submission ## Key Sections in This ## References ## Literature Cited	[]	14/11/2024			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
iiae3	iiae3	[ "Acute Necrotizing Encephalopathy (ANE1)", "Acute Necrotizing Encephalopathy (ANE1)", "E3 SUMO-protein ligase RanBP2", "RANBP2", "Susceptibility to Infection-Induced Acute Encephalopathy 3" ]	Susceptibility to Infection-Induced Acute Encephalopathy 3 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY	Derek Neilson	Summary Infection-induced acute encephalopathy 3 (IIAE3) is the susceptibility to recurrent acute necrotizing encephalopathy (ANE) caused by a heterozygous pathogenic variant in IIAE3 is suspected in individuals with typical clinical and MRI findings, and is confirmed in those with a heterozygous pathogenic variant in Susceptibility to IIAE3 is inherited in an autosomal dominant manner. To date the majority of individuals diagnosed with IIAE3 have a parent who is heterozygous for a	## Diagnosis Infection-induced acute encephalopathy 3 (IIAE3) refers to the susceptibility to recurrent acute necrotizing encephalopathy (ANE) caused by mutation of Infection-induced acute encephalopathy 3 (IIAE3) No preceding developmental or neurologic defects [ Signs at onset that can be attributed to a viral trigger, such as fever, cough, rhinorrhea, vomiting, diarrhea, and malaise Viruses known to precipitate ANE include influenza A, influenza B, parainfluenza II, human herpesvirus 6, coxsackie virus, and enteroviruses [ The only bacterium known to precipitate ANE is Onset of ANE beginning within 12 hours to three or four days of the first awareness of viral symptoms. The most common sign of ANE is lethargy that progresses to coma and seizures (50%). At the time of hospital admission, brain MRI demonstrating: T Additional involved regions including the limbic system (e.g., the amygdala, mammillary bodies) and lateral regions such as the claustra and external capsules [ Note: The presence of lesions in these areas should prompt consideration of IIAE3, even in the absence of recurrence or family history [ Less commonly, involvement of the basal ganglia [ Note: It has been reported that gadolinium can identify lesions prior to their recognition on noncontrast MRI [ Pathologic findings that are similar to those of Leigh syndrome and Wernicke encephalopathy (i.e., regions of neuronal necrosis, capillary proliferation and dilation, hemorrhage, and edema, without local infiltration of other inflammatory cells) [ The diagnosis of IIAE3 is based on the presence of a heterozygous pathogenic variant in Molecular Genetic Testing Used in Susceptibility to Infection-Induced Acute Encephalopathy 3 See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Author [unpublished data]. Denominator represents unrelated probands who either have a positive family history or represent simplex cases (i.e., a single occurrence in a family). Each proband independently fulfilled criteria for ANE. • No preceding developmental or neurologic defects [ • Signs at onset that can be attributed to a viral trigger, such as fever, cough, rhinorrhea, vomiting, diarrhea, and malaise • Viruses known to precipitate ANE include influenza A, influenza B, parainfluenza II, human herpesvirus 6, coxsackie virus, and enteroviruses [ • The only bacterium known to precipitate ANE is • Viruses known to precipitate ANE include influenza A, influenza B, parainfluenza II, human herpesvirus 6, coxsackie virus, and enteroviruses [ • The only bacterium known to precipitate ANE is • Onset of ANE beginning within 12 hours to three or four days of the first awareness of viral symptoms. The most common sign of ANE is lethargy that progresses to coma and seizures (50%). • At the time of hospital admission, brain MRI demonstrating: • T • Additional involved regions including the limbic system (e.g., the amygdala, mammillary bodies) and lateral regions such as the claustra and external capsules [ • Note: The presence of lesions in these areas should prompt consideration of IIAE3, even in the absence of recurrence or family history [ • Less commonly, involvement of the basal ganglia [ • Note: It has been reported that gadolinium can identify lesions prior to their recognition on noncontrast MRI [ • T • Additional involved regions including the limbic system (e.g., the amygdala, mammillary bodies) and lateral regions such as the claustra and external capsules [ • Note: The presence of lesions in these areas should prompt consideration of IIAE3, even in the absence of recurrence or family history [ • Less commonly, involvement of the basal ganglia [ • Note: It has been reported that gadolinium can identify lesions prior to their recognition on noncontrast MRI [ • Pathologic findings that are similar to those of Leigh syndrome and Wernicke encephalopathy (i.e., regions of neuronal necrosis, capillary proliferation and dilation, hemorrhage, and edema, without local infiltration of other inflammatory cells) [ • Viruses known to precipitate ANE include influenza A, influenza B, parainfluenza II, human herpesvirus 6, coxsackie virus, and enteroviruses [ • The only bacterium known to precipitate ANE is • T • Additional involved regions including the limbic system (e.g., the amygdala, mammillary bodies) and lateral regions such as the claustra and external capsules [ • Note: The presence of lesions in these areas should prompt consideration of IIAE3, even in the absence of recurrence or family history [ • Less commonly, involvement of the basal ganglia [ • Note: It has been reported that gadolinium can identify lesions prior to their recognition on noncontrast MRI [ ## Suggestive Findings Infection-induced acute encephalopathy 3 (IIAE3) No preceding developmental or neurologic defects [ Signs at onset that can be attributed to a viral trigger, such as fever, cough, rhinorrhea, vomiting, diarrhea, and malaise Viruses known to precipitate ANE include influenza A, influenza B, parainfluenza II, human herpesvirus 6, coxsackie virus, and enteroviruses [ The only bacterium known to precipitate ANE is Onset of ANE beginning within 12 hours to three or four days of the first awareness of viral symptoms. The most common sign of ANE is lethargy that progresses to coma and seizures (50%). At the time of hospital admission, brain MRI demonstrating: T Additional involved regions including the limbic system (e.g., the amygdala, mammillary bodies) and lateral regions such as the claustra and external capsules [ Note: The presence of lesions in these areas should prompt consideration of IIAE3, even in the absence of recurrence or family history [ Less commonly, involvement of the basal ganglia [ Note: It has been reported that gadolinium can identify lesions prior to their recognition on noncontrast MRI [ Pathologic findings that are similar to those of Leigh syndrome and Wernicke encephalopathy (i.e., regions of neuronal necrosis, capillary proliferation and dilation, hemorrhage, and edema, without local infiltration of other inflammatory cells) [ • No preceding developmental or neurologic defects [ • Signs at onset that can be attributed to a viral trigger, such as fever, cough, rhinorrhea, vomiting, diarrhea, and malaise • Viruses known to precipitate ANE include influenza A, influenza B, parainfluenza II, human herpesvirus 6, coxsackie virus, and enteroviruses [ • The only bacterium known to precipitate ANE is • Viruses known to precipitate ANE include influenza A, influenza B, parainfluenza II, human herpesvirus 6, coxsackie virus, and enteroviruses [ • The only bacterium known to precipitate ANE is • Onset of ANE beginning within 12 hours to three or four days of the first awareness of viral symptoms. The most common sign of ANE is lethargy that progresses to coma and seizures (50%). • At the time of hospital admission, brain MRI demonstrating: • T • Additional involved regions including the limbic system (e.g., the amygdala, mammillary bodies) and lateral regions such as the claustra and external capsules [ • Note: The presence of lesions in these areas should prompt consideration of IIAE3, even in the absence of recurrence or family history [ • Less commonly, involvement of the basal ganglia [ • Note: It has been reported that gadolinium can identify lesions prior to their recognition on noncontrast MRI [ • T • Additional involved regions including the limbic system (e.g., the amygdala, mammillary bodies) and lateral regions such as the claustra and external capsules [ • Note: The presence of lesions in these areas should prompt consideration of IIAE3, even in the absence of recurrence or family history [ • Less commonly, involvement of the basal ganglia [ • Note: It has been reported that gadolinium can identify lesions prior to their recognition on noncontrast MRI [ • Pathologic findings that are similar to those of Leigh syndrome and Wernicke encephalopathy (i.e., regions of neuronal necrosis, capillary proliferation and dilation, hemorrhage, and edema, without local infiltration of other inflammatory cells) [ • Viruses known to precipitate ANE include influenza A, influenza B, parainfluenza II, human herpesvirus 6, coxsackie virus, and enteroviruses [ • The only bacterium known to precipitate ANE is • T • Additional involved regions including the limbic system (e.g., the amygdala, mammillary bodies) and lateral regions such as the claustra and external capsules [ • Note: The presence of lesions in these areas should prompt consideration of IIAE3, even in the absence of recurrence or family history [ • Less commonly, involvement of the basal ganglia [ • Note: It has been reported that gadolinium can identify lesions prior to their recognition on noncontrast MRI [ ## Establishing the Diagnosis The diagnosis of IIAE3 is based on the presence of a heterozygous pathogenic variant in Molecular Genetic Testing Used in Susceptibility to Infection-Induced Acute Encephalopathy 3 See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Author [unpublished data]. Denominator represents unrelated probands who either have a positive family history or represent simplex cases (i.e., a single occurrence in a family). Each proband independently fulfilled criteria for ANE. ## Clinical Characteristics Most infection-induced acute encephalopathy 3 (IIAE3) (which by definition is caused by mutation of Acute necrotizing encephalopathy (ANE) is always preceded by a febrile infection that is usually viral [ The progression to acute neurologic dysfunction may occur within hours to days following the onset of the febrile infection. Initial manifestations include decreased consciousness and seizures. Neurologic findings that may accompany the encephalopathy include hallucination, ataxia, hypotonia, hypertonia, and decerebrate or decorticate posturing. Most affected persons present with or progress to coma [ One third of affected individuals die during the acute phase of the encephalopathy [ Fifty per cent of persons with IIAE3 will have at least one repeat episode and some will have multiple repeat episodes [ The three single nucleotide variants identified in Penetrance is incomplete and age dependent. Forty percent of heterozygotes for a Genetic anticipation does not occur with IIAE3, although families may appear to have anticipation on the basis of earlier recognition of the diagnosis in subsequent generations [ The term "acute necrotizing encephalopathy" (ANE) continues to be used for ANE that is sporadic (i.e., a single occurrence in a family of unknown cause). Infection-induced acute encephalopathy 3 (IIAE3) is reserved for ANE with a documented The infection-induced acute encephalopathy (IIAE) series describes genetic predispositions to CNS dysfunction following infections: IIAE1, IIAE2, IIAE5, and IIAE6 refer to genetic variants that allow herpes simplex virus to invade the CNS. IIAE3 refers to non-neuronopathic infections of different types that can trigger encephalopathy without evidence of direct CNS invasion. IIAE4 refers specifically to influenza-mediated encephalopathy, also without CNS invasion factor [ ANE1 defines the previous symbol assigned to the 2q12.1-2q13 genomic locus in which Note: While ANE caused by mutation of Acute necrotizing encephalopathy (ANE) is underreported; the prevalence and incidence of ANE remain unknown. Due to ascertainment bias, it is not possible to estimate the proportion of ANE that results from mutation of In a two-year surveillance study of influenza in the UK, four cases of ANE were identified, suggesting an incidence in the total population of approximately one per 30 million person-years [ An estimate of ten to 50 cases of ANE in the United States per year seems appropriate [Author, personal prediction based on observed cases] and may depend on the viral strains present in a given year. • IIAE1, IIAE2, IIAE5, and IIAE6 refer to genetic variants that allow herpes simplex virus to invade the CNS. • IIAE3 refers to non-neuronopathic infections of different types that can trigger encephalopathy without evidence of direct CNS invasion. • IIAE4 refers specifically to influenza-mediated encephalopathy, also without CNS invasion factor [ • In a two-year surveillance study of influenza in the UK, four cases of ANE were identified, suggesting an incidence in the total population of approximately one per 30 million person-years [ • An estimate of ten to 50 cases of ANE in the United States per year seems appropriate [Author, personal prediction based on observed cases] and may depend on the viral strains present in a given year. ## Clinical Description Most infection-induced acute encephalopathy 3 (IIAE3) (which by definition is caused by mutation of Acute necrotizing encephalopathy (ANE) is always preceded by a febrile infection that is usually viral [ The progression to acute neurologic dysfunction may occur within hours to days following the onset of the febrile infection. Initial manifestations include decreased consciousness and seizures. Neurologic findings that may accompany the encephalopathy include hallucination, ataxia, hypotonia, hypertonia, and decerebrate or decorticate posturing. Most affected persons present with or progress to coma [ One third of affected individuals die during the acute phase of the encephalopathy [ Fifty per cent of persons with IIAE3 will have at least one repeat episode and some will have multiple repeat episodes [ ## Genotype-Phenotype Correlations The three single nucleotide variants identified in ## Penetrance Penetrance is incomplete and age dependent. Forty percent of heterozygotes for a ## Anticipation Genetic anticipation does not occur with IIAE3, although families may appear to have anticipation on the basis of earlier recognition of the diagnosis in subsequent generations [ ## Nomenclature The term "acute necrotizing encephalopathy" (ANE) continues to be used for ANE that is sporadic (i.e., a single occurrence in a family of unknown cause). Infection-induced acute encephalopathy 3 (IIAE3) is reserved for ANE with a documented The infection-induced acute encephalopathy (IIAE) series describes genetic predispositions to CNS dysfunction following infections: IIAE1, IIAE2, IIAE5, and IIAE6 refer to genetic variants that allow herpes simplex virus to invade the CNS. IIAE3 refers to non-neuronopathic infections of different types that can trigger encephalopathy without evidence of direct CNS invasion. IIAE4 refers specifically to influenza-mediated encephalopathy, also without CNS invasion factor [ ANE1 defines the previous symbol assigned to the 2q12.1-2q13 genomic locus in which Note: While ANE caused by mutation of • IIAE1, IIAE2, IIAE5, and IIAE6 refer to genetic variants that allow herpes simplex virus to invade the CNS. • IIAE3 refers to non-neuronopathic infections of different types that can trigger encephalopathy without evidence of direct CNS invasion. • IIAE4 refers specifically to influenza-mediated encephalopathy, also without CNS invasion factor [ ## Prevalence Acute necrotizing encephalopathy (ANE) is underreported; the prevalence and incidence of ANE remain unknown. Due to ascertainment bias, it is not possible to estimate the proportion of ANE that results from mutation of In a two-year surveillance study of influenza in the UK, four cases of ANE were identified, suggesting an incidence in the total population of approximately one per 30 million person-years [ An estimate of ten to 50 cases of ANE in the United States per year seems appropriate [Author, personal prediction based on observed cases] and may depend on the viral strains present in a given year. • In a two-year surveillance study of influenza in the UK, four cases of ANE were identified, suggesting an incidence in the total population of approximately one per 30 million person-years [ • An estimate of ten to 50 cases of ANE in the United States per year seems appropriate [Author, personal prediction based on observed cases] and may depend on the viral strains present in a given year. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this Sporadic cancers (including myelomonocytic leukemia and inflammatory myofibroblastic tumor) occurring as single tumors in the absence of any other findings of this syndrome may harbor somatic pathogenic variants in ## Differential Diagnosis ## Management To establish the extent of disease and needs in an individual diagnosed with susceptibility to infection-induced acute encephalopathy 3 (IIAE3), the following evaluations are recommended after an episode of acute necrotizing encephalopathy (ANE): Brain MRI during a quiescent period. This should demonstrate resolution of the edema signals and may reveal regions of necrosis. This interval baseline will be helpful in distinguishing new versus old lesions in subsequent febrile events. Rehabilitation/OT/PT consultation Neurology consultation Clinical genetics consultation Treatment has been aimed at reducing the inflammatory state [ During an acute episode of encephalopathy, early administration of corticosteroids has been associated with improved outcomes in patients with sporadic ANE [ Anecdotally, treatment has mirrored that of acute demyelinating encephalomyelopathy (ADEM) with the use of steroids, IVIg, and plasmapheresis. TNFα antagonists have also been used. Because the diagnosis of ANE is usually made days into the encephalopathy, initiation of therapy occurs after the onset of damage. Thus, anecdotally, these interventions have shown varied, but overall limited, therapeutic effects. Repeat episodes of encephalopathy presumably result in cellular damage and, thus, outcomes become progressively worse [ Prior identification of an With behavioral changes during febrile episodes, early evaluation by a neurologist with prompt hospitalization, CNS imaging, and initiation of steroid therapy may provide the best chance to terminate an ANE episode before damage occurs. Routine vaccinations and yearly influenza vaccinations are recommended, but caution with certain live virus vaccines may need to be observed (see No standard tests allow prediction of the triggering of an ANE event or progression of an event once one occurs. In intervals between ANE events neurologic function is stable. Follow-up evaluations focus on developmental progression and addressing functional deficits related to neurologic damage. In the absence of other risks for seizures, anticonvulsant therapy started during an ANE event can often be discontinued. Avoid individuals who are ill with an infectious disease and adhere to strict precautions regarding hand washing. Only one episode of ANE following an immunization has been reported: cellular pertussis was given to a child age six months representing a simplex case (i.e., a single occurrence in a family) in whom In mice, intranasal inoculation of certain influenza subtypes can result in CNS invasion [ In a family with IIAE3 in which the disease-associated The ability to clarify the genetic status of at-risk relatives also reduces unnecessary utilization of resources, such as emergency room visits, for those who have not inherited the See Search • Brain MRI during a quiescent period. This should demonstrate resolution of the edema signals and may reveal regions of necrosis. This interval baseline will be helpful in distinguishing new versus old lesions in subsequent febrile events. • Rehabilitation/OT/PT consultation • Neurology consultation • Clinical genetics consultation • Prior identification of an • With behavioral changes during febrile episodes, early evaluation by a neurologist with prompt hospitalization, CNS imaging, and initiation of steroid therapy may provide the best chance to terminate an ANE episode before damage occurs. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with susceptibility to infection-induced acute encephalopathy 3 (IIAE3), the following evaluations are recommended after an episode of acute necrotizing encephalopathy (ANE): Brain MRI during a quiescent period. This should demonstrate resolution of the edema signals and may reveal regions of necrosis. This interval baseline will be helpful in distinguishing new versus old lesions in subsequent febrile events. Rehabilitation/OT/PT consultation Neurology consultation Clinical genetics consultation • Brain MRI during a quiescent period. This should demonstrate resolution of the edema signals and may reveal regions of necrosis. This interval baseline will be helpful in distinguishing new versus old lesions in subsequent febrile events. • Rehabilitation/OT/PT consultation • Neurology consultation • Clinical genetics consultation ## Treatment of Manifestations Treatment has been aimed at reducing the inflammatory state [ During an acute episode of encephalopathy, early administration of corticosteroids has been associated with improved outcomes in patients with sporadic ANE [ Anecdotally, treatment has mirrored that of acute demyelinating encephalomyelopathy (ADEM) with the use of steroids, IVIg, and plasmapheresis. TNFα antagonists have also been used. Because the diagnosis of ANE is usually made days into the encephalopathy, initiation of therapy occurs after the onset of damage. Thus, anecdotally, these interventions have shown varied, but overall limited, therapeutic effects. Repeat episodes of encephalopathy presumably result in cellular damage and, thus, outcomes become progressively worse [ Prior identification of an With behavioral changes during febrile episodes, early evaluation by a neurologist with prompt hospitalization, CNS imaging, and initiation of steroid therapy may provide the best chance to terminate an ANE episode before damage occurs. • Prior identification of an • With behavioral changes during febrile episodes, early evaluation by a neurologist with prompt hospitalization, CNS imaging, and initiation of steroid therapy may provide the best chance to terminate an ANE episode before damage occurs. ## Prevention of Primary Manifestations Routine vaccinations and yearly influenza vaccinations are recommended, but caution with certain live virus vaccines may need to be observed (see ## Surveillance No standard tests allow prediction of the triggering of an ANE event or progression of an event once one occurs. In intervals between ANE events neurologic function is stable. Follow-up evaluations focus on developmental progression and addressing functional deficits related to neurologic damage. In the absence of other risks for seizures, anticonvulsant therapy started during an ANE event can often be discontinued. ## Agents/Circumstances to Avoid Avoid individuals who are ill with an infectious disease and adhere to strict precautions regarding hand washing. Only one episode of ANE following an immunization has been reported: cellular pertussis was given to a child age six months representing a simplex case (i.e., a single occurrence in a family) in whom In mice, intranasal inoculation of certain influenza subtypes can result in CNS invasion [ ## Evaluation of Relatives at Risk In a family with IIAE3 in which the disease-associated The ability to clarify the genetic status of at-risk relatives also reduces unnecessary utilization of resources, such as emergency room visits, for those who have not inherited the See ## Therapies Under Investigation Search ## Genetic Counseling Susceptibility to infection-induced acute encephalopathy 3 (IIAE3) is inherited in an autosomal dominant manner. Many individuals diagnosed with susceptibility to IIAE3 have a parent who is heterozygous for a A proband with susceptibility to IIAE3 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 germline mosaicism in a parent or a Recommendations for the evaluation of parents of a proband with an apparent If a parent has the The sibs of a proband with clinically unaffected parents are still at increased risk for susceptibility to IIAE3 because of the possibility of reduced penetrance in a parent. If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism. See Management, 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 at risk for IIAE3. 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 decisions regarding prenatal testing are the choice of the parents, discussion of these issues is appropriate. • Many individuals diagnosed with susceptibility to IIAE3 have a parent who is heterozygous for a • A proband with susceptibility to IIAE3 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 germline mosaicism in a parent or a • Recommendations for the evaluation of parents of a proband with an apparent • If a parent has the • The sibs of a proband with clinically unaffected parents are still at increased risk for susceptibility to IIAE3 because of the possibility of reduced penetrance in a parent. • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism. • 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 at risk for IIAE3. ## Mode of Inheritance Susceptibility to infection-induced acute encephalopathy 3 (IIAE3) is inherited in an autosomal dominant manner. ## Risk to Family Members Many individuals diagnosed with susceptibility to IIAE3 have a parent who is heterozygous for a A proband with susceptibility to IIAE3 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 germline mosaicism in a parent or a Recommendations for the evaluation of parents of a proband with an apparent If a parent has the The sibs of a proband with clinically unaffected parents are still at increased risk for susceptibility to IIAE3 because of the possibility of reduced penetrance in a parent. If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism. • Many individuals diagnosed with susceptibility to IIAE3 have a parent who is heterozygous for a • A proband with susceptibility to IIAE3 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 germline mosaicism in a parent or a • Recommendations for the evaluation of parents of a proband with an apparent • If a parent has the • The sibs of a proband with clinically unaffected parents are still at increased risk for susceptibility to IIAE3 because of the possibility of reduced penetrance in a parent. • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism. ## Related Genetic Counseling Issues See Management, 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 at risk for IIAE3. • 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 at risk for IIAE3. ## 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 decisions regarding prenatal testing are the choice of the parents, discussion of these issues is appropriate. ## Resources PO Box 5801 Bethesda MD 20824 • • PO Box 5801 • Bethesda MD 20824 • ## Molecular Genetics Susceptibility to Infection-Induced Acute Encephalopathy 3: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Susceptibility to Infection-Induced Acute Encephalopathy 3 ( Variants listed in the table have been provided by the author. RANBP2 contributes to the nuclear filaments present on the cytoplasmic surface of the nuclear pore. RANBP2 has been shown to participate in multiple functions including nuclear import and export, intracellular trafficking, mitochondrial distribution, and maintenance of chromosomal mitotic segregation. It also serves as a nuclear docking site for certain viruses, such as HIV [ Sporadic cancers (including myelomonoctyic leukemia and inflammatory myofibroblastic tumor) occurring as single tumors in the absence of any other findings of this syndrome may harbor somatic variants in ## Cancer and Benign Tumors Sporadic cancers (including myelomonoctyic leukemia and inflammatory myofibroblastic tumor) occurring as single tumors in the absence of any other findings of this syndrome may harbor somatic variants in ## References ## Literature Cited ## Chapter Notes Special thanks to the families who participated in this genetic research and to the physicians, genetic counselors, and nurses who helped facilitate that process. 10 September 2020 (ma) Chapter retired: extremely rare 4 December 2014 (me) Review posted live 19 February 2014 (dn) Original submission • 10 September 2020 (ma) Chapter retired: extremely rare • 4 December 2014 (me) Review posted live • 19 February 2014 (dn) Original submission ## Acknowledgments Special thanks to the families who participated in this genetic research and to the physicians, genetic counselors, and nurses who helped facilitate that process. ## Revision History 10 September 2020 (ma) Chapter retired: extremely rare 4 December 2014 (me) Review posted live 19 February 2014 (dn) Original submission • 10 September 2020 (ma) Chapter retired: extremely rare • 4 December 2014 (me) Review posted live • 19 February 2014 (dn) Original submission	[ "G Alper. Acute disseminated encephalomyelitis.. J Child Neurol. 2012;27:1408-25", "CS Ashtekar, T Jaspan, D Thomas, V Weston, NA Gayatri, WP Whitehouse. Acute bilateral thalamic necrosis in a child with Mycoplasma pneumoniae.. Dev Med Child Neurol 2003;45:634-7", "H Aydin, E Ozgul, AM Agildere. Acute necrotizing encephalopathy secondary to diphtheria, tetanus toxoid and whole-cell pertussis vaccination: diffusion-weighted imaging and proton MR spectroscopy findings.. Pediatr Radiol 2010;40:1281-4", "F Baertling, RJ Rodenburg, J Schaper, JA Smeitink, WJ Koopman, E Mayatepek, E Morava, F Distelmaier. A guide to diagnosis and treatment of Leigh syndrome.. J Neurol Neurosurg Psychiatry 2014;85:257-65", "L Bergamino, V Capra, R Biancheri, A Rossi, A Tacchella, L Ambrosini, M Mizuguchi, M Saitoh, MG Marazzi. Immunomodulatory therapy in recurrent acute necrotizing encephalopathy ANE1: is it useful?. Brain Dev 2012;34:384-91", "ST Chen, JC Lee. An inflammatory myofibroblastic tumor in liver with ALK and RANBP2 gene rearrangement: combination of distinct morphologic, immunohistochemical, and genetic features.. Hum Pathol. 2008;39:1854-8", "FD Ciccarelli, C Von Mering, M Suyama, ED Harrington, E Izaurralde, P Bork. Complex genomic rearrangements lead to novel primate gene function.. Genome Res 2005;15:343-51", "F Di Nunzio, A Danckaert, T Fricke, P Perez, J Fernandez, E Perret, P Roux, S Shorte, P Charneau, F Diaz-Griffero, NJ Arhel. Human nucleoporins promote HIV-1 docking at the nuclear pore, nuclear import and integration.. PLoS One 2012;7", "A Goenka, BD Michael, E Ledger, IJ Hart, M Absoud, G Chow, J Lilleker, M Lunn, D Mckee, D Peake, K Pysden, M Roberts, ED Carrol, M Lim, S Avula, T Solomon, R Kneen. Neurological manifestations of influenza infection in children and adults: Results of a National British Surveillance study.. Clin Infect Dis. 2014;58:775-84", "SM Kansagra, WB Gallentine. Cytokine storm of acute necrotizing encephalopathy.. Pediatr Neurol 2011;45:400-2", "D Karussis. The diagnosis of multiple sclerosis and the various related demyelinating syndromes: A critical review.. J Autoimmun. 2014;48-49:134-42", "PD Larsen, D Crisp. Acute bilateral striatal necrosis associated with Mycoplasma pneumoniae infection.. Pediatr Infect Dis J 1996;15:1124-6", "J Li, WH Yin, K Takeuchi, H Guan, YH Huang, JK Chan. Inflammatory myofibroblastic tumor with RANBP2 and ALK gene rearrangement: a report of two cases and literature review.. Diagn Pathol. 2013;8:147", "JH Lim, S Jang, CJ Park, YU Cho, JH Lee, KH Lee, JO Lee, JY Shin, JI Kim, J Huh, EJ Seo. RANBP2-ALK fusion combined with monosomy 7 in acute myelomonocytic leukemia.. Cancer Genet. 2014;207:40-5", "EJ Marco, JE Anderson, DE Neilson, JB Strober. Acute necrotizing encephalopathy in 3 brothers.. Pediatrics 2010;125:e693-8", "M Mizuguchi. Acute necrotizing encephalopathy of childhood: a novel form of acute encephalopathy prevalent in Japan and Taiwan.. Brain Dev 1997;19:81-92", "M Mizuguchi, J Abe, K Mikkaichi, S Noma, K Yoshida, T Yamanaka, S Kamoshita. Acute necrotising encephalopathy of childhood: a new syndrome presenting with multifocal, symmetric brain lesions.. J Neurol Neurosurg Psychiatry 1995;58:555-61", "DE Neilson. The interplay of infection and genetics in acute necrotizing encephalopathy.. Curr Opin Pediatr 2010;22:751-7", "DE Neilson, MD Adams, CM Orr, DK Schelling, RM Eiben, DS Kerr, J Anderson, AG Bassuk, AM Bye, AM Childs, A Clarke, YJ Crow, M Di Rocco, C Dohna-Schwake, G Dueckers, AE Fasano, AD Gika, D Gionnis, MP Gorman, PJ Grattan-Smith, A Hackenberg, A Kuster, MG Lentschig, E Lopez-Laso, EJ Marco, S Mastroyianni, J Perrier, T Schmitt-Mechelke, S Servidei, A Skardoutsou, P Uldall, MS Van Der Knaap, KC Goglin, DL Tefft, C Aubin, P De Jager, D Hafler, ML Warman. Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2.. Am J Hum Genet 2009;84:44-51", "DE Neilson, RM Eiben, S Waniewski, CL Hoppel, ME Varnes, BA Bangert, M Wiznitzer, ML Warman, DS Kerr. Autosomal dominant acute necrotizing encephalopathy.. Neurology 2003;61:226-30", "A Okumura, M Mizuguchi, H Kidokoro, M Tanaka, S Abe, M Hosoya, H Aiba, Y Maegaki, H Yamamoto, T Tanabe, E Noda, G Imataka, H Kurahashi. Outcome of acute necrotizing encephalopathy in relation to treatment with corticosteroids and gammaglobulin.. Brain Dev 2009;31:221-7", "AS Patel, KM Murphy, AL Hawkins, JS Cohen, PP Long, EJ Perlman, CA Griffin. RANBP2 and CLTC are involved in ALK rearrangements in inflammatory myofibroblastic tumors.. Cancer Genet Cytogenet. 2007;176:107-14", "M Shinohara, M Saitoh, J Takanashi, H Yamanouchi, M Kubota, T Goto, M Kikuchi, T Shiihara, G Yamanaka, M Mizuguchi. Carnitine palmitoyl transferase II polymorphism is associated with multiple syndromes of acute encephalopathy with various infectious diseases.. Brain Dev 2011;33:512-7", "K Shinya, A Shimada, T Ito, K Otsuki, T Morita, H Tanaka, A Takada, H Kida, T Umemura. Avian influenza virus intranasally inoculated infects the central nervous system of mice through the general visceral afferent nerve.. Arch Virol 2000;145:187-95", "T Yoshida, T Tamura, Y Nagai, H Ueda, T Awaya, M Shibata, T Kato, T Heike. MRI gadolinium enhancement precedes neuroradiological findings in acute necrotizing encephalopathy.. Brain Dev 2013;35:921-4" ]	4/12/2014			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
image	image	[ "Intrauterine Growth Restriction, Metaphyseal Dysplasia, Adrenal Hypoplasia Congenita, and Genital Anomalies", "Intrauterine Growth Restriction, Metaphyseal Dysplasia, Adrenal Hypoplasia Congenita, and Genital Anomalies", "Cyclin-dependent kinase inhibitor 1C", "CDKN1C", "IMAGe Syndrome" ]	IMAGe Syndrome	Samantha A Schrier Vergano, Matthew A Deardorff	Summary IMAGe syndrome is an acronym for the major findings of IUGR; Some type of skeletal abnormality (most commonly delayed bone age and short stature, and occasionally, metaphyseal and epiphyseal dysplasia of varying severity); Adrenal insufficiency often presenting in the first month of life as an adrenal crisis or (rarely) later in childhood with failure to thrive and recurrent vomiting; Genital abnormalities in males (cryptorchidism, micropenis, and hypospadias) but not in females. Hypotonia and developmental delay are reported in some individuals; cognitive outcome appears to be normal in the majority of individuals. The diagnosis of IMAGe syndrome is established in a proband with suggestive findings and/or a heterozygous Typically, a	## Diagnosis IMAGe syndrome is an acronym for the major findings in this disorder: No formal clinical diagnostic criteria for IMAGe syndrome have been defined. IMAGe syndrome Intrauterine growth restriction (IUGR) * Postnatal growth deficiency, with variable growth hormone deficiency Adrenal hypoplasia congenita (AHC), often presenting as spontaneous adrenal crisis in the first week to month of life, with hypotension, hyponatremia, and hyperkalemia, which can be life-threatening Some individuals with AHC may present with adrenal insufficiency during childhood or early adulthood. Later-onset adrenal insufficiency can be precipitated by stress, such as that associated with illness or surgery. Genital abnormalities in males including unilateral or bilateral cryptorchidism, hypospadias, micropenis, and chordee Note: The clinical features of IUGR and AHC, with or without a family history of IMAGe syndrome, are highly suggestive of the diagnosis. Metaphyseal and/or epiphyseal dysplasia, mesomelia, osteopenia, gracile long bones, and delayed bone age on radiographs Note: Skeletal abnormalities, which are age dependent, can be absent or subtle. Adrenal imaging that suggests small or normal-sized adrenal glands, in contrast to enlarged adrenal glands seen in individuals with congenital adrenal hyperplasia (CAH) Evidence of adrenal insufficiency during a crisis including hyponatremia, hyperkalemia, and elevated ACTH levels (frequently >1000 pg/mL [normal: 10-60 pg/mL]) Lack of findings consistent with other causes of adrenal insufficiency The diagnosis of IMAGe syndrome Molecular genetic testing approaches can include a combination of When the clinical, radiographic, and laboratory findings suggest the diagnosis of IMAGe syndrome, molecular genetic testing approaches can include For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by growth deficiency and adrenal hypoplasia, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in IMAGe 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 At present all six reported pathogenic variants in Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No deletions or duplications of • Intrauterine growth restriction (IUGR) * • Postnatal growth deficiency, with variable growth hormone deficiency • Adrenal hypoplasia congenita (AHC), often presenting as spontaneous adrenal crisis in the first week to month of life, with hypotension, hyponatremia, and hyperkalemia, which can be life-threatening • Some individuals with AHC may present with adrenal insufficiency during childhood or early adulthood. • Later-onset adrenal insufficiency can be precipitated by stress, such as that associated with illness or surgery. • Some individuals with AHC may present with adrenal insufficiency during childhood or early adulthood. • Later-onset adrenal insufficiency can be precipitated by stress, such as that associated with illness or surgery. • Genital abnormalities in males including unilateral or bilateral cryptorchidism, hypospadias, micropenis, and chordee • Some individuals with AHC may present with adrenal insufficiency during childhood or early adulthood. • Later-onset adrenal insufficiency can be precipitated by stress, such as that associated with illness or surgery. • Metaphyseal and/or epiphyseal dysplasia, mesomelia, osteopenia, gracile long bones, and delayed bone age on radiographs • Note: Skeletal abnormalities, which are age dependent, can be absent or subtle. • Adrenal imaging that suggests small or normal-sized adrenal glands, in contrast to enlarged adrenal glands seen in individuals with congenital adrenal hyperplasia (CAH) • Evidence of adrenal insufficiency during a crisis including hyponatremia, hyperkalemia, and elevated ACTH levels (frequently >1000 pg/mL [normal: 10-60 pg/mL]) • Lack of findings consistent with other causes of adrenal insufficiency ## Suggestive Findings IMAGe syndrome Intrauterine growth restriction (IUGR) Postnatal growth deficiency, with variable growth hormone deficiency Adrenal hypoplasia congenita (AHC), often presenting as spontaneous adrenal crisis in the first week to month of life, with hypotension, hyponatremia, and hyperkalemia, which can be life-threatening Some individuals with AHC may present with adrenal insufficiency during childhood or early adulthood. Later-onset adrenal insufficiency can be precipitated by stress, such as that associated with illness or surgery. Genital abnormalities in males including unilateral or bilateral cryptorchidism, hypospadias, micropenis, and chordee Note: The clinical features of IUGR and AHC, with or without a family history of IMAGe syndrome, are highly suggestive of the diagnosis. Metaphyseal and/or epiphyseal dysplasia, mesomelia, osteopenia, gracile long bones, and delayed bone age on radiographs Note: Skeletal abnormalities, which are age dependent, can be absent or subtle. Adrenal imaging that suggests small or normal-sized adrenal glands, in contrast to enlarged adrenal glands seen in individuals with congenital adrenal hyperplasia (CAH) Evidence of adrenal insufficiency during a crisis including hyponatremia, hyperkalemia, and elevated ACTH levels (frequently >1000 pg/mL [normal: 10-60 pg/mL]) Lack of findings consistent with other causes of adrenal insufficiency • Intrauterine growth restriction (IUGR) * • Postnatal growth deficiency, with variable growth hormone deficiency • Adrenal hypoplasia congenita (AHC)*, often presenting as spontaneous adrenal crisis in the first week to month of life, with hypotension, hyponatremia, and hyperkalemia, which can be life-threatening • Some individuals with AHC may present with adrenal insufficiency during childhood or early adulthood. • Later-onset adrenal insufficiency can be precipitated by stress, such as that associated with illness or surgery. • Some individuals with AHC may present with adrenal insufficiency during childhood or early adulthood. • Later-onset adrenal insufficiency can be precipitated by stress, such as that associated with illness or surgery. • Genital abnormalities in males including unilateral or bilateral cryptorchidism, hypospadias, micropenis, and chordee • Some individuals with AHC may present with adrenal insufficiency during childhood or early adulthood. • Later-onset adrenal insufficiency can be precipitated by stress, such as that associated with illness or surgery. • Metaphyseal and/or epiphyseal dysplasia, mesomelia, osteopenia, gracile long bones, and delayed bone age on radiographs • Note: Skeletal abnormalities, which are age dependent, can be absent or subtle. • Adrenal imaging that suggests small or normal-sized adrenal glands, in contrast to enlarged adrenal glands seen in individuals with congenital adrenal hyperplasia (CAH) • Evidence of adrenal insufficiency during a crisis including hyponatremia, hyperkalemia, and elevated ACTH levels (frequently >1000 pg/mL [normal: 10-60 pg/mL]) • Lack of findings consistent with other causes of adrenal insufficiency ## Establishing the Diagnosis The diagnosis of IMAGe syndrome Molecular genetic testing approaches can include a combination of When the clinical, radiographic, and laboratory findings suggest the diagnosis of IMAGe syndrome, molecular genetic testing approaches can include For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by growth deficiency and adrenal hypoplasia, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in IMAGe 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 At present all six reported pathogenic variants in Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No deletions or duplications of ## Option 1 For an introduction to multigene panels click ## Option 2 When the phenotype is indistinguishable from many other inherited disorders characterized by growth deficiency and adrenal hypoplasia, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in IMAGe 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 At present all six reported pathogenic variants in Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No deletions or duplications of ## Clinical Characteristics Thirty-one individuals reported from 19 families have features consistent with the clinical diagnosis of IMAGe syndrome [ A diagnosis of IMAGe syndrome has been considered in other published cases; however, the clinical information was either significantly different from the 31 typical cases or insufficient to determine the diagnosis with certainty, and pathogenic It is likely that the spectrum and natural history of IMAGe syndrome will be refined as more affected individuals are identified. Individuals with IMAGe syndrome consistently demonstrate continued short stature (height -2.7 to -6.5 SD) and postnatal failure to thrive (weight -2 to -7 SD). Of the nine on whom longitudinal information was available, postnatal OFC was normal in seven and below -2 SD in two individuals. A significant degree of age-dependent variation is observed: in some, the metaphyseal dysplasia may be late, mild, and/or easily missed. Most children have radiologic evidence of skeletal abnormality by age five years. Less common skeletal features include progressive and severe scoliosis with onset before age five years, ovoid-shaped vertebral bodies, short first metatarsals, hallux valgus, and hip dysplasia. In one individual, fractures of the humerus and tibia were present at birth [ Adrenal crisis, presenting with hyponatremia, hyperkalemia, and life-threatening hypotension, can occur within the first month of life, typically within the first week; extremely elevated ACTH levels, frequently above 1000 pg/mL (normal 10-60 pg/mL), can cause severe hyperpigmentation in these infants [ A few individuals do not have adrenal crisis, but rather milder adrenal insufficiency, presenting with failure to thrive and recurrent vomiting. One child, who experienced recurrent vomiting associated with mild infections from birth, was diagnosed with adrenal insufficiency at age five years following the diagnosis of IMAGe syndrome in her younger brother [ Of the 31 individuals reported with IMAGe syndrome 22 are male, which may represent ascertainment bias due to the presence of genital abnormalities in males only. Two females with IMAGe syndrome have had children [Authors, unpublished observations]. No males with IMAGe syndrome are known to have reproduced. Hydronephrosis has been reported; however, the majority of affected individuals are reported to have normal renal ultrasound examinations. Hypotonia was reported in six individuals and noted to be absent in four others; some of those reported with developmental delay likely had motor delays secondary to hypotonia. In one affected individual who had wasting of facial and distal muscles, muscle biopsy showed nonspecific myopathic changes [ Of 31 individuals with IMAGe syndrome, head imaging was reported for seven (3 via cranial ultrasound examination, 1 via head CT, and 3 via brain MRI), all were normal. Characteristic facial features that have been reported in the vast majority of individuals include frontal bossing, depressed or wide nasal bridge, and small/low-set ears; features are typically appreciated by age one year. The facial profile can be similar to the "triangular" facies seen in One individual has been reported with rhabdomyosarcoma [ Variable hypercalcemia of unclear etiology, occasionally with evidence of soft tissue calcifications, was reported in eight of 16 affected individuals on whom information was available. Several individuals have had nephrocalcinosis-associated hypercalciuria. While hypercalcemia may be a feature of IMAGe syndrome, it may also be secondary to sodium chloride supplementation, which is part of the treatment of the mineralocorticoid deficiency associated with adrenal insufficiency [ Currently, no genotype-phenotype correlations are known. Although few large pedigrees with IMAGe syndrome have been reported to date, it is clear that the mode of inheritance is autosomal dominant in which only maternal transmission of the imprinted pathogenic variant results in IMAGe syndrome [ In one large family of 24 individuals, all seven individuals with IMAGe syndrome inherited the Prior to the identification of its molecular basis [ Historically the term "intrauterine growth retardation" was used. More recently, the term "intrauterine growth restriction" has come into favor. The prevalence of IMAGe syndrome is currently unknown. A total of 31 affected individuals from 19 families have been reported to date. • Characteristic facial features that have been reported in the vast majority of individuals include frontal bossing, depressed or wide nasal bridge, and small/low-set ears; features are typically appreciated by age one year. The facial profile can be similar to the "triangular" facies seen in • One individual has been reported with rhabdomyosarcoma [ • Variable hypercalcemia of unclear etiology, occasionally with evidence of soft tissue calcifications, was reported in eight of 16 affected individuals on whom information was available. Several individuals have had nephrocalcinosis-associated hypercalciuria. While hypercalcemia may be a feature of IMAGe syndrome, it may also be secondary to sodium chloride supplementation, which is part of the treatment of the mineralocorticoid deficiency associated with adrenal insufficiency [ ## Clinical Description Thirty-one individuals reported from 19 families have features consistent with the clinical diagnosis of IMAGe syndrome [ A diagnosis of IMAGe syndrome has been considered in other published cases; however, the clinical information was either significantly different from the 31 typical cases or insufficient to determine the diagnosis with certainty, and pathogenic It is likely that the spectrum and natural history of IMAGe syndrome will be refined as more affected individuals are identified. Individuals with IMAGe syndrome consistently demonstrate continued short stature (height -2.7 to -6.5 SD) and postnatal failure to thrive (weight -2 to -7 SD). Of the nine on whom longitudinal information was available, postnatal OFC was normal in seven and below -2 SD in two individuals. A significant degree of age-dependent variation is observed: in some, the metaphyseal dysplasia may be late, mild, and/or easily missed. Most children have radiologic evidence of skeletal abnormality by age five years. Less common skeletal features include progressive and severe scoliosis with onset before age five years, ovoid-shaped vertebral bodies, short first metatarsals, hallux valgus, and hip dysplasia. In one individual, fractures of the humerus and tibia were present at birth [ Adrenal crisis, presenting with hyponatremia, hyperkalemia, and life-threatening hypotension, can occur within the first month of life, typically within the first week; extremely elevated ACTH levels, frequently above 1000 pg/mL (normal 10-60 pg/mL), can cause severe hyperpigmentation in these infants [ A few individuals do not have adrenal crisis, but rather milder adrenal insufficiency, presenting with failure to thrive and recurrent vomiting. One child, who experienced recurrent vomiting associated with mild infections from birth, was diagnosed with adrenal insufficiency at age five years following the diagnosis of IMAGe syndrome in her younger brother [ Of the 31 individuals reported with IMAGe syndrome 22 are male, which may represent ascertainment bias due to the presence of genital abnormalities in males only. Two females with IMAGe syndrome have had children [Authors, unpublished observations]. No males with IMAGe syndrome are known to have reproduced. Hydronephrosis has been reported; however, the majority of affected individuals are reported to have normal renal ultrasound examinations. Hypotonia was reported in six individuals and noted to be absent in four others; some of those reported with developmental delay likely had motor delays secondary to hypotonia. In one affected individual who had wasting of facial and distal muscles, muscle biopsy showed nonspecific myopathic changes [ Of 31 individuals with IMAGe syndrome, head imaging was reported for seven (3 via cranial ultrasound examination, 1 via head CT, and 3 via brain MRI), all were normal. Characteristic facial features that have been reported in the vast majority of individuals include frontal bossing, depressed or wide nasal bridge, and small/low-set ears; features are typically appreciated by age one year. The facial profile can be similar to the "triangular" facies seen in One individual has been reported with rhabdomyosarcoma [ Variable hypercalcemia of unclear etiology, occasionally with evidence of soft tissue calcifications, was reported in eight of 16 affected individuals on whom information was available. Several individuals have had nephrocalcinosis-associated hypercalciuria. While hypercalcemia may be a feature of IMAGe syndrome, it may also be secondary to sodium chloride supplementation, which is part of the treatment of the mineralocorticoid deficiency associated with adrenal insufficiency [ • Characteristic facial features that have been reported in the vast majority of individuals include frontal bossing, depressed or wide nasal bridge, and small/low-set ears; features are typically appreciated by age one year. The facial profile can be similar to the "triangular" facies seen in • One individual has been reported with rhabdomyosarcoma [ • Variable hypercalcemia of unclear etiology, occasionally with evidence of soft tissue calcifications, was reported in eight of 16 affected individuals on whom information was available. Several individuals have had nephrocalcinosis-associated hypercalciuria. While hypercalcemia may be a feature of IMAGe syndrome, it may also be secondary to sodium chloride supplementation, which is part of the treatment of the mineralocorticoid deficiency associated with adrenal insufficiency [ ## Genotype-Phenotype Correlations Currently, no genotype-phenotype correlations are known. ## Penetrance Although few large pedigrees with IMAGe syndrome have been reported to date, it is clear that the mode of inheritance is autosomal dominant in which only maternal transmission of the imprinted pathogenic variant results in IMAGe syndrome [ In one large family of 24 individuals, all seven individuals with IMAGe syndrome inherited the ## Nomenclature Prior to the identification of its molecular basis [ Historically the term "intrauterine growth retardation" was used. More recently, the term "intrauterine growth restriction" has come into favor. ## Prevalence The prevalence of IMAGe syndrome is currently unknown. A total of 31 affected individuals from 19 families have been reported to date. ## Genetically Related (Allelic) Disorders Three families comprising 13 individuals with SRS caused by A mixed phenotype involving features of both BWS and IMAGe syndrome as well as developmental delay and microcephaly was reported in one individual with a novel multiple base-pair pathogenic variant that results in tissue-specific frameshifting [ ## Differential Diagnosis Disorders with Adrenal Insufficiency in the Differential Diagnosis of IMAGe Syndrome Infants w/CAH rarely have IUGR. Genital abnormalities in CAH: typically virilization of females (vs undervirilization of males incl cryptorchidism & hypospadias in IMAGe syndrome) Adrenal glands in CAH: hypertrophic (vs hypoplastic in IMAGe syndrome). Note: CAH is far more common than IMAGe syndrome. Xp21 deletion ABS = Antley-Bixler syndrome; AD = autosomal dominant; AHC = adrenal hypoplasia congenita; AR = autosomal recessive; CAH = congenital adrenal hyperplasia; DiffDx = differential diagnosis; IUGR = intrauterine growth restriction; MOI = mode of inheritance; XL = X-linked Non-recurrent Xp21 deletion that includes Frequently children with IMAGe syndrome have short stature with a normal head size and normal cognitive development. Other disorders of growth with these features should be considered (see Disorders of Growth in the Differential Diagnosis of IMAGe Syndrome AR = autosomal recessive; DiffDx = differential diagnosis; IUGR = intrauterine growth restriction; MOI = mode of inheritance; nl = normal Genetic testing confirms clinical diagnosis in ~60% of affected individuals. Hypomethylation of the imprinted control region 1 at 11p15.5 causes SRS in 35%-50% of individuals, and maternal uniparental disomy causes SRS in 7%-10% of individuals. There are a small number of individuals with SRS who have duplications, deletions or translocations involving the imprinting centers at 11p15.5 or duplications, deletions, or translocations involving chromosome 7. Rarely, affected individuals with pathogenic variants in SRS has multiple etiologies and typically has a low recurrence risk. In most families, a proband with SRS represents a simplex case (a single affected family member) and has SRS as the result of an apparent • Infants w/CAH rarely have IUGR. • Genital abnormalities in CAH: typically virilization of females (vs undervirilization of males incl cryptorchidism & hypospadias in IMAGe syndrome) • Adrenal glands in CAH: hypertrophic (vs hypoplastic in IMAGe syndrome). • Note: CAH is far more common than IMAGe syndrome. ## Adrenal Insufficiency Disorders with Adrenal Insufficiency in the Differential Diagnosis of IMAGe Syndrome Infants w/CAH rarely have IUGR. Genital abnormalities in CAH: typically virilization of females (vs undervirilization of males incl cryptorchidism & hypospadias in IMAGe syndrome) Adrenal glands in CAH: hypertrophic (vs hypoplastic in IMAGe syndrome). Note: CAH is far more common than IMAGe syndrome. Xp21 deletion ABS = Antley-Bixler syndrome; AD = autosomal dominant; AHC = adrenal hypoplasia congenita; AR = autosomal recessive; CAH = congenital adrenal hyperplasia; DiffDx = differential diagnosis; IUGR = intrauterine growth restriction; MOI = mode of inheritance; XL = X-linked Non-recurrent Xp21 deletion that includes • Infants w/CAH rarely have IUGR. • Genital abnormalities in CAH: typically virilization of females (vs undervirilization of males incl cryptorchidism & hypospadias in IMAGe syndrome) • Adrenal glands in CAH: hypertrophic (vs hypoplastic in IMAGe syndrome). • Note: CAH is far more common than IMAGe syndrome. ## Disorders of Growth Frequently children with IMAGe syndrome have short stature with a normal head size and normal cognitive development. Other disorders of growth with these features should be considered (see Disorders of Growth in the Differential Diagnosis of IMAGe Syndrome AR = autosomal recessive; DiffDx = differential diagnosis; IUGR = intrauterine growth restriction; MOI = mode of inheritance; nl = normal Genetic testing confirms clinical diagnosis in ~60% of affected individuals. Hypomethylation of the imprinted control region 1 at 11p15.5 causes SRS in 35%-50% of individuals, and maternal uniparental disomy causes SRS in 7%-10% of individuals. There are a small number of individuals with SRS who have duplications, deletions or translocations involving the imprinting centers at 11p15.5 or duplications, deletions, or translocations involving chromosome 7. Rarely, affected individuals with pathogenic variants in SRS has multiple etiologies and typically has a low recurrence risk. In most families, a proband with SRS represents a simplex case (a single affected family member) and has SRS as the result of an apparent ## Management To establish the extent of disease and needs in an individual diagnosed with IMAGe syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with IMAGe Syndrome Consultation w/endocrinologist for adrenal insufficiency, typically: Serum & urine concentration of electrolytes, incl calcium Serum concentration of glucose & ACTH Assessment of arterial blood gases Growth assessment Assessment for hypogonadotropic hypogonadism in males Use of community or Need for social work involvement for parental support; Need for home nursing referral. MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse Episodes of acute adrenal insufficiency require close monitoring of blood pressure, hydration, clinical status, and serum concentration of glucose and electrolytes. Treatment with IV saline, glucose, and cortisol are utilized. If the serum electrolytes do not improve, a mineralocorticoid (fludrocortisone) is added or the dose of cortisol is increased. Once the acute episode has been managed, replacement doses of glucocorticoids and mineralocorticoids and oral supplements of sodium chloride are given. Steroid dosages must be increased with stress, such as that associated with intercurrent illness, surgery, or trauma. Steroid doses need to be managed to enable optimal linear growth without risking an adrenal crisis. Vigilance for proactive medical management and early recognition of adrenal insufficiency is required during illnesses and surgeries to prevent adrenal crisis. The wearing of a Medic Alert Males with hypogonadotropic hypogonadism are likely to need increasing doses of testosterone to induce puberty. Long-term adrenal steroid replacement and testosterone replacement should be managed by an experienced endocrinologist. Recommended Surveillance for Individuals with IMAGe Syndrome Neurologic assessment for hypotonia Monitor developmental progress & educational needs. If prenatal testing for IMAGe syndrome has not been performed, it is appropriate to evaluate newborn sibs of a proband to enable prompt diagnosis and management of adrenal insufficiency. Molecular genetic testing is indicated if the If the See Pregnant women with IMAGe syndrome are at increased risk for adrenal insufficiency and should be followed by an endocrinologist. Risks during delivery include cephalopelvic disproportion. Search • Serum & urine concentration of electrolytes, incl calcium • Serum concentration of glucose & ACTH • Assessment of arterial blood gases • Growth assessment • Assessment for hypogonadotropic hypogonadism in males • Use of community or • Need for social work involvement for parental support; • Need for home nursing referral. • Neurologic assessment for hypotonia • Monitor developmental progress & educational needs. • Molecular genetic testing is indicated if the • If the ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with IMAGe syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with IMAGe Syndrome Consultation w/endocrinologist for adrenal insufficiency, typically: Serum & urine concentration of electrolytes, incl calcium Serum concentration of glucose & ACTH Assessment of arterial blood gases Growth assessment Assessment for hypogonadotropic hypogonadism in males Use of community or Need for social work involvement for parental support; Need for home nursing referral. MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Serum & urine concentration of electrolytes, incl calcium • Serum concentration of glucose & ACTH • Assessment of arterial blood gases • Growth assessment • Assessment for hypogonadotropic hypogonadism in males • Use of community or • Need for social work involvement for parental support; • Need for home nursing referral. ## Treatment of Manifestations Episodes of acute adrenal insufficiency require close monitoring of blood pressure, hydration, clinical status, and serum concentration of glucose and electrolytes. Treatment with IV saline, glucose, and cortisol are utilized. If the serum electrolytes do not improve, a mineralocorticoid (fludrocortisone) is added or the dose of cortisol is increased. Once the acute episode has been managed, replacement doses of glucocorticoids and mineralocorticoids and oral supplements of sodium chloride are given. Steroid dosages must be increased with stress, such as that associated with intercurrent illness, surgery, or trauma. Steroid doses need to be managed to enable optimal linear growth without risking an adrenal crisis. Vigilance for proactive medical management and early recognition of adrenal insufficiency is required during illnesses and surgeries to prevent adrenal crisis. The wearing of a Medic Alert Males with hypogonadotropic hypogonadism are likely to need increasing doses of testosterone to induce puberty. Long-term adrenal steroid replacement and testosterone replacement should be managed by an experienced endocrinologist. ## Surveillance Recommended Surveillance for Individuals with IMAGe Syndrome Neurologic assessment for hypotonia Monitor developmental progress & educational needs. • Neurologic assessment for hypotonia • Monitor developmental progress & educational needs. ## Evaluation of Relatives at Risk If prenatal testing for IMAGe syndrome has not been performed, it is appropriate to evaluate newborn sibs of a proband to enable prompt diagnosis and management of adrenal insufficiency. Molecular genetic testing is indicated if the If the See • Molecular genetic testing is indicated if the • If the ## Pregnancy Management Pregnant women with IMAGe syndrome are at increased risk for adrenal insufficiency and should be followed by an endocrinologist. Risks during delivery include cephalopelvic disproportion. ## Therapies Under Investigation Search ## Genetic Counseling The In many families with molecularly confirmed IMAGe syndrome, the mother is heterozygous for the In many families, the pathogenic In at least two other families, two women with IMAGe syndrome and a known If the pathogenic variant identified in the proband is not identified in the mother and parental identity testing has confirmed biological maternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a mother with germline (or somatic and germline) mosaicism. 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 cells only. The father of an affected child with IMAGe syndrome caused by a pathogenic If the mother of the proband has the If the Each child of a woman with IMAGe syndrome has a 50% chance of inheriting the Each child of a man with IMAGe syndrome has a 50% chance of inheriting the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having a child with IMAGe syndrome. 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. • In many families with molecularly confirmed IMAGe syndrome, the mother is heterozygous for the • In many families, the pathogenic • In at least two other families, two women with IMAGe syndrome and a known • In many families, the pathogenic • In at least two other families, two women with IMAGe syndrome and a known • If the pathogenic variant identified in the proband is not identified in the mother and parental identity testing has confirmed biological maternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a mother with germline (or somatic and germline) mosaicism. 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 cells only. • The proband has a • The proband inherited a pathogenic variant from a mother with germline (or somatic and germline) mosaicism. 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 cells only. • The father of an affected child with IMAGe syndrome caused by a pathogenic • In many families, the pathogenic • In at least two other families, two women with IMAGe syndrome and a known • The proband has a • The proband inherited a pathogenic variant from a mother with germline (or somatic and germline) mosaicism. 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 cells only. • If the mother of the proband has the • If the • Each child of a woman with IMAGe syndrome has a 50% chance of inheriting the • Each child of a man with IMAGe syndrome has a 50% chance of inheriting 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 a child with IMAGe syndrome. ## Mode of Inheritance The ## Risk to Family Members In many families with molecularly confirmed IMAGe syndrome, the mother is heterozygous for the In many families, the pathogenic In at least two other families, two women with IMAGe syndrome and a known If the pathogenic variant identified in the proband is not identified in the mother and parental identity testing has confirmed biological maternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a mother with germline (or somatic and germline) mosaicism. 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 cells only. The father of an affected child with IMAGe syndrome caused by a pathogenic If the mother of the proband has the If the Each child of a woman with IMAGe syndrome has a 50% chance of inheriting the Each child of a man with IMAGe syndrome has a 50% chance of inheriting the • In many families with molecularly confirmed IMAGe syndrome, the mother is heterozygous for the • In many families, the pathogenic • In at least two other families, two women with IMAGe syndrome and a known • In many families, the pathogenic • In at least two other families, two women with IMAGe syndrome and a known • If the pathogenic variant identified in the proband is not identified in the mother and parental identity testing has confirmed biological maternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a mother with germline (or somatic and germline) mosaicism. 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 cells only. • The proband has a • The proband inherited a pathogenic variant from a mother with germline (or somatic and germline) mosaicism. 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 cells only. • The father of an affected child with IMAGe syndrome caused by a pathogenic • In many families, the pathogenic • In at least two other families, two women with IMAGe syndrome and a known • The proband has a • The proband inherited a pathogenic variant from a mother with germline (or somatic and germline) mosaicism. 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 cells only. • If the mother of the proband has the • If the • Each child of a woman with IMAGe syndrome has a 50% chance of inheriting the • Each child of a man with IMAGe syndrome has a 50% chance of inheriting the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having a child with IMAGe syndrome. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having a child with IMAGe syndrome. ## 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 IMAGe Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for IMAGe Syndrome ( See OMIM The longest isoform of Coimmunoprecipitation studies in HEK293T cells suggest that pathogenic variants associated with IMAGe syndrome disrupt binding to PCNA, which likely is required for ubiquitin-mediated degradation of p57KIP2/CDKN1C [ This pathogenic mechanism causing IMAGe syndrome and related conditions is in contrast to loss-of-function pathogenic variants in Notable Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis See OMIM The longest isoform of Coimmunoprecipitation studies in HEK293T cells suggest that pathogenic variants associated with IMAGe syndrome disrupt binding to PCNA, which likely is required for ubiquitin-mediated degradation of p57KIP2/CDKN1C [ This pathogenic mechanism causing IMAGe syndrome and related conditions is in contrast to loss-of-function pathogenic variants in Notable Variants listed in the table have been provided by the authors. ## Chapter Notes James Bennett, MD, PhD; Seattle Children’s Hospital (2014-2021)Matthew A Deardorff, MD, PhD (2014-present)Samantha A Schrier Vergano, MD (2014-present) 5 August 2021 (sw) Comprehensive update posted live 8 September 2016 (ma) Comprehensive update posted live 13 March 2014 (me) Review posted live 11 September 2013 (md) Original submission • 5 August 2021 (sw) Comprehensive update posted live • 8 September 2016 (ma) Comprehensive update posted live • 13 March 2014 (me) Review posted live • 11 September 2013 (md) Original submission ## Author History James Bennett, MD, PhD; Seattle Children’s Hospital (2014-2021)Matthew A Deardorff, MD, PhD (2014-present)Samantha A Schrier Vergano, MD (2014-present) ## Revision History 5 August 2021 (sw) Comprehensive update posted live 8 September 2016 (ma) Comprehensive update posted live 13 March 2014 (me) Review posted live 11 September 2013 (md) Original submission • 5 August 2021 (sw) Comprehensive update posted live • 8 September 2016 (ma) Comprehensive update posted live • 13 March 2014 (me) Review posted live • 11 September 2013 (md) Original submission ## References ## Literature Cited The chromosome 11p15.5 imprinted region and pathogenic The chromosome 11p15.5 imprinting cluster is functionally divided into Domain 1 and Domain 2. Domain 2 includes the imprinted gene Symbols above and below the protein schematic indicate the domain locations of IMAGe syndrome is caused by gain-of-function pathogenic missense variants in the BWS, in contrast, is caused by one of the five following mechanisms: (1) pathogenic loss-of-function variants in the maternal Although 11p15.5-related Silver-Russell syndrome (like IMAGe syndrome) is a disorder of reduced growth, it is caused by (1) hypomethylation of IC1 on the paternal chromosome or (2) chromosome abnormalities that reduce relative expression of this region from the paternal chromosome (e.g., maternal uniparental disomy, maternally inherited duplications, and other rare chromosome abnormalities). See Pedigree of a family demonstrating autosomal dominant maternally imprinted inheritance of IMAGe syndrome. Individuals labeled T/G are heterozygous for the normal "T" allele and the "G" pathogenic variant (	[ "N Amano, H Naoaki, T Ishii, S Narumi, R Hachiya, G Nishimura, T. Hasegawa. Radiological evolution in IMAGe association: a case report.. Am J Med Genet A. 2008;146A:2130-3", "VA Arboleda, H Lee, R Parnaik, A Fleming, A Banerjee, B Ferraz-de-Souza, EC Délot, IA Rodriguez-Fernandez, D Braslavsky, I Bergadá, EC Dell'Angelica, SF Nelson, JA Martinez-Agosto, JC Achermann, E Vilain. Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome.. Nat Genet. 2012;44:788-92", "M Balasubramanian, A Sprigg, DS Johnson. IMAGe syndrome: Case report with a previously unreported feature and review of published literature.. Am J Med Genet A. 2010;152A:3138-42", "I Bergadá, G Del Rey, P Lapunzina, C Bergadá, M Fellous, S Copelli. Familial occurrence of the IMAGe association: additional clinical variants and a proposed mode of inheritance.. J Clin Endocrinol Metab. 2005;90:3186-90", "S Berland, BI Haukanes, PB Juliusson, G Houge. Deep exploration of a CDKN1C mutation causing a mixture of Beckwith-Wiedemann and IMAGe syndromes revealed a novel transcript associated with developmental delay.. J Med Genet. 2022;59:155-64", "G Binder, J Ziegler, R Schweizer, W Habhab, TB Haack, T Heinrich, T Eggermann. Novel mutation points to a hot spot in CDKN1C causing Silver-Russell syndrome.. Clin Epigenetics. 2020;12:152", "SL Blethen, GB Wenick, LA Hawkins. Congenital adrenal hypoplasia in association with growth hormone deficiency, developmental delay, partial androgen resistance, unusual facies, and skeletal abnormalities.. Clin Genet 1990;4:110-6", "DL Bodian, BD Solomon, A Khromykh, DC Thach, RK Iyer, K Link, RL Baker, R Baveja, JG Vockley, JE Niederhuber. Diagnosis of an imprinted-gene syndrome by a novel bioinformatics analysis of whole-genome sequences from a family trio.. Mol Genet Genomic Med. 2014;2:530-8", "M Bolomiti, E Batnes-Pedersen, G Telman, D Januszkiewicz-Lewandowska. A Case report: Co-occurrence of IMAGe syndrome and Rhabdomyosarcoma.. Cancer Genet. 2021;256-257:100-5", "KS Borges, VA Arboleda, E Vilain. Mutations in the PCNA-binding site of CDKN1C inhibit cell proliferation by impairing the entry into S phase.. Cell Div. 2015;10:2", "F Brioude, I Oliver-Petit, A Blaise, F Praz, S Rossignol, M Le Jule, N Thibaud, AM Faussat, M Tauber, Y Le Bouc, I Netchine. CDKN1C mutation affecting the PCNA-binding domain as a cause of familial Russell Silver syndrome.. J Med Genet. 2013;50:823-30", "E Çamtosun, İ Dündar, A Akıncı, L Kayaş, N Çiftci. Pediatric primary adrenal insufficiency: a 21-year single center experience.. J Clin Res Pediatr Endocrinol. 2021;13:88-99", "DJ Coman, SM White, DJ Amor. Two siblings with 46,XY DSD, congenital adrenal hypoplasia, aniridia, craniofacial, and skeletal abnormalities and intrauterine growth retardation: a new syndrome?. Am J Med Genet A. 2007;143A:2085-8", "BD Hall, MW Stelling. Adrenal hypoplasia associated with severe growth deficiency, specific pattern of malformations and psychomotor retardation.. Clin Res. 1991;39:63A", "N Hamajima, Y Johmura, S Suzuki, M Nakanishi, S Saitoh. Increased protein stability of CDKN1C causes a gain-of-function phenotype in patients with IMAGe syndrome.. PLoS One. 2013;8", "JE Hutz, AS Krause, JC Achermann, E Vilain, M Tauber, C Lecointre, ER McCabe, GD Hammer, CE Keegan. IMAGe association and congenital adrenal hypoplasia: no disease-causing mutations found in the ACD gene.. Mol Genet Metab. 2006;88:66-70", "F Kato, T Hamajima, T Hasegawa, N Amano, R Horikawa, G Nishimura, S Nakashima, T Fuke, S Sano, M Fukami, T Ogata. IMAGe syndrome: clinical and genetic implications based on investigations in three Japanese patients.. Clin Endocrinol (Oxf) 2014;80:706-13", "SL Kerns, J Guevara-Aguirre, S Andrew, J Geng, C Guevara, M Guevara-Aguirre, M Guo, C Oddoux, Y Shen, A Zurita, RG Rosenfeld, H Ostrer, V Hwa, A Dauber. A novel variant in CDKN1C is associated with intrauterine growth restriction, short stature, and early-adulthood-onset diabetes.. J Clin Endocrinol Metab. 2014;99:E2117-22", "JM Ko, JH Lee, GH Kim, AR Kim, HW Yoo. A case of a Korean newborn with IMAGe association presenting with hyperpigmented skin at birth.. Eur J Pediatr. 2007;166:879-80", "SQ Le, WH Kutteh. Monosomy 7 syndrome associated with congenital adrenal hypoplasia and male pseudohermaphroditism.. Obstet Gynecol. 1996;87:854-6", "A Lienhardt, JC Mas, G Kalifa, JL Chaussain, M Tauber. IMAGe association: additional clinical features and evidence for recessive autosomal inheritance.. Horm Res. 2002;57:71-8", "RG Lindemeyer, SE Rashewsky, PJ Louie, L Schleelein. Anesthetic and dental management of a child with IMAGe syndrome.. Anesth Prog. 2014;61:165-8", "S McDonald, DB Wilson, E Pumbo, S Kulkarni, PJ Mason, T Else, M Bessler, T Ferkol, S Shenoy. Acquired monosomy 7 myelodysplastic syndrome in a child with clinical features suggestive of dyskeratosis congenita and IMAGe association.. Pediatr Blood Cancer. 2010;54:154-7", "CC Pedreira, R Savarirayan, MR Zacharin. IMAGe syndrome: a complex disorder affecting growth, adrenal and gonadal function, and skeletal development.. J Pediatr. 2004;144:274-7", "AH Sabir, G Ryan, Z Mohammed, J Kirk, N Kiely, M Thyagarajan, T Cole. Familial Russell-Silver syndrome like phenotype in the PCNA domain of the CDKN1C gene, a further case.. Case Rep Genet. 2019;2019", "H Soejima, K Higashimoto. Epigenetic and genetic alterations of the imprinting disorder Beckwith-Wiedemann syndrome and related disorders.. J Hum Genet. 2013;58:402-9", "TY Tan, JL Jameson, PE Campbell, PG Ekert, M Zacharin, R Savarirayan. Two sisters with IMAGe syndrome: cytomegalic adrenal histopathology, support for autosomal recessive inheritance and literature review.. Am J Med Genet A. 2006;140:1778-84", "E Vilain, M Le Merrer, C Lecointre, F Desangles, MA Kay, P Maroteaux, ER McCabe. IMAGe, a new clinical association of intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies.. J Clin Endocrinol Metab. 1999;84:4335-40" ]	13/3/2014	5/8/2021		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
inad	inad	[ "NBIA2", "PLA2G6-Related Disorders", "PLAN", "PLAN", "PLA2G6-Related Disorders", "NBIA2", "Atypical Neuroaxonal Dystrophy", "Infantile Neuroaxonal Dystrophy", "PLA2G6-Related Dystonia-Parkinsonism", "85/88 kDa calcium-independent phospholipase A2", "PLA2G6", "PLA2G6-Associated Neurodegeneration" ]		Allison Gregory, Manju A Kurian, Eamonn R Maher, Penelope Hogarth, Susan J Hayflick	Summary Infantile neuroaxonal dystrophy (INAD) Atypical neuroaxonal dystrophy (atypical NAD) INAD usually begins between ages six months and three years with psychomotor regression or delay, hypotonia, and progressive spastic tetraparesis. Many affected children never learn to walk or lose the ability shortly after attaining it. Strabismus, nystagmus, and optic atrophy are common. Disease progression is rapid, resulting in severe spasticity, progressive cognitive decline, and visual impairment. Many affected children do not survive beyond their first decade. Atypical NAD shows more phenotypic variability than INAD. In general, onset is in early childhood but can be as late as the end of the second decade. The presenting signs may be gait instability, ataxia, or speech delay and autistic features, which are sometimes the only evidence of disease for a year or more. Strabismus, nystagmus, and optic atrophy are common. Neuropsychiatric disturbances including impulsivity, poor attention span, hyperactivity, and emotional lability are also common. The course is fairly stable during early childhood and resembles static encephalopathy but is followed by neurologic deterioration between ages seven and 12 years. The diagnosis of Individuals with INAD and atypical NAD. Routine pharmacologic treatment of spasticity and seizures; trial of oral or intrathecal baclofen for dystonia associated with atypical INAD; treatment by a psychiatrist for those with later-onset neuropsychiatric symptoms; fiber supplements and/or stool softener treatment for constipation; control of secretions with transdermal scopolamine patch as needed; feeding modifications as needed to prevent aspiration pneumonia and achieve adequate nutrition. Individuals with	Infantile neuroaxonal dystrophy (INAD) Atypical neuroaxonal dystrophy (atypical NAD) For synonyms and outdated names see For other genetic causes of these phenotypes see • Infantile neuroaxonal dystrophy (INAD) • Atypical neuroaxonal dystrophy (atypical NAD) ## Diagnosis Infantile neuroaxonal dystrophy (INAD) Atypical neuroaxonal dystrophy (atypical NAD) Onset before age three years Psychomotor regression (most common presenting feature) Early truncal hypotonia followed by spastic tetraparesis (usually with hyperreflexia in the early disease stages with progression to areflexia later in the disease course) Visual abnormalities: strabismus, nystagmus, optic atrophy Elevated aspartate aminotransferase / alanine aminotransferase ratio Elevated lactate dehydrogenase Cerebellar atrophy (See T EMG (electromyogram). Evidence of denervation EEG (electroencephalogram). Fast rhythms VEP (visual evoked potential). Delayed with reduced amplitudes NCV (nerve conduction velocity). Distal axonal-type sensorimotor neuropathy Seizures that may present early or late in the disease course [ Onset before age 20 years Psychomotor regression Gait abnormalities Prominent expressive language difficulties Psychiatric/behavioral abnormalities including autistic-like behavior Visual abnormalities: nystagmus, optic atrophy Spasticity (without preceding hypotonia) Joint contractures Progressive dystonia and dysarthria Disease progression slower than in INAD Cerebellar atrophy T VEP. Delayed with reduced amplitudes Seizures Onset varying from childhood to young adulthood Parkinsonism (tremor, bradykinesia, rigidity, and markedly impaired postural responses) Dystonia Dysarthria Autonomic involvement (e.g., cold/blue hands and feet, difficulty regulating core body temperature, constipation) Cognitive decline Neuropsychiatric changes Initial dramatic response to dopaminergic treatment followed by the early development of dyskinesias Cerebral atrophy Cerebellar atrophy Abnormal brain iron accumulation in the globus pallidus, substantia nigra, and/or striatum; findings are variable and may not be evident on MRI studies until late in the disease course for some individuals. Reduced dopamine transporter labeling similar to that seen in idiopathic Parkinson disease In some individuals, frontotemporal atrophy/hypoperfusion on single-photon emission computed tomography The diagnosis of 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 See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Of all individuals identified with Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Deletion and duplication of multiple exons have been identified Linkage data support the presence of at least one additional INAD locus [ Membranotubular profiles; Mitochondrial aggregates; Increased axonal diameter and thinned membrane. Note: (1) Because axonal spheroids accumulate with age and may not be evident in all tissues, individuals suspected to have INAD or atypical NAD without identifiable • Infantile neuroaxonal dystrophy (INAD) • Atypical neuroaxonal dystrophy (atypical NAD) • Onset before age three years • Psychomotor regression (most common presenting feature) • Early truncal hypotonia followed by spastic tetraparesis (usually with hyperreflexia in the early disease stages with progression to areflexia later in the disease course) • Visual abnormalities: strabismus, nystagmus, optic atrophy • Elevated aspartate aminotransferase / alanine aminotransferase ratio • Elevated lactate dehydrogenase • Cerebellar atrophy (See • T • EMG (electromyogram). Evidence of denervation • EEG (electroencephalogram). Fast rhythms • VEP (visual evoked potential). Delayed with reduced amplitudes • NCV (nerve conduction velocity). Distal axonal-type sensorimotor neuropathy • Seizures that may present early or late in the disease course [ • Onset before age 20 years • Psychomotor regression • Gait abnormalities • Prominent expressive language difficulties • Psychiatric/behavioral abnormalities including autistic-like behavior • Visual abnormalities: nystagmus, optic atrophy • Spasticity (without preceding hypotonia) • Joint contractures • Progressive dystonia and dysarthria • Disease progression slower than in INAD • Cerebellar atrophy • T • VEP. Delayed with reduced amplitudes • Seizures • Onset varying from childhood to young adulthood • Parkinsonism (tremor, bradykinesia, rigidity, and markedly impaired postural responses) • Dystonia • Dysarthria • Autonomic involvement (e.g., cold/blue hands and feet, difficulty regulating core body temperature, constipation) • Cognitive decline • Neuropsychiatric changes • Initial dramatic response to dopaminergic treatment followed by the early development of dyskinesias • Cerebral atrophy • Cerebellar atrophy • Abnormal brain iron accumulation in the globus pallidus, substantia nigra, and/or striatum; findings are variable and may not be evident on MRI studies until late in the disease course for some individuals. • Reduced dopamine transporter labeling similar to that seen in idiopathic Parkinson disease • In some individuals, frontotemporal atrophy/hypoperfusion on single-photon emission computed tomography • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click • Membranotubular profiles; • Mitochondrial aggregates; • Increased axonal diameter and thinned membrane. ## Suggestive Findings Infantile neuroaxonal dystrophy (INAD) Atypical neuroaxonal dystrophy (atypical NAD) Onset before age three years Psychomotor regression (most common presenting feature) Early truncal hypotonia followed by spastic tetraparesis (usually with hyperreflexia in the early disease stages with progression to areflexia later in the disease course) Visual abnormalities: strabismus, nystagmus, optic atrophy Elevated aspartate aminotransferase / alanine aminotransferase ratio Elevated lactate dehydrogenase Cerebellar atrophy (See T EMG (electromyogram). Evidence of denervation EEG (electroencephalogram). Fast rhythms VEP (visual evoked potential). Delayed with reduced amplitudes NCV (nerve conduction velocity). Distal axonal-type sensorimotor neuropathy Seizures that may present early or late in the disease course [ Onset before age 20 years Psychomotor regression Gait abnormalities Prominent expressive language difficulties Psychiatric/behavioral abnormalities including autistic-like behavior Visual abnormalities: nystagmus, optic atrophy Spasticity (without preceding hypotonia) Joint contractures Progressive dystonia and dysarthria Disease progression slower than in INAD Cerebellar atrophy T VEP. Delayed with reduced amplitudes Seizures Onset varying from childhood to young adulthood Parkinsonism (tremor, bradykinesia, rigidity, and markedly impaired postural responses) Dystonia Dysarthria Autonomic involvement (e.g., cold/blue hands and feet, difficulty regulating core body temperature, constipation) Cognitive decline Neuropsychiatric changes Initial dramatic response to dopaminergic treatment followed by the early development of dyskinesias Cerebral atrophy Cerebellar atrophy Abnormal brain iron accumulation in the globus pallidus, substantia nigra, and/or striatum; findings are variable and may not be evident on MRI studies until late in the disease course for some individuals. Reduced dopamine transporter labeling similar to that seen in idiopathic Parkinson disease In some individuals, frontotemporal atrophy/hypoperfusion on single-photon emission computed tomography • Infantile neuroaxonal dystrophy (INAD) • Atypical neuroaxonal dystrophy (atypical NAD) • Onset before age three years • Psychomotor regression (most common presenting feature) • Early truncal hypotonia followed by spastic tetraparesis (usually with hyperreflexia in the early disease stages with progression to areflexia later in the disease course) • Visual abnormalities: strabismus, nystagmus, optic atrophy • Elevated aspartate aminotransferase / alanine aminotransferase ratio • Elevated lactate dehydrogenase • Cerebellar atrophy (See • T • EMG (electromyogram). Evidence of denervation • EEG (electroencephalogram). Fast rhythms • VEP (visual evoked potential). Delayed with reduced amplitudes • NCV (nerve conduction velocity). Distal axonal-type sensorimotor neuropathy • Seizures that may present early or late in the disease course [ • Onset before age 20 years • Psychomotor regression • Gait abnormalities • Prominent expressive language difficulties • Psychiatric/behavioral abnormalities including autistic-like behavior • Visual abnormalities: nystagmus, optic atrophy • Spasticity (without preceding hypotonia) • Joint contractures • Progressive dystonia and dysarthria • Disease progression slower than in INAD • Cerebellar atrophy • T • VEP. Delayed with reduced amplitudes • Seizures • Onset varying from childhood to young adulthood • Parkinsonism (tremor, bradykinesia, rigidity, and markedly impaired postural responses) • Dystonia • Dysarthria • Autonomic involvement (e.g., cold/blue hands and feet, difficulty regulating core body temperature, constipation) • Cognitive decline • Neuropsychiatric changes • Initial dramatic response to dopaminergic treatment followed by the early development of dyskinesias • Cerebral atrophy • Cerebellar atrophy • Abnormal brain iron accumulation in the globus pallidus, substantia nigra, and/or striatum; findings are variable and may not be evident on MRI studies until late in the disease course for some individuals. • Reduced dopamine transporter labeling similar to that seen in idiopathic Parkinson disease • In some individuals, frontotemporal atrophy/hypoperfusion on single-photon emission computed tomography ## Infantile Neuroaxonal Dystrophy (INAD) Onset before age three years Psychomotor regression (most common presenting feature) Early truncal hypotonia followed by spastic tetraparesis (usually with hyperreflexia in the early disease stages with progression to areflexia later in the disease course) Visual abnormalities: strabismus, nystagmus, optic atrophy Elevated aspartate aminotransferase / alanine aminotransferase ratio Elevated lactate dehydrogenase Cerebellar atrophy (See T EMG (electromyogram). Evidence of denervation EEG (electroencephalogram). Fast rhythms VEP (visual evoked potential). Delayed with reduced amplitudes NCV (nerve conduction velocity). Distal axonal-type sensorimotor neuropathy Seizures that may present early or late in the disease course [ • Onset before age three years • Psychomotor regression (most common presenting feature) • Early truncal hypotonia followed by spastic tetraparesis (usually with hyperreflexia in the early disease stages with progression to areflexia later in the disease course) • Visual abnormalities: strabismus, nystagmus, optic atrophy • Elevated aspartate aminotransferase / alanine aminotransferase ratio • Elevated lactate dehydrogenase • Cerebellar atrophy (See • T • EMG (electromyogram). Evidence of denervation • EEG (electroencephalogram). Fast rhythms • VEP (visual evoked potential). Delayed with reduced amplitudes • NCV (nerve conduction velocity). Distal axonal-type sensorimotor neuropathy • Seizures that may present early or late in the disease course [ ## Atypical Neuroaxonal Dystrophy (NAD) Onset before age 20 years Psychomotor regression Gait abnormalities Prominent expressive language difficulties Psychiatric/behavioral abnormalities including autistic-like behavior Visual abnormalities: nystagmus, optic atrophy Spasticity (without preceding hypotonia) Joint contractures Progressive dystonia and dysarthria Disease progression slower than in INAD Cerebellar atrophy T VEP. Delayed with reduced amplitudes Seizures • Onset before age 20 years • Psychomotor regression • Gait abnormalities • Prominent expressive language difficulties • Psychiatric/behavioral abnormalities including autistic-like behavior • Visual abnormalities: nystagmus, optic atrophy • Spasticity (without preceding hypotonia) • Joint contractures • Progressive dystonia and dysarthria • Disease progression slower than in INAD • Cerebellar atrophy • T • VEP. Delayed with reduced amplitudes • Seizures Onset varying from childhood to young adulthood Parkinsonism (tremor, bradykinesia, rigidity, and markedly impaired postural responses) Dystonia Dysarthria Autonomic involvement (e.g., cold/blue hands and feet, difficulty regulating core body temperature, constipation) Cognitive decline Neuropsychiatric changes Initial dramatic response to dopaminergic treatment followed by the early development of dyskinesias Cerebral atrophy Cerebellar atrophy Abnormal brain iron accumulation in the globus pallidus, substantia nigra, and/or striatum; findings are variable and may not be evident on MRI studies until late in the disease course for some individuals. Reduced dopamine transporter labeling similar to that seen in idiopathic Parkinson disease In some individuals, frontotemporal atrophy/hypoperfusion on single-photon emission computed tomography • Onset varying from childhood to young adulthood • Parkinsonism (tremor, bradykinesia, rigidity, and markedly impaired postural responses) • Dystonia • Dysarthria • Autonomic involvement (e.g., cold/blue hands and feet, difficulty regulating core body temperature, constipation) • Cognitive decline • Neuropsychiatric changes • Initial dramatic response to dopaminergic treatment followed by the early development of dyskinesias • Cerebral atrophy • Cerebellar atrophy • Abnormal brain iron accumulation in the globus pallidus, substantia nigra, and/or striatum; findings are variable and may not be evident on MRI studies until late in the disease course for some individuals. • Reduced dopamine transporter labeling similar to that seen in idiopathic Parkinson disease • In some individuals, frontotemporal atrophy/hypoperfusion on single-photon emission computed tomography ## Establishing the Diagnosis The diagnosis of 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 See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Of all individuals identified with Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Deletion and duplication of multiple exons have been identified Linkage data support the presence of at least one additional INAD locus [ Membranotubular profiles; Mitochondrial aggregates; Increased axonal diameter and thinned membrane. Note: (1) Because axonal spheroids accumulate with age and may not be evident in all tissues, individuals suspected to have INAD or atypical NAD without identifiable • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click • Membranotubular profiles; • Mitochondrial aggregates; • Increased axonal diameter and thinned membrane. ## Clinical Characteristics Truncal hypotonia is observed early in the disease course. Over time, affected persons develop a spastic tetraparesis, with symmetric pyramidal tract signs on clinical examination. Visual signs and symptoms are common. Strabismus and nystagmus are early features of the disease. Later optic atrophy occurs in most individuals. Optic atrophy may be observed early as optic nerve pallor; thin optic chiasm and tracts have also been reported on brain MRI [ Seizures occur in a minority of individuals as a later symptom [ Autonomic involvement may present early as constipation or cold extremities. With progression, some individuals require body temperature monitors because of dangerous fluctuations in core body temperature. The progression of disease is usually rapid. Many affected children never learn to walk or lose this ability shortly after attaining it. During the end stages of disease, severe spasticity, progressive cognitive decline, and visual impairment result in a vegetative state. Death occurs as a result of secondary illnesses such as aspiration pneumonia, associated with bulbar dysfunction. Many affected children do not survive beyond their first decade, but some survive into their teens or later. Supportive care can contribute to a longer life span by reducing the risk of infection and other complications. In general, onset in atypical NAD is in early childhood but can be as late as the late teens. In a series of 13 individuals, four had onset by age three years but a fairly stable course during early childhood resembling static encephalopathy, followed by neurologic deterioration between ages seven and 12 years [ The presenting signs and symptoms may be similar to INAD, including gait instability or ataxia. Others may present with speech delay and autistic features, which may remain as the only evidence of disease for a year or more, given the slow progression of atypical NAD compared to INAD [ Although spastic tetraparesis is evident late in the disease, it is rarely preceded by early truncal hypotonia. In contrast to classic disease, extrapyramidal findings (i.e., dystonia and dysarthria) predominate in atypical NAD. Eye findings are similar to those seen in classic INAD. Neuropsychiatric disturbances including impulsivity, poor attention span, hyperactivity, and emotional lability are also common [ Atypical NAD is rare, and the life span is not known; however, it is expected to be longer than that observed in classic disease. Regardless of the age at onset, affected individuals consistently develop dystonia and parkinsonism (which may be accompanied by rapid cognitive decline) in their late teens to early twenties. Neuropsychiatric changes may precede the movement disorder or occur concomitantly. Dystonia is most common in the hands and feet but may be more generalized. The most common features of parkinsonism in these individuals are bradykinesia, resting tremor, rigidity, and postural instability. Of note, it is common to have an initially dramatic positive response to dopaminergic agents; however, this tends to be short-lived and followed quickly by the development of motor fluctuations and dyskinesias. Genotype correlates with phenotype to a limited extent: All individuals with two null alleles of The less severe atypical NAD phenotype is caused almost exclusively by pathogenic missense variants. Common pathogenic variants associated with INAD impair the catalytic activity of the PLA2G6 protein, whereas three pathogenic variants associated with Karak syndrome was described in two sibs with early-onset cerebellar ataxia, dystonia, spasticity, and intellectual decline. Brain MRI findings included cerebellar atrophy and iron accumulation in the globus pallidus and substantia nigra [ The authors propose the following usage: Disease prevalence is not established; it is estimated at 1:1,000,000. • All individuals with two null alleles of • The less severe atypical NAD phenotype is caused almost exclusively by pathogenic missense variants. • Common pathogenic variants associated with INAD impair the catalytic activity of the PLA2G6 protein, whereas three pathogenic variants associated with • Karak syndrome was described in two sibs with early-onset cerebellar ataxia, dystonia, spasticity, and intellectual decline. Brain MRI findings included cerebellar atrophy and iron accumulation in the globus pallidus and substantia nigra [ ## Clinical Description Truncal hypotonia is observed early in the disease course. Over time, affected persons develop a spastic tetraparesis, with symmetric pyramidal tract signs on clinical examination. Visual signs and symptoms are common. Strabismus and nystagmus are early features of the disease. Later optic atrophy occurs in most individuals. Optic atrophy may be observed early as optic nerve pallor; thin optic chiasm and tracts have also been reported on brain MRI [ Seizures occur in a minority of individuals as a later symptom [ Autonomic involvement may present early as constipation or cold extremities. With progression, some individuals require body temperature monitors because of dangerous fluctuations in core body temperature. The progression of disease is usually rapid. Many affected children never learn to walk or lose this ability shortly after attaining it. During the end stages of disease, severe spasticity, progressive cognitive decline, and visual impairment result in a vegetative state. Death occurs as a result of secondary illnesses such as aspiration pneumonia, associated with bulbar dysfunction. Many affected children do not survive beyond their first decade, but some survive into their teens or later. Supportive care can contribute to a longer life span by reducing the risk of infection and other complications. In general, onset in atypical NAD is in early childhood but can be as late as the late teens. In a series of 13 individuals, four had onset by age three years but a fairly stable course during early childhood resembling static encephalopathy, followed by neurologic deterioration between ages seven and 12 years [ The presenting signs and symptoms may be similar to INAD, including gait instability or ataxia. Others may present with speech delay and autistic features, which may remain as the only evidence of disease for a year or more, given the slow progression of atypical NAD compared to INAD [ Although spastic tetraparesis is evident late in the disease, it is rarely preceded by early truncal hypotonia. In contrast to classic disease, extrapyramidal findings (i.e., dystonia and dysarthria) predominate in atypical NAD. Eye findings are similar to those seen in classic INAD. Neuropsychiatric disturbances including impulsivity, poor attention span, hyperactivity, and emotional lability are also common [ Atypical NAD is rare, and the life span is not known; however, it is expected to be longer than that observed in classic disease. Regardless of the age at onset, affected individuals consistently develop dystonia and parkinsonism (which may be accompanied by rapid cognitive decline) in their late teens to early twenties. Neuropsychiatric changes may precede the movement disorder or occur concomitantly. Dystonia is most common in the hands and feet but may be more generalized. The most common features of parkinsonism in these individuals are bradykinesia, resting tremor, rigidity, and postural instability. Of note, it is common to have an initially dramatic positive response to dopaminergic agents; however, this tends to be short-lived and followed quickly by the development of motor fluctuations and dyskinesias. ## Genotype-Phenotype Correlations Genotype correlates with phenotype to a limited extent: All individuals with two null alleles of The less severe atypical NAD phenotype is caused almost exclusively by pathogenic missense variants. Common pathogenic variants associated with INAD impair the catalytic activity of the PLA2G6 protein, whereas three pathogenic variants associated with • All individuals with two null alleles of • The less severe atypical NAD phenotype is caused almost exclusively by pathogenic missense variants. • Common pathogenic variants associated with INAD impair the catalytic activity of the PLA2G6 protein, whereas three pathogenic variants associated with ## Nomenclature Karak syndrome was described in two sibs with early-onset cerebellar ataxia, dystonia, spasticity, and intellectual decline. Brain MRI findings included cerebellar atrophy and iron accumulation in the globus pallidus and substantia nigra [ The authors propose the following usage: • Karak syndrome was described in two sibs with early-onset cerebellar ataxia, dystonia, spasticity, and intellectual decline. Brain MRI findings included cerebellar atrophy and iron accumulation in the globus pallidus and substantia nigra [ ## Prevalence Disease prevalence is not established; it is estimated at 1:1,000,000. ## Genetically Related (Allelic) Disorders Though still only speculative, pathogenic variants in The authors have proposed that pathogenic variants in ## Differential Diagnosis Early diagnosis is challenging because the initial symptoms of psychomotor regression and progression are also observed in other conditions. The observation of an elevated aspartate aminotransferase / alanine aminotransferase ratio and elevated lactate dehydrogenase in combination with these findings is more suspicious for INAD [ The degree of weakness early in the disease course may initially direct the clinician toward a myopathy or Cerebellar atrophy can be detected by brain MRI before age two years in some children [ An estimated 40%-50% of individuals with INAD have abnormal iron accumulation in the basal ganglia (primarily the globus pallidus), which is best detected on T Since the identification of Initial speech delay and limited social interaction may be consistent with autism. Spasticity, dystonia, and dysarthria – findings similar to those of other forms of NBIA – eventually predominate; high brain iron in the globus pallidus and substantia nigra has been observed in nearly all individuals, although ascertainment is likely to be biased [ When high brain iron is present and pathogenic variants in Other forms of early-onset dystonia-parkinsonism must also be considered, including: ## Infantile Neuroaxonal Dystrophy (INAD) Early diagnosis is challenging because the initial symptoms of psychomotor regression and progression are also observed in other conditions. The observation of an elevated aspartate aminotransferase / alanine aminotransferase ratio and elevated lactate dehydrogenase in combination with these findings is more suspicious for INAD [ The degree of weakness early in the disease course may initially direct the clinician toward a myopathy or Cerebellar atrophy can be detected by brain MRI before age two years in some children [ An estimated 40%-50% of individuals with INAD have abnormal iron accumulation in the basal ganglia (primarily the globus pallidus), which is best detected on T Since the identification of ## Atypical Neuroaxonal Dystrophy (NAD) Initial speech delay and limited social interaction may be consistent with autism. Spasticity, dystonia, and dysarthria – findings similar to those of other forms of NBIA – eventually predominate; high brain iron in the globus pallidus and substantia nigra has been observed in nearly all individuals, although ascertainment is likely to be biased [ When high brain iron is present and pathogenic variants in Other forms of early-onset dystonia-parkinsonism must also be considered, including: ## Management To establish the extent of disease and needs in an individual diagnosed with Thorough ophthalmologic examination to assess for optic atrophy EEG for the possibility of unrecognized seizure activity Consultation with a clinical geneticist and/or genetic counselor Note: The extent of disease is often well characterized by the time of diagnosis, since the diagnostic workup frequently includes neurophysiologic studies (EEG, EMG, nerve conduction studies, ERG [electroretinogram], and/or VEP) and brain MRI. The following treatments for Pharmacologic treatment of spasticity and seizures Trial of oral or intrathecal baclofen for those with atypical INAD who have significant dystonia (See Deep brain stimulation has been successfully utilized in one individual with atypical NAD who had intractable dystonia [ Treatment by a psychiatrist for those with a later-onset, more protracted course accompanied by neuropsychiatric symptoms Over-the-counter fiber supplements and/or stool softeners to treat constipation that is likely caused by a combination of immobility, diet, and medications Transdermal scopolamine patch to reduce the volume of secretions in those with excessive drooling or difficulty controlling secretions Measures such as a gastric feeding tube or tracheostomy as needed to prevent aspiration pneumonia Treatments for Treatment with dopaminergic agents is likely to be beneficial for the motor symptoms of parkinsonism and dystonia and may initially produce a dramatic response. In individuals treated to date, this response diminished over time, and affected individuals often developed prominent early dyskinesias, complicating medical management. Despite the dyskinesias, treatment with dopaminergic agents may still be indicated, as affected individuals typically experience benefit for a period of time and the dyskinesias are expected to decline after discontinuation of treatment. In one case report, an individual age 32 years with dystonia-parkinsonism developed episodes of non-painful, fixed upward gaze with neck extension that started shortly after levodopa administration and persisted until the drug wore off [ Treatment by a psychiatrist for neuropsychiatric symptoms is indicated. Evaluation by physical therapy may guide the management of postural instability and gait difficulties. Occupational therapy may offer tools to assist with activities of daily living. Interventions such as a gastric feeding tube or tracheostomy may be needed to reduce the risk of aspiration pneumonia. A rehabilitation program including physical therapy and orthopedic management should be initiated early in the disease course to prevent contractures when the individual is permanently nonambulatory. Body temperature monitors may be required for individuals with progressive autonomic involvement to identify dangerous fluctuations in core body temperature. Periodic assessment of vision and hearing of nonverbal children is indicated as needed to determine the level of sensory deficits. See Women with the INAD and atypical NAD forms of PLAN have not been known to reproduce due to the relatively early onset and severity of disease. Two women with Because some individuals with PLAN have high brain iron and this disorder falls into the category of A proof-of-concept gene therapy strategy is currently under investigation in murine disease models of PLAN [Dr. Manju Kurian, personal communication]. Development of small molecule therapies is also under investigation in cell and murine disease models [Dr. Paul Kotzbauer, personal communication]. Search • Thorough ophthalmologic examination to assess for optic atrophy • EEG for the possibility of unrecognized seizure activity • Consultation with a clinical geneticist and/or genetic counselor • Pharmacologic treatment of spasticity and seizures • Trial of oral or intrathecal baclofen for those with atypical INAD who have significant dystonia (See • Deep brain stimulation has been successfully utilized in one individual with atypical NAD who had intractable dystonia [ • Treatment by a psychiatrist for those with a later-onset, more protracted course accompanied by neuropsychiatric symptoms • Over-the-counter fiber supplements and/or stool softeners to treat constipation that is likely caused by a combination of immobility, diet, and medications • Transdermal scopolamine patch to reduce the volume of secretions in those with excessive drooling or difficulty controlling secretions • Measures such as a gastric feeding tube or tracheostomy as needed to prevent aspiration pneumonia • Treatment with dopaminergic agents is likely to be beneficial for the motor symptoms of parkinsonism and dystonia and may initially produce a dramatic response. In individuals treated to date, this response diminished over time, and affected individuals often developed prominent early dyskinesias, complicating medical management. Despite the dyskinesias, treatment with dopaminergic agents may still be indicated, as affected individuals typically experience benefit for a period of time and the dyskinesias are expected to decline after discontinuation of treatment. In one case report, an individual age 32 years with dystonia-parkinsonism developed episodes of non-painful, fixed upward gaze with neck extension that started shortly after levodopa administration and persisted until the drug wore off [ • Treatment by a psychiatrist for neuropsychiatric symptoms is indicated. • Evaluation by physical therapy may guide the management of postural instability and gait difficulties. • Occupational therapy may offer tools to assist with activities of daily living. • Interventions such as a gastric feeding tube or tracheostomy may be needed to reduce the risk of aspiration pneumonia. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Thorough ophthalmologic examination to assess for optic atrophy EEG for the possibility of unrecognized seizure activity Consultation with a clinical geneticist and/or genetic counselor Note: The extent of disease is often well characterized by the time of diagnosis, since the diagnostic workup frequently includes neurophysiologic studies (EEG, EMG, nerve conduction studies, ERG [electroretinogram], and/or VEP) and brain MRI. • Thorough ophthalmologic examination to assess for optic atrophy • EEG for the possibility of unrecognized seizure activity • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations The following treatments for Pharmacologic treatment of spasticity and seizures Trial of oral or intrathecal baclofen for those with atypical INAD who have significant dystonia (See Deep brain stimulation has been successfully utilized in one individual with atypical NAD who had intractable dystonia [ Treatment by a psychiatrist for those with a later-onset, more protracted course accompanied by neuropsychiatric symptoms Over-the-counter fiber supplements and/or stool softeners to treat constipation that is likely caused by a combination of immobility, diet, and medications Transdermal scopolamine patch to reduce the volume of secretions in those with excessive drooling or difficulty controlling secretions Measures such as a gastric feeding tube or tracheostomy as needed to prevent aspiration pneumonia Treatments for Treatment with dopaminergic agents is likely to be beneficial for the motor symptoms of parkinsonism and dystonia and may initially produce a dramatic response. In individuals treated to date, this response diminished over time, and affected individuals often developed prominent early dyskinesias, complicating medical management. Despite the dyskinesias, treatment with dopaminergic agents may still be indicated, as affected individuals typically experience benefit for a period of time and the dyskinesias are expected to decline after discontinuation of treatment. In one case report, an individual age 32 years with dystonia-parkinsonism developed episodes of non-painful, fixed upward gaze with neck extension that started shortly after levodopa administration and persisted until the drug wore off [ Treatment by a psychiatrist for neuropsychiatric symptoms is indicated. Evaluation by physical therapy may guide the management of postural instability and gait difficulties. Occupational therapy may offer tools to assist with activities of daily living. Interventions such as a gastric feeding tube or tracheostomy may be needed to reduce the risk of aspiration pneumonia. • Pharmacologic treatment of spasticity and seizures • Trial of oral or intrathecal baclofen for those with atypical INAD who have significant dystonia (See • Deep brain stimulation has been successfully utilized in one individual with atypical NAD who had intractable dystonia [ • Treatment by a psychiatrist for those with a later-onset, more protracted course accompanied by neuropsychiatric symptoms • Over-the-counter fiber supplements and/or stool softeners to treat constipation that is likely caused by a combination of immobility, diet, and medications • Transdermal scopolamine patch to reduce the volume of secretions in those with excessive drooling or difficulty controlling secretions • Measures such as a gastric feeding tube or tracheostomy as needed to prevent aspiration pneumonia • Treatment with dopaminergic agents is likely to be beneficial for the motor symptoms of parkinsonism and dystonia and may initially produce a dramatic response. In individuals treated to date, this response diminished over time, and affected individuals often developed prominent early dyskinesias, complicating medical management. Despite the dyskinesias, treatment with dopaminergic agents may still be indicated, as affected individuals typically experience benefit for a period of time and the dyskinesias are expected to decline after discontinuation of treatment. In one case report, an individual age 32 years with dystonia-parkinsonism developed episodes of non-painful, fixed upward gaze with neck extension that started shortly after levodopa administration and persisted until the drug wore off [ • Treatment by a psychiatrist for neuropsychiatric symptoms is indicated. • Evaluation by physical therapy may guide the management of postural instability and gait difficulties. • Occupational therapy may offer tools to assist with activities of daily living. • Interventions such as a gastric feeding tube or tracheostomy may be needed to reduce the risk of aspiration pneumonia. ## Prevention of Secondary Complications A rehabilitation program including physical therapy and orthopedic management should be initiated early in the disease course to prevent contractures when the individual is permanently nonambulatory. Body temperature monitors may be required for individuals with progressive autonomic involvement to identify dangerous fluctuations in core body temperature. ## Surveillance Periodic assessment of vision and hearing of nonverbal children is indicated as needed to determine the level of sensory deficits. ## Evaluation of Relatives at Risk See ## Pregnancy Management Women with the INAD and atypical NAD forms of PLAN have not been known to reproduce due to the relatively early onset and severity of disease. Two women with ## Therapies Under Investigation Because some individuals with PLAN have high brain iron and this disorder falls into the category of A proof-of-concept gene therapy strategy is currently under investigation in murine disease models of PLAN [Dr. Manju Kurian, personal communication]. Development of small molecule therapies is also under investigation in cell and murine disease models [Dr. Paul Kotzbauer, personal communication]. Search ## Other ## Genetic Counseling The parents of an affected individual are obligate heterozygotes (i.e., carriers of one Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Individuals with infantile neuroaxonal dystrophy (INAD) and atypical NAD have not been known to reproduce. All offspring of individuals with later-onset If the reproductive partner of a person with Carrier testing for at-risk relatives requires prior identification of the If both If the Note: Neither the absence of axonal spheroids nor a normal brain MRI rules out INAD or atypical NAD, as these findings develop over time and spheroids vary by location. Diagnostic tests may need to be repeated at a later age for at-risk sibs in families without identified Predictions of clinical course and age of onset are more challenging in asymptomatic individuals diagnosed with 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 • The parents of an affected individual are obligate heterozygotes (i.e., carriers of one • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • Individuals with infantile neuroaxonal dystrophy (INAD) and atypical NAD have not been known to reproduce. • All offspring of individuals with later-onset • If the reproductive partner of a person with • If both • If the • Note: Neither the absence of axonal spheroids nor a normal brain MRI rules out INAD or atypical NAD, as these findings develop over time and spheroids vary by location. Diagnostic tests may need to be repeated at a later age for at-risk sibs in families without identified • Predictions of clinical course and age of onset are more challenging in asymptomatic individuals diagnosed with • 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 individual are obligate heterozygotes (i.e., carriers of one Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Individuals with infantile neuroaxonal dystrophy (INAD) and atypical NAD have not been known to reproduce. All offspring of individuals with later-onset If the reproductive partner of a person with • The parents of an affected individual are obligate heterozygotes (i.e., carriers of one • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • Individuals with infantile neuroaxonal dystrophy (INAD) and atypical NAD have not been known to reproduce. • All offspring of individuals with later-onset • If the reproductive partner of a person with ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues If both If the Note: Neither the absence of axonal spheroids nor a normal brain MRI rules out INAD or atypical NAD, as these findings develop over time and spheroids vary by location. Diagnostic tests may need to be repeated at a later age for at-risk sibs in families without identified Predictions of clinical course and age of onset are more challenging in asymptomatic individuals diagnosed with The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • If both • If the • Note: Neither the absence of axonal spheroids nor a normal brain MRI rules out INAD or atypical NAD, as these findings develop over time and spheroids vary by location. Diagnostic tests may need to be repeated at a later age for at-risk sibs in families without identified • Predictions of clinical course and age of onset are more challenging in asymptomatic individuals diagnosed with • 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 ## Resources Center of Excellence for NBIA Clinical Care and Research International Registry for NBIA and Related Disorders Oregon Health & Science University Germany • • • • • • Center of Excellence for NBIA Clinical Care and Research • International Registry for NBIA and Related Disorders • Oregon Health & Science University • • • Germany • ## Molecular Genetics PLA2G6-Associated Neurodegeneration: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for PLA2G6-Associated Neurodegeneration ( c.2070_2072del p.Val691del Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis c.2070_2072del p.Val691del Variants listed in the table have been provided by the authors. ## Chapter Notes This work was supported in part by grants from the National Institute of Child Health and Human Development, the National Eye Institute, L'Association Internationale de Dystrophie Neuro Axonale Infantile, and the NBIA Disorders Association. This work was made possible by support from the Oregon Clinical and Translational Research Institute (OCTRI), grant number UL1 RR024140 01 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. 23 March 2017 (sw) Comprehensive update posted live 19 March 2015 (ag) Revision: docosahexaenoic acid added as a treatment for PLAN 21 August 2014 (me) Comprehensive update posted live 19 April 2012 (me) Comprehensive update posted live 1 September 2009 (cd) Revision: deletion/duplication analysis available clinically 19 June 2008 (me) Review posted live 14 June 2007 (ag) Original submission • 23 March 2017 (sw) Comprehensive update posted live • 19 March 2015 (ag) Revision: docosahexaenoic acid added as a treatment for PLAN • 21 August 2014 (me) Comprehensive update posted live • 19 April 2012 (me) Comprehensive update posted live • 1 September 2009 (cd) Revision: deletion/duplication analysis available clinically • 19 June 2008 (me) Review posted live • 14 June 2007 (ag) Original submission ## Acknowledgments This work was supported in part by grants from the National Institute of Child Health and Human Development, the National Eye Institute, L'Association Internationale de Dystrophie Neuro Axonale Infantile, and the NBIA Disorders Association. This work was made possible by support from the Oregon Clinical and Translational Research Institute (OCTRI), grant number UL1 RR024140 01 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. ## Revision History 23 March 2017 (sw) Comprehensive update posted live 19 March 2015 (ag) Revision: docosahexaenoic acid added as a treatment for PLAN 21 August 2014 (me) Comprehensive update posted live 19 April 2012 (me) Comprehensive update posted live 1 September 2009 (cd) Revision: deletion/duplication analysis available clinically 19 June 2008 (me) Review posted live 14 June 2007 (ag) Original submission • 23 March 2017 (sw) Comprehensive update posted live • 19 March 2015 (ag) Revision: docosahexaenoic acid added as a treatment for PLAN • 21 August 2014 (me) Comprehensive update posted live • 19 April 2012 (me) Comprehensive update posted live • 1 September 2009 (cd) Revision: deletion/duplication analysis available clinically • 19 June 2008 (me) Review posted live • 14 June 2007 (ag) Original submission ## References ## Literature Cited A. Left axial image shows high brain iron in the globus pallidus (see arrow) on T B. Right sagittal image shows cerebellar atrophy (see arrow).	[ "A Al-Maawali, G Yoon, AS Feigenbaum, WC Halliday, JT Clarke, HM Branson, BL Banwell, D Chitayat, SI Blaser. Validation of the finding of hypertrophy of the clava in infantile neuroaxonal dystrophy/PLA2G6 by biometric analysis.. Neuroradiology 2016;58:1035-42", "I Baburina, S Jackowski. Cellular responses to excess phospholipid.. J Biol Chem 1999;274:9400-8", "HD Bakker, ML de Sonnaville, P Vreken, NG Abeling, JE Groener, JL Keulemans, OP van Diggelen. Human alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency: no association with neuroaxonal dystrophy?. Eur J Hum Genet 2001;9:91-6", "J Balsinde, MA Balboa. Cellular regulation and proposed biological functions of group VIA calcium-independent phospholipase A2 in activated cells.. Cell Signal 2005;17:1052-62", "M Basselin, AO Rosa, E Ramadan, Y Cheon, L Chang, M Chen, D Greenstein, M Wohltmann, J Turk, SI Rapoport. Imaging decreased brain docosahexaenoic acid metabolism and signaling in iPLA2B (VIA)-deficient mice.. J Lipid Res 2010;51:3166-73", "MA Bower, K Bushara, MA Dempsey, S Das, PJ Tuite. Novel mutations in siblings with later-onset PLA2G6-associated neurodegeneration (PLAN).. Mov Disord 2011;26:1768-69", "L Cif, MA Kurian, V Gonzalez, S Garcia-Ptacek, T Roujeau, P Gelisse, AM Moura de Ribeiro, A Crespel, L Macpherson, P Coubes. Atypical PLA2G6-associated neurodegeneration: social communication impairment, dystonia and response to deep brain stimulation.. Mov Disord Clin Pract. 2014;1:128-31", "D Crompton, PK Rehal, L MacPherson, K Foster, P Lunt, I Hughes, AF Brady, MG Pike, S De Gressi, NV Morgan, C Hardy, M Smith, F MacDonald, ER Maher, MA Kurian. Multiplex ligation-dependent probe amplification (MLPA) analysis is an effective tool for the detection of novel intragenic PLA2G6 mutations: implications for molecular diagnosis.. Mol Genet Metab. 2010;100:207-12", "LA Engel, Z Jing, DE O'Brien, M Sun, PT Kotzbauer. Catalytic function of PLA2G6 is impaired by mutations associated with infantile neuroaxonal dystrophy but not dystonia-parkinsonism.. PLoS One. 2010;5", "L Farina, N Nardocci, MG Bruzzone, L D'Incerti, G Zorzi, L Verga, M Morbin, M Savoiardo. Infantile neuroaxonal dystrophy: neuroradiological studies in 11 patients.. Neuroradiology 1999;41:376-80", "C Fusco, D Frattini, C Panteghini, R Pascarella, B Garavaglia. A case of infantile neuroaxonal dystrophy of neonatal onset.. J Child Neurol 2015;30:368-70", "A Gregory, SK Westaway, IE Holm, PT Kotzbauer, P Hogarth, S Sonek, JC Coryell, TM Nguyen, N Nardocci, G Zorzi, D Rodriguez, I Desguerre, E Bertini, A Simonati, B Levinson, C Dias, C Barbot, I Carrilho, M Santos, I Malik, J Gitschier, SJ Hayflick. Neurodegeneration associated with genetic defects in phospholipase A2.. Neurology 2008;71:1402-9", "SJ Hayflick, SK Westaway, B Levinson, B Zhou, MA Johnson, KH Ching, J Gitschier. Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome.. N Engl J Med 2003;348:33-40", "MA Illingworth, E Meyer, WK Chong, AY Manzur, LJ Carr, R Younis, C Hardy, F McDonald, AM Childs, B Stewart, D Warren, R Kneen, MD King, SJ Hayflick, MA Kurian. PLA2G6-associated neurodegeneration (PLAN): further expansion of the clinical, radiological and mutation spectrum associated with infantile and atypical childhood-onset disease.. Mol Genet Metab. 2014;112:183-9", "S Karkheiran, GA Shahidi, RH Walker, C Paisán-Ruiz. PLA2G6-associated Dystonia-Parkinsonism: Case Report and Literature Review.. Tremor Other Hyperkinet Mov (N Y) 2015;5:317", "JL Keulemans, AJ Reuser, MA Kroos, R Willemsen, MM Hermans, AM van den Ouweland, JG de Jong, RA Wevers, WO Renier, D Schindler, MJ Coll, A Chabas, H Sakuraba, Y Suzuki, OP van Diggelen. Human alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency: new mutations and the paradox between genotype and phenotype.. J Med Genet 1996;33:458-64", "I Kraoua, M Romani, D Tonduti, H BenRhouma, G Zorzi, F Zibordi, A Ardissone, N Gouider-Khouja, I Ben Youssef-Turki, N Nardocci, EM Valente. Elevated aspartate aminotransferase and lactate dehydrogenase levels are a constant finding in PLA2G6-associated neurodegeneration.. Eur J Neurol 2016;23:e24-5", "PK Larsson, HE Claesson, BP Kennedy. Multiple splice variants of the human calcium-independent phospholipase A2 and their effect on enzyme activity.. J Biol Chem 1998;273:207-14", "D Mazzocchi-Jones. Impaired corticostriatal LTP and depotentiation following iPLA2 inhibition is restored following acute application of DHA.. Brain Res Bull 2015;111:69-75", "NV Morgan, SK Westaway, JE Morton, A Gregory, P Gissen, S Sonek, H Cangul, J Coryell, N Canham, N Nardocci, G Zorzi, S Pasha, D Rodriguez, I Desguerre, A Mubaidin, E Bertini, RC Trembath, A Simonati, C Schanen, CA Johnson, B Levinson, CG Woods, B Wilmot, P Kramer, J Gitschier, ER Maher, SJ Hayflick. PLA2G6, encoding a phospholipase A(2), is mutated in neurodegenerative disorders with high brain iron.. Nat Genet 2006;38:752-4", "A Mubaidin, E Roberts, D Hampshire, M Dehyyat, A Shurbaji, M Mubaidien, A Jamil, A Al-Din, A Kurdi, CG Woods. Karak syndrome: a novel degenerative disorder of the basal ganglia and cerebellum.. J Med Genet 2003;40:543-6", "N Nardocci, G Zorzi, L Farina, S Binelli, W Scaioli, C Ciano, L Verga, L Angelini, M Savoiardo, O Bugiani. Infantile neuroaxonal dystrophy: clinical spectrum and diagnostic criteria.. Neurology 1999;52:1472-8", "C Paisán-Ruiz, KP Bhatia, A Li, D Hernandez, M Davis, NW Wood, J Hardy, H Houlden, A Singleton, SA Schneider. Characterization of PLA2G6 as a locus for dystonia-parkinsonism.. Ann Neurol. 2009;65:19-23", "C Paisán-Ruiz, R Guevara, M Federoff, H Hanagasi, F Sina, E Elahi, SA Schneider, P Schwingenschuh, N Bajaj, M Emre, AB Singleton, J Hardy, KP Bhatia, S Brandner, AJ Lees, H Houldon. Early-onset L-dopa-responsive parkinsonism with pyramidal signs due to ATP13A2, PLA2G6, FBX07, and spatacsin mutations.. Mov Disord 2010;25:1791-800", "C Paisán-Ruiz, A Li, SA Schneider, JL Holton, R Johnson, D Kidd, J Chataway, KP Bhatia, AJ Lees, J Hardy, T Revesz, H Hould. Widespread Lewy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations.. Neurobiol Aging. 2012;33:814-23", "M Romani, I Kraoua, A Micalizzi, H Klaa, H Benrhouma, C Drissi, I Turki, S Castellana, T Mazza, EM Valente, N Gouider-Khouja. Infantile and childhood onset PLA2G6-associated neurodegeneration in a large North African Cohort.. Eur J Neurol 2015;22:178-86", "D Schindler, DF Bishop, DE Wolfe, AM Wang, H Egge, RU Lemieux, RJ Desnick. Neuroaxonal dystrophy due to lysosomal alpha-N-acetylgalactosaminidase deficiency.. N Engl J Med 1989;320:1735-40", "SA Schneider, KP Bhatia. Rare causes of dystonia parkinsonism.. Curr Neurol Neurosci Rep 2010;10:431-9", "A Tonelli, R Romaniello, R Grasso, A Cavallini, A Righini, N Bresolin, R Borgatti, MT Bassi. Novel splice-site mutations and a large intragenic deletion in PLA2G6 associated with a severe and rapidly progressive form of infantile neuroaxonal dystrophy.. Clin Genet. 2010;78:432-40", "T Virmani, MA Thenganatt, JS Goldman, C Kubisch, PE Greene, RN Alcalay. Oculogyric crises induced by levodopa in PLA2G6 parkinsonism-dystonia.. Parkinsonism Relat Disord. 2014;20:245-7", "SK Westaway, A Gregory, SJ Hayflick. Mutations in PLA2G6 and the riddle of Schindler disease.. J Med Genet 2007;44", "Y Wu, Y Jiang, Z Gao, J Wang, Y Yuan, H Xiong, X Chang, X Bao, Y Zhang, J Xiao, X Wu. Clinical study and PLA2G6 mutation screening analysis in Chinese patients with infantile neuroaxonal dystrophy.. Eur J Neurol. 2009;16:240-5", "T Yamamoto, K Shimojima, T Shibata, M Akiyama, M Oka, T Akiyama, H Yoshinaga, K. Kobayashi. Novel PLA2G6 mutations associated with an exonic deletion due to non-allelic homologous recombination in a patient with infantile neuroaxonal dystrophy.. Hum Genome Var. 2015;2:15048", "H Yoshino, H Tomiyama, N Tachibana, K Ogaki, Y Li, M Funayama, T Hashimoto, S Takashima, N Hattori. Phenotypic spectrum of patients with PLA2G6 mutation and PARK14-linked parkinsonism.. Neurology. 2010;75:1356-61" ]	19/6/2008	23/3/2017	19/3/2015	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
inppl1-opsmd	inppl1-opsmd	[ "Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2", "INPPL1", "INPPL1-Related Opsismodysplasia" ]		Samuel Huang, Dawn Earl, Klane White	Summary The diagnosis of	## Diagnosis Prenatal-onset disproportionate short stature with short limbs Characteristic facial features (relative macrocephaly, prominent forehead, midface retrusion, depressed nasal bridge, short nose, anteverted nares, and a relatively long philtrum) Narrow thorax Small hands and feet Respiratory insufficiency Severe renal phosphate wasting Hypophosphatemia Shortened, bowed long bones Narrow thorax Delayed epiphyseal mineralization (See Platyspondyly Metaphyseal cupping (See Short and broad metacarpals and phalanges with square appearance, flared metaphyses, and irregular ossification (patchy, with some areas less ossified than others) Additional radiographic findings can include handlebar clavicles, hypoplastic and square iliac wings, hypoplastic pubic bones, horizontal acetabular roof, acetabular dysplasia, coxa vara, broad femoral heads, small tapered middle phalanges, and calcaneal spurs. 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 can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click When the phenotype is indistinguishable from many other skeletal dysplasias, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small 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, no large intragenic deletions/duplications have been reported in individuals with • Prenatal-onset disproportionate short stature with short limbs • Characteristic facial features (relative macrocephaly, prominent forehead, midface retrusion, depressed nasal bridge, short nose, anteverted nares, and a relatively long philtrum) • Narrow thorax • Small hands and feet • Respiratory insufficiency • Severe renal phosphate wasting • Hypophosphatemia • Shortened, bowed long bones • Narrow thorax • Delayed epiphyseal mineralization (See • Platyspondyly • Metaphyseal cupping (See • Short and broad metacarpals and phalanges with square appearance, flared metaphyses, and irregular ossification (patchy, with some areas less ossified than others) • Additional radiographic findings can include handlebar clavicles, hypoplastic and square iliac wings, hypoplastic pubic bones, horizontal acetabular roof, acetabular dysplasia, coxa vara, broad femoral heads, small tapered middle phalanges, and calcaneal spurs. ## Suggestive Findings Prenatal-onset disproportionate short stature with short limbs Characteristic facial features (relative macrocephaly, prominent forehead, midface retrusion, depressed nasal bridge, short nose, anteverted nares, and a relatively long philtrum) Narrow thorax Small hands and feet Respiratory insufficiency Severe renal phosphate wasting Hypophosphatemia Shortened, bowed long bones Narrow thorax Delayed epiphyseal mineralization (See Platyspondyly Metaphyseal cupping (See Short and broad metacarpals and phalanges with square appearance, flared metaphyses, and irregular ossification (patchy, with some areas less ossified than others) Additional radiographic findings can include handlebar clavicles, hypoplastic and square iliac wings, hypoplastic pubic bones, horizontal acetabular roof, acetabular dysplasia, coxa vara, broad femoral heads, small tapered middle phalanges, and calcaneal spurs. • Prenatal-onset disproportionate short stature with short limbs • Characteristic facial features (relative macrocephaly, prominent forehead, midface retrusion, depressed nasal bridge, short nose, anteverted nares, and a relatively long philtrum) • Narrow thorax • Small hands and feet • Respiratory insufficiency • Severe renal phosphate wasting • Hypophosphatemia • Shortened, bowed long bones • Narrow thorax • Delayed epiphyseal mineralization (See • Platyspondyly • Metaphyseal cupping (See • Short and broad metacarpals and phalanges with square appearance, flared metaphyses, and irregular ossification (patchy, with some areas less ossified than others) • Additional radiographic findings can include handlebar clavicles, hypoplastic and square iliac wings, hypoplastic pubic bones, horizontal acetabular roof, acetabular dysplasia, coxa vara, broad femoral heads, small tapered middle phalanges, and calcaneal spurs. ## 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 can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click When the phenotype is indistinguishable from many other skeletal dysplasias, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small 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, no large intragenic deletions/duplications have been reported in individuals with ## Option 1 For an introduction to multigene panels click ## Option 2 When the phenotype is indistinguishable from many other skeletal dysplasias, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small 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, no large intragenic deletions/duplications have been reported in individuals with ## Clinical Characteristics Skeletal deformities and pain contribute to the Normal intelligence has been reported, while cognitive impairment has not been specifically noted [ No clinically relevant genotype-phenotype correlations have been identified. • Skeletal deformities and pain contribute to the ## Clinical Description Skeletal deformities and pain contribute to the Normal intelligence has been reported, while cognitive impairment has not been specifically noted [ • Skeletal deformities and pain contribute to the ## Genotype-Phenotype Correlations No clinically relevant genotype-phenotype correlations have been identified. ## Nomenclature ## Prevalence ## Genetically Related (Allelic) Disorders Biallelic variants in ## Differential Diagnosis Biallelic pathogenic variants in Genes of Interest in the Differential Diagnosis of Wormian bones & lack of other skeletal findings assoc w/ No renal phosphate wasting / hypophosphatemia May be lethal in perinatal period Short stature, short limbs, platyspondyly, cervical instability, epiphyseal delay, metaphyseal cupping Incomplete vertebral ossification, vertebral clefting/wedging, short ribs in severe phenotypes Lack of brachydactyly assoc w/ Characteristic facial features No renal phosphate wasting / hypophosphatemia Short stature, short limbs, brachydactyly, metatarsal irregularity, lower extremity bowing, platyspondyly Renal phosphate wasting / hypophosphatemia Often lethal in perinatal period Short stature, short limbs, brachydactyly, platyspondyly, narrow chest, & relative macrocephaly Cloverleaf skull, foramen magnum narrowing, severely bowed femurs, & trident hand No renal phosphate wasting / hypophosphatemia Often lethal in perinatal period Short stature, short limbs, metaphyseal flaring, brachydactyly, bone fractures Craniosynostosis, slender long bones w/cortical thickening & medullary stenosis Lack of platyspondyly & epiphyseal delay Primary hypoparathyroidism, hypocalcemia, & hyperphosphatemia Less severe platyspondyly, less severe epiphyseal/ossification delay, lacy iliac crease, long fibula, tarsal irregularity, cardiac arrythmia, CNS anomalies No renal phosphate wasting / hypophosphatemia Acetabulae w/medial & lateral spurs, improvement in bony differences over time No renal phosphate wasting / hypophosphatemia Onset within first 2 yrs of life Lack of typical radiographic findings of Renal phosphate wasting/hypophosphatemia Radiographic findings in infancy may incl osteopenia, wide & cupped metaphyses, brachydactyly Infrequently diagnosed in infancy, but sclerosis of skull base evident Progressive postnatal findings incl growth plate changes, lower extremity bowing, joint contractures, & short stature of postnatal onset Less severe platyspondyly, less severe epiphyseal delay, lacy iliac crest, & hematologic, pancreatic, & hepatic abnormalities No renal phosphate wasting / hypophosphatemia Delay in vertebral body ossification, snail-like appearance of ilia, very short limbs, precocious carpal/tarsal ossification No renal phosphate wasting / hypophosphatemia Coronal vertebral clefts, progressive metaphyseal changes resembling enchondromas, lacy iliac crest, elongation of femoral neck & fibula, dentinogenesis imperfecta No renal phosphate wasting / hypophosphatemia Wafer-thin vertebrae, coccygeal tail, prominent joints, progressive joint contractures, Halberd-shaped pelvis No renal phosphate wasting / hypophosphatemia AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system; MOI = mode of inheritance Type II collagen disorders are inherited in an autosomal dominant manner. However, rare instances of autosomal recessive inheritance in spondyloepiphyseal dysplasia congenita have been reported. See also X-Linked Hypophosphatemia, Pathogenic variants in • Wormian bones & lack of other skeletal findings assoc w/ • No renal phosphate wasting / hypophosphatemia • May be lethal in perinatal period • Short stature, short limbs, platyspondyly, cervical instability, epiphyseal delay, metaphyseal cupping • Incomplete vertebral ossification, vertebral clefting/wedging, short ribs in severe phenotypes • Lack of brachydactyly assoc w/ • Characteristic facial features • No renal phosphate wasting / hypophosphatemia • Short stature, short limbs, brachydactyly, metatarsal irregularity, lower extremity bowing, platyspondyly • Renal phosphate wasting / hypophosphatemia • Often lethal in perinatal period • Short stature, short limbs, brachydactyly, platyspondyly, narrow chest, & relative macrocephaly • Cloverleaf skull, foramen magnum narrowing, severely bowed femurs, & trident hand • No renal phosphate wasting / hypophosphatemia • Often lethal in perinatal period • Short stature, short limbs, metaphyseal flaring, brachydactyly, bone fractures • Craniosynostosis, slender long bones w/cortical thickening & medullary stenosis • Lack of platyspondyly & epiphyseal delay • Primary hypoparathyroidism, hypocalcemia, & hyperphosphatemia • Less severe platyspondyly, less severe epiphyseal/ossification delay, lacy iliac crease, long fibula, tarsal irregularity, cardiac arrythmia, CNS anomalies • No renal phosphate wasting / hypophosphatemia • Acetabulae w/medial & lateral spurs, improvement in bony differences over time • No renal phosphate wasting / hypophosphatemia • Onset within first 2 yrs of life • Lack of typical radiographic findings of • Renal phosphate wasting/hypophosphatemia • Radiographic findings in infancy may incl osteopenia, wide & cupped metaphyses, brachydactyly • Infrequently diagnosed in infancy, but sclerosis of skull base evident • Progressive postnatal findings incl growth plate changes, lower extremity bowing, joint contractures, & short stature of postnatal onset • Less severe platyspondyly, less severe epiphyseal delay, lacy iliac crest, & hematologic, pancreatic, & hepatic abnormalities • No renal phosphate wasting / hypophosphatemia • Delay in vertebral body ossification, snail-like appearance of ilia, very short limbs, precocious carpal/tarsal ossification • No renal phosphate wasting / hypophosphatemia • Coronal vertebral clefts, progressive metaphyseal changes resembling enchondromas, lacy iliac crest, elongation of femoral neck & fibula, dentinogenesis imperfecta • No renal phosphate wasting / hypophosphatemia • Wafer-thin vertebrae, coccygeal tail, prominent joints, progressive joint contractures, Halberd-shaped pelvis • No renal phosphate wasting / hypophosphatemia ## Management No clinical practice guidelines have been published for To establish the extent of disease and needs in an individual diagnosed with Clinical exam, preferably by experts in skeletal dysplasia incl orthopedist Complete skeletal radiographs Cervical spine flexion-extension radiographs Flexion-extension cervical spine MRI if instability, risk of cervical cord compression, or limited radiograph interpretation due to delayed ossification of cervical vertebrae &/or odontoid hypoplasia Serum ALT, AST, albumin, ALP, bilirubin, BUN, calcium, bicarbonate, chloride, creatinine, glucose, potassium, sodium, phosphorus, parathyroid hormone, 25-hydroxyvitamin D Urine phosphate & creatinine Renal phosphate wasting is assoc w/bone demineralization & more severe skeletal phenotype. TRP = 1 − (urinary phosphate ÷ serum phosphorus) × (serum creatinine ÷ urinary creatinine) Pulmonology, sleep medicine, & ENT consultations when indicated Chest radiographs, pulmonary function studies, & polysomnography when indicated Assess for swallowing difficulties, chronic cough, & recurrent pneumonia Swallowing eval when indicated Developmental assessment to assess gross motor skills Rehab medicine, PT, & OT consultations Audiology testing ENT & orthodontic consultations when indicated Community or online resources such as Social work involvement for parental support; Home nursing referral ALP = alkaline phosphatase; ALT = alanine transaminase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; TRP = tubular reabsorption phosphate Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) There is no cure for There has been a single report of intravenous bisphosphonate therapy in two sibs 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 Mgmt per orthopedist Surgery when indicated for progressive, symptomatic, &/or severe scoliosis Endocrinology eval for treatment as indicated DXA scan when indicated Oral phosphorus & calcitriol have been reported to improve metaphyseal mineralization (w/persistent relatively low serum phosphate & renal phosphate wasting). Improved clinical progress & bone mineral density has been reported w/IV pamidronate therapy (see Treatment per pulmonologist Vaccines to prevent respiratory illnesses (e.g., COVID-19, influenza, pneumonia, pertussis, RSV) Feeding therapy, modification of fluid or food texture Aerodigestive eval for possible endoscopy & surgery as indicated Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or CPAP = continuous positive airway pressure; DXA = dual-energy x-ray absorptiometry; IV = intravenous; RSV = respiratory syncytial virus To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Every 3-6 mos until cervical instability can be excluded Then every 2-3 years, preoperatively, & when indicated Endocrinology follow up for hypophosphatemia & renal phosphate wasting Serum & urine phosphate & creatinine Consider electrolytes & 25-hydroxyvitamin D. Pulmonary function studies Chest radiographs Swallowing eval Sleep study Developmental assessment to assess gross motor skills Rehab medicine, PT, & OT consultations when indicated to evaluate function & need for adaptive devices to support activities of daily living & mobility DXA = dual-energy x-ray absorptiometry; OT = occupational therapy; PT = physical therapy Individuals with cervical spine instability or who are at risk for cervical spine instability should avoid extreme neck flexion and extension, contact sports, and other at-risk activities. Individuals with bone demineralization should avoid contact sports and other activities associated with an increased risk for fractures. It is appropriate to clarify the genetic status of apparently asymptomatic at-risk sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of See To date, there are no published reports of pregnancies in women with Search • Clinical exam, preferably by experts in skeletal dysplasia incl orthopedist • Complete skeletal radiographs • Cervical spine flexion-extension radiographs • Flexion-extension cervical spine MRI if instability, risk of cervical cord compression, or limited radiograph interpretation due to delayed ossification of cervical vertebrae &/or odontoid hypoplasia • Serum ALT, AST, albumin, ALP, bilirubin, BUN, calcium, bicarbonate, chloride, creatinine, glucose, potassium, sodium, phosphorus, parathyroid hormone, 25-hydroxyvitamin D • Urine phosphate & creatinine • Renal phosphate wasting is assoc w/bone demineralization & more severe skeletal phenotype. • TRP = 1 − (urinary phosphate ÷ serum phosphorus) × (serum creatinine ÷ urinary creatinine) • Pulmonology, sleep medicine, & ENT consultations when indicated • Chest radiographs, pulmonary function studies, & polysomnography when indicated • Assess for swallowing difficulties, chronic cough, & recurrent pneumonia • Swallowing eval when indicated • Developmental assessment to assess gross motor skills • Rehab medicine, PT, & OT consultations • Audiology testing • ENT & orthodontic consultations when indicated • Community or online resources such as • Social work involvement for parental support; • Home nursing referral • Mgmt per orthopedist • Surgery when indicated for progressive, symptomatic, &/or severe scoliosis • Endocrinology eval for treatment as indicated • DXA scan when indicated • Oral phosphorus & calcitriol have been reported to improve metaphyseal mineralization (w/persistent relatively low serum phosphate & renal phosphate wasting). • Improved clinical progress & bone mineral density has been reported w/IV pamidronate therapy (see • Treatment per pulmonologist • Vaccines to prevent respiratory illnesses (e.g., COVID-19, influenza, pneumonia, pertussis, RSV) • Feeding therapy, modification of fluid or food texture • Aerodigestive eval for possible endoscopy & surgery as indicated • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • Every 3-6 mos until cervical instability can be excluded • Then every 2-3 years, preoperatively, & when indicated • Endocrinology follow up for hypophosphatemia & renal phosphate wasting • Serum & urine phosphate & creatinine • Consider electrolytes & 25-hydroxyvitamin D. • Pulmonary function studies • Chest radiographs • Swallowing eval • Sleep study • Developmental assessment to assess gross motor skills • Rehab medicine, PT, & OT consultations when indicated to evaluate function & need for adaptive devices to support activities of daily living & mobility ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Clinical exam, preferably by experts in skeletal dysplasia incl orthopedist Complete skeletal radiographs Cervical spine flexion-extension radiographs Flexion-extension cervical spine MRI if instability, risk of cervical cord compression, or limited radiograph interpretation due to delayed ossification of cervical vertebrae &/or odontoid hypoplasia Serum ALT, AST, albumin, ALP, bilirubin, BUN, calcium, bicarbonate, chloride, creatinine, glucose, potassium, sodium, phosphorus, parathyroid hormone, 25-hydroxyvitamin D Urine phosphate & creatinine Renal phosphate wasting is assoc w/bone demineralization & more severe skeletal phenotype. TRP = 1 − (urinary phosphate ÷ serum phosphorus) × (serum creatinine ÷ urinary creatinine) Pulmonology, sleep medicine, & ENT consultations when indicated Chest radiographs, pulmonary function studies, & polysomnography when indicated Assess for swallowing difficulties, chronic cough, & recurrent pneumonia Swallowing eval when indicated Developmental assessment to assess gross motor skills Rehab medicine, PT, & OT consultations Audiology testing ENT & orthodontic consultations when indicated Community or online resources such as Social work involvement for parental support; Home nursing referral ALP = alkaline phosphatase; ALT = alanine transaminase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; TRP = tubular reabsorption phosphate Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Clinical exam, preferably by experts in skeletal dysplasia incl orthopedist • Complete skeletal radiographs • Cervical spine flexion-extension radiographs • Flexion-extension cervical spine MRI if instability, risk of cervical cord compression, or limited radiograph interpretation due to delayed ossification of cervical vertebrae &/or odontoid hypoplasia • Serum ALT, AST, albumin, ALP, bilirubin, BUN, calcium, bicarbonate, chloride, creatinine, glucose, potassium, sodium, phosphorus, parathyroid hormone, 25-hydroxyvitamin D • Urine phosphate & creatinine • Renal phosphate wasting is assoc w/bone demineralization & more severe skeletal phenotype. • TRP = 1 − (urinary phosphate ÷ serum phosphorus) × (serum creatinine ÷ urinary creatinine) • Pulmonology, sleep medicine, & ENT consultations when indicated • Chest radiographs, pulmonary function studies, & polysomnography when indicated • Assess for swallowing difficulties, chronic cough, & recurrent pneumonia • Swallowing eval when indicated • Developmental assessment to assess gross motor skills • Rehab medicine, PT, & OT consultations • Audiology testing • ENT & orthodontic consultations when indicated • Community or online resources such as • Social work involvement for parental support; • Home nursing referral ## Treatment of Manifestations There is no cure for There has been a single report of intravenous bisphosphonate therapy in two sibs 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 Mgmt per orthopedist Surgery when indicated for progressive, symptomatic, &/or severe scoliosis Endocrinology eval for treatment as indicated DXA scan when indicated Oral phosphorus & calcitriol have been reported to improve metaphyseal mineralization (w/persistent relatively low serum phosphate & renal phosphate wasting). Improved clinical progress & bone mineral density has been reported w/IV pamidronate therapy (see Treatment per pulmonologist Vaccines to prevent respiratory illnesses (e.g., COVID-19, influenza, pneumonia, pertussis, RSV) Feeding therapy, modification of fluid or food texture Aerodigestive eval for possible endoscopy & surgery as indicated Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or CPAP = continuous positive airway pressure; DXA = dual-energy x-ray absorptiometry; IV = intravenous; RSV = respiratory syncytial virus • Mgmt per orthopedist • Surgery when indicated for progressive, symptomatic, &/or severe scoliosis • Endocrinology eval for treatment as indicated • DXA scan when indicated • Oral phosphorus & calcitriol have been reported to improve metaphyseal mineralization (w/persistent relatively low serum phosphate & renal phosphate wasting). • Improved clinical progress & bone mineral density has been reported w/IV pamidronate therapy (see • Treatment per pulmonologist • Vaccines to prevent respiratory illnesses (e.g., COVID-19, influenza, pneumonia, pertussis, RSV) • Feeding therapy, modification of fluid or food texture • Aerodigestive eval for possible endoscopy & surgery as indicated • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or ## Targeted Therapy There has been a single report of intravenous bisphosphonate therapy in two sibs 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 Mgmt per orthopedist Surgery when indicated for progressive, symptomatic, &/or severe scoliosis Endocrinology eval for treatment as indicated DXA scan when indicated Oral phosphorus & calcitriol have been reported to improve metaphyseal mineralization (w/persistent relatively low serum phosphate & renal phosphate wasting). Improved clinical progress & bone mineral density has been reported w/IV pamidronate therapy (see Treatment per pulmonologist Vaccines to prevent respiratory illnesses (e.g., COVID-19, influenza, pneumonia, pertussis, RSV) Feeding therapy, modification of fluid or food texture Aerodigestive eval for possible endoscopy & surgery as indicated Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or CPAP = continuous positive airway pressure; DXA = dual-energy x-ray absorptiometry; IV = intravenous; RSV = respiratory syncytial virus • Mgmt per orthopedist • Surgery when indicated for progressive, symptomatic, &/or severe scoliosis • Endocrinology eval for treatment as indicated • DXA scan when indicated • Oral phosphorus & calcitriol have been reported to improve metaphyseal mineralization (w/persistent relatively low serum phosphate & renal phosphate wasting). • Improved clinical progress & bone mineral density has been reported w/IV pamidronate therapy (see • Treatment per pulmonologist • Vaccines to prevent respiratory illnesses (e.g., COVID-19, influenza, pneumonia, pertussis, RSV) • Feeding therapy, modification of fluid or food texture • Aerodigestive eval for possible endoscopy & surgery as indicated • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Every 3-6 mos until cervical instability can be excluded Then every 2-3 years, preoperatively, & when indicated Endocrinology follow up for hypophosphatemia & renal phosphate wasting Serum & urine phosphate & creatinine Consider electrolytes & 25-hydroxyvitamin D. Pulmonary function studies Chest radiographs Swallowing eval Sleep study Developmental assessment to assess gross motor skills Rehab medicine, PT, & OT consultations when indicated to evaluate function & need for adaptive devices to support activities of daily living & mobility DXA = dual-energy x-ray absorptiometry; OT = occupational therapy; PT = physical therapy • Every 3-6 mos until cervical instability can be excluded • Then every 2-3 years, preoperatively, & when indicated • Endocrinology follow up for hypophosphatemia & renal phosphate wasting • Serum & urine phosphate & creatinine • Consider electrolytes & 25-hydroxyvitamin D. • Pulmonary function studies • Chest radiographs • Swallowing eval • Sleep study • Developmental assessment to assess gross motor skills • Rehab medicine, PT, & OT consultations when indicated to evaluate function & need for adaptive devices to support activities of daily living & mobility ## Agents/Circumstances to Avoid Individuals with cervical spine instability or who are at risk for cervical spine instability should avoid extreme neck flexion and extension, contact sports, and other at-risk activities. Individuals with bone demineralization should avoid contact sports and other activities associated with an increased risk for fractures. ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic at-risk sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of See ## Pregnancy Management To date, there are no published reports of pregnancies in women with ## 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 INPPL1-Related Opsismodysplasia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for INPPL1-Related Opsismodysplasia ( ## Molecular Pathogenesis ## Chapter Notes 12 June 2025 (sw) Review posted live 24 April 2024 (de) Original submission • 12 June 2025 (sw) Review posted live • 24 April 2024 (de) Original submission ## Revision History 12 June 2025 (sw) Review posted live 24 April 2024 (de) Original submission • 12 June 2025 (sw) Review posted live • 24 April 2024 (de) Original submission ## Key Sections in This ## References ## Literature Cited AP and lateral spine radiographs and AP chest radiograph show undermineralization of the vertebrae, platyspondyly, and narrow thorax. AP lower extremity radiographs from the first week of life show decreased mineralization, delayed ossification of the epiphyses, and metaphyseal flaring of the long bones. AP hand and feet radiographs at birth. The metacarpals, metatarsals, and phalanges have flared metaphyses with metaphyseal cupping. There is delayed carpal ossification.	[]	12/6/2025			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
insr-ir	insr-ir	[ "Rabson-Mendenhall Syndrome", "Donohue Syndrome", "Insulin receptor", "INSR", "INSR-Related Severe Insulin Resistance Syndrome" ]		Aviv Mesika, Aharon Klar, Tzipora C Falik Zaccai	Summary Donohue syndrome is characterized by severe insulin resistance (hyperinsulinemia with associated fasting hypoglycemia and postprandial hyperglycemia), severe prenatal growth restriction, postnatal growth failure, hypotonia, developmental delay, characteristic facies (proptosis, infraorbital folds, large, low-set, posteriorly rotated ears, thick vermilion of the upper and lower lips, and gingival hypertrophy), and organomegaly involving the heart, kidneys, liver, spleen, and ovaries. Death usually occurs before age one year. RMS, at the milder end of the spectrum, is characterized by severe insulin resistance that, although not as severe as that of Donohue syndrome, is nonetheless accompanied by fluctuations in blood glucose levels, diabetic ketoacidosis, and – in the second decade – microvascular complications. Findings can range from severe growth delay and intellectual disability to normal growth and development. Facial features can be milder than those of Donohue syndrome. Complications of longstanding hyperglycemia are the most common cause of death. While death usually occurs in the second decade, some affected individuals live longer. The diagnosis of RMS: Insulin sensitizers are used first to decrease levels of glucose and glycosylated hemoglobin (HbA1c); however, their effect diminishes with time, often requiring dose adjustments and multidrug therapy. When hyperglycemia persists, insulin is started – usually in high doses, especially during the treatment of diabetic ketoacidosis. Standard treatment for hypothyroidism; oral contraceptives, antiandrogen therapies, and gonadotropin-releasing hormone agonists can be used to treat hyperandrogenism; oophorectomy may be needed for enlarged ovaries; nutritional, developmental, and educational support; rigorous workup and treatment of intercurrent infections; beta-blockers for cardiomyopathy; treatment of nephrocalcinosis per nephrologist; treatment of cholestasis per gastroenterologist; treatment of rectal prolapse per surgeon; standard treatments for malignancies; social work and family support.	Donohue syndrome Rabson-Mendenhall syndrome For synonyms, see • Donohue syndrome • Rabson-Mendenhall syndrome ## Diagnosis Progressive intrauterine growth restriction (IUGR) from the early third trimester and postnatal poor weight gain, growth deficiency, and reduced subcutaneous fat Dysmorphic facial features ( Hypotonia Developmental delay Integument, including dry skin, hypertrichosis ( Prominent nipples ( Abdominal distention ( Genital enlargement (males and females) ( Rectal hypertrophy and prolapse ( Dysmorphic facial features that can resemble those of Donohue syndrome [ Integument, including hypertrichosis and acanthosis nigricans Prominent nipples Genital enlargement (males and females) Early dental eruption and dental crowding [ Growth deficiency (less severe than in Donohue syndrome) [ Developmental delay (in some individuals) [ Severe hyperinsulinemia. Extremely high plasma insulin and C-peptide levels with fluctuating blood glucose levels (typically fasting hypoglycemia and postprandial hyperglycemia) Ketoacidosis not reported. Low triglyceride levels, high high-density lipoprotein (HDL) levels [ High adiponectin levels [ Hypertrophic cardiomyopathy Enlarged kidneys, liver, and spleen Nephrocalcinosis Enlarged polycystic ovaries The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • Progressive intrauterine growth restriction (IUGR) from the early third trimester and postnatal poor weight gain, growth deficiency, and reduced subcutaneous fat • Dysmorphic facial features ( • Hypotonia • Developmental delay • Integument, including dry skin, hypertrichosis ( • Prominent nipples ( • Abdominal distention ( • Genital enlargement (males and females) ( • Rectal hypertrophy and prolapse ( • Dysmorphic facial features that can resemble those of Donohue syndrome [ • Integument, including hypertrichosis and acanthosis nigricans • Prominent nipples • Genital enlargement (males and females) • Early dental eruption and dental crowding [ • Growth deficiency (less severe than in Donohue syndrome) [ • Developmental delay (in some individuals) [ • Severe hyperinsulinemia. Extremely high plasma insulin and C-peptide levels with fluctuating blood glucose levels (typically fasting hypoglycemia and postprandial hyperglycemia) • Ketoacidosis not reported. • Low triglyceride levels, high high-density lipoprotein (HDL) levels [ • High adiponectin levels [ • Hypertrophic cardiomyopathy • Enlarged kidneys, liver, and spleen • Nephrocalcinosis • Enlarged polycystic ovaries ## Suggestive Findings Progressive intrauterine growth restriction (IUGR) from the early third trimester and postnatal poor weight gain, growth deficiency, and reduced subcutaneous fat Dysmorphic facial features ( Hypotonia Developmental delay Integument, including dry skin, hypertrichosis ( Prominent nipples ( Abdominal distention ( Genital enlargement (males and females) ( Rectal hypertrophy and prolapse ( Dysmorphic facial features that can resemble those of Donohue syndrome [ Integument, including hypertrichosis and acanthosis nigricans Prominent nipples Genital enlargement (males and females) Early dental eruption and dental crowding [ Growth deficiency (less severe than in Donohue syndrome) [ Developmental delay (in some individuals) [ Severe hyperinsulinemia. Extremely high plasma insulin and C-peptide levels with fluctuating blood glucose levels (typically fasting hypoglycemia and postprandial hyperglycemia) Ketoacidosis not reported. Low triglyceride levels, high high-density lipoprotein (HDL) levels [ High adiponectin levels [ Hypertrophic cardiomyopathy Enlarged kidneys, liver, and spleen Nephrocalcinosis Enlarged polycystic ovaries • Progressive intrauterine growth restriction (IUGR) from the early third trimester and postnatal poor weight gain, growth deficiency, and reduced subcutaneous fat • Dysmorphic facial features ( • Hypotonia • Developmental delay • Integument, including dry skin, hypertrichosis ( • Prominent nipples ( • Abdominal distention ( • Genital enlargement (males and females) ( • Rectal hypertrophy and prolapse ( • Dysmorphic facial features that can resemble those of Donohue syndrome [ • Integument, including hypertrichosis and acanthosis nigricans • Prominent nipples • Genital enlargement (males and females) • Early dental eruption and dental crowding [ • Growth deficiency (less severe than in Donohue syndrome) [ • Developmental delay (in some individuals) [ • Severe hyperinsulinemia. Extremely high plasma insulin and C-peptide levels with fluctuating blood glucose levels (typically fasting hypoglycemia and postprandial hyperglycemia) • Ketoacidosis not reported. • Low triglyceride levels, high high-density lipoprotein (HDL) levels [ • High adiponectin levels [ • Hypertrophic cardiomyopathy • Enlarged kidneys, liver, and spleen • Nephrocalcinosis • Enlarged polycystic ovaries ## Clinical Findings Progressive intrauterine growth restriction (IUGR) from the early third trimester and postnatal poor weight gain, growth deficiency, and reduced subcutaneous fat Dysmorphic facial features ( Hypotonia Developmental delay Integument, including dry skin, hypertrichosis ( Prominent nipples ( Abdominal distention ( Genital enlargement (males and females) ( Rectal hypertrophy and prolapse ( Dysmorphic facial features that can resemble those of Donohue syndrome [ Integument, including hypertrichosis and acanthosis nigricans Prominent nipples Genital enlargement (males and females) Early dental eruption and dental crowding [ Growth deficiency (less severe than in Donohue syndrome) [ Developmental delay (in some individuals) [ • Progressive intrauterine growth restriction (IUGR) from the early third trimester and postnatal poor weight gain, growth deficiency, and reduced subcutaneous fat • Dysmorphic facial features ( • Hypotonia • Developmental delay • Integument, including dry skin, hypertrichosis ( • Prominent nipples ( • Abdominal distention ( • Genital enlargement (males and females) ( • Rectal hypertrophy and prolapse ( • Dysmorphic facial features that can resemble those of Donohue syndrome [ • Integument, including hypertrichosis and acanthosis nigricans • Prominent nipples • Genital enlargement (males and females) • Early dental eruption and dental crowding [ • Growth deficiency (less severe than in Donohue syndrome) [ • Developmental delay (in some individuals) [ ## Laboratory Findings Severe hyperinsulinemia. Extremely high plasma insulin and C-peptide levels with fluctuating blood glucose levels (typically fasting hypoglycemia and postprandial hyperglycemia) Ketoacidosis not reported. Low triglyceride levels, high high-density lipoprotein (HDL) levels [ High adiponectin levels [ • Severe hyperinsulinemia. Extremely high plasma insulin and C-peptide levels with fluctuating blood glucose levels (typically fasting hypoglycemia and postprandial hyperglycemia) • Ketoacidosis not reported. • Low triglyceride levels, high high-density lipoprotein (HDL) levels [ • High adiponectin levels [ ## Imaging Findings Hypertrophic cardiomyopathy Enlarged kidneys, liver, and spleen Nephrocalcinosis Enlarged polycystic ovaries • Hypertrophic cardiomyopathy • Enlarged kidneys, liver, and spleen • Nephrocalcinosis • Enlarged polycystic ovaries ## Establishing the Diagnosis The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Option 1 For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Clinical Characteristics Based on + = reported feature; incidence unknown Donohue syndrome is characterized by severe insulin resistance, growth failure, hypotonia, developmental delay, characteristic facies, and organomegaly. Enlargement of the external genitalia occurs in both males (enlargement of the penis) and females (labial hypertrophy and clitoral enlargement). Ovarian enlargement is characteristic; ovarian ultrasonography usually reveals multiple peripheral cysts, as seen in idiopathic polycystic ovary syndrome. Cysts may become very large and vulnerable to hemorrhage or torsion, and surgical removal may be required [ Central hypothyroidism has been reported [ RMS, at the milder end of the spectrum, is characterized by severe insulin resistance with fluctuations in blood glucose levels, diabetic ketoacidosis, and microvascular complications. Findings can range from severe growth deficiency and intellectual disability to normal growth and development. Facial features can be milder than those of Donohue syndrome. Enlargement of the external genitalia in both males and females typically appears later in childhood in individuals with RMS compared to those with Donohue syndrome. Enlarged ovaries are reported in some individuals and may be complicated by multiple cysts and development of tumors [ Thyroid abnormalities reported in RMS include high prevalence of thyroid nodules and thyromegaly [ There are no known genotype-phenotype correlations in Leprechaunism is a synonym of Donohue syndrome. Donohue syndrome is extremely rare, estimated at 1:1,000,000 [ To date, 96 individuals with Donohue syndrome and RMS have been molecularly diagnosed and reported [ ## Clinical Description Based on + = reported feature; incidence unknown Donohue syndrome is characterized by severe insulin resistance, growth failure, hypotonia, developmental delay, characteristic facies, and organomegaly. Enlargement of the external genitalia occurs in both males (enlargement of the penis) and females (labial hypertrophy and clitoral enlargement). Ovarian enlargement is characteristic; ovarian ultrasonography usually reveals multiple peripheral cysts, as seen in idiopathic polycystic ovary syndrome. Cysts may become very large and vulnerable to hemorrhage or torsion, and surgical removal may be required [ Central hypothyroidism has been reported [ RMS, at the milder end of the spectrum, is characterized by severe insulin resistance with fluctuations in blood glucose levels, diabetic ketoacidosis, and microvascular complications. Findings can range from severe growth deficiency and intellectual disability to normal growth and development. Facial features can be milder than those of Donohue syndrome. Enlargement of the external genitalia in both males and females typically appears later in childhood in individuals with RMS compared to those with Donohue syndrome. Enlarged ovaries are reported in some individuals and may be complicated by multiple cysts and development of tumors [ Thyroid abnormalities reported in RMS include high prevalence of thyroid nodules and thyromegaly [ ## Donohue Syndrome Donohue syndrome is characterized by severe insulin resistance, growth failure, hypotonia, developmental delay, characteristic facies, and organomegaly. Enlargement of the external genitalia occurs in both males (enlargement of the penis) and females (labial hypertrophy and clitoral enlargement). Ovarian enlargement is characteristic; ovarian ultrasonography usually reveals multiple peripheral cysts, as seen in idiopathic polycystic ovary syndrome. Cysts may become very large and vulnerable to hemorrhage or torsion, and surgical removal may be required [ Central hypothyroidism has been reported [ ## Rabson-Mendenhall Syndrome (RMS) RMS, at the milder end of the spectrum, is characterized by severe insulin resistance with fluctuations in blood glucose levels, diabetic ketoacidosis, and microvascular complications. Findings can range from severe growth deficiency and intellectual disability to normal growth and development. Facial features can be milder than those of Donohue syndrome. Enlargement of the external genitalia in both males and females typically appears later in childhood in individuals with RMS compared to those with Donohue syndrome. Enlarged ovaries are reported in some individuals and may be complicated by multiple cysts and development of tumors [ Thyroid abnormalities reported in RMS include high prevalence of thyroid nodules and thyromegaly [ ## Genotype-Phenotype Correlations There are no known genotype-phenotype correlations in ## Nomenclature Leprechaunism is a synonym of Donohue syndrome. ## Prevalence Donohue syndrome is extremely rare, estimated at 1:1,000,000 [ To date, 96 individuals with Donohue syndrome and RMS have been molecularly diagnosed and reported [ ## Genetically Related (Allelic) Disorders ## Differential Diagnosis The differential diagnosis of Selected Disorders of Interest in the Differential Diagnosis of IUGR & postnatal growth deficiency ↑ risk for hypoglycemia Dysmorphic features unlike those in DS/RMS Limb, body, &/or facial asymmetry Hypoglycemia assoc w/fasting only Hyperinsulinemia is not a feature in SRS. Congenital hyperinsulinemia Hypoglycemia (ranging from severe neonatal-onset disease to childhood-onset disease w/mild symptoms in FHI) Dysmorphism & growth deficiency are not characteristic of FHI. Insulin levels are usually much higher in DS/RMS. Congenital hyperinsulinemia Insulin resistance Hepatomegaly (due to hepatic steatosis & skeletal muscle hypertrophy in BSCL) Hypertrophic cardiomyopathy Dysmorphic features (due to absence of subcutaneous fat) in BSCL are unlike those in DS/RMS. Hyperlipidemia & liver steatosis in BSCL IUGR & postnatal growth deficiency Mildly impaired glucose tolerance Delayed psychomotor development Mild dysmorphic features No hyperinsulinemia Only mildly impaired glucose tolerance AD = autosomal dominant; AR = autosomal recessive; DS = Donohue syndrome; Silver-Russell syndrome (SRS) is a genetically heterogeneous condition. Genetic testing confirms clinical diagnosis in ~60% of affected individuals. Accurate assessment of SRS recurrence requires identification of the causative genetic mechanism in the proband. The birth weight of infants with SRS is typically ≥2 standard deviations (SD) below the mean, and postnatal growth ≥2 SD below the mean for length or height. Familial hyperinsulinism (FHI) is characterized by hypoglycemia that ranges from difficult-to-manage severe neonatal-onset disease to childhood-onset disease with mild symptoms and difficult-to-diagnose hypoglycemia. Neonatal-onset disease manifests within hours to two days after birth. In the newborn period, presenting symptoms (including seizures, hypotonia, poor feeding, and apnea) may be nonspecific. In severe FHI, serum glucose concentrations are typically extremely low and thus easily recognized. Childhood-onset disease manifests during the first months or years of life, and in milder FHI, diagnosis may be difficult to establish due to variable and/or mild hypoglycemia. Approximately 25%-35% of affected individuals develop diabetes mellitus between ages 15 and 20 years. Hypertrophic cardiomyopathy is reported in 20%-25% of affected individuals. • IUGR & postnatal growth deficiency • ↑ risk for hypoglycemia • Dysmorphic features unlike those in DS/RMS • Limb, body, &/or facial asymmetry • Hypoglycemia assoc w/fasting only • Hyperinsulinemia is not a feature in SRS. • Congenital hyperinsulinemia • Hypoglycemia (ranging from severe neonatal-onset disease to childhood-onset disease w/mild symptoms in FHI) • Dysmorphism & growth deficiency are not characteristic of FHI. • Insulin levels are usually much higher in DS/RMS. • Congenital hyperinsulinemia • Insulin resistance • Hepatomegaly (due to hepatic steatosis & skeletal muscle hypertrophy in BSCL) • Hypertrophic cardiomyopathy • Dysmorphic features (due to absence of subcutaneous fat) in BSCL are unlike those in DS/RMS. • Hyperlipidemia & liver steatosis in BSCL • IUGR & postnatal growth deficiency • Mildly impaired glucose tolerance • Delayed psychomotor development • Mild dysmorphic features • No hyperinsulinemia • Only mildly impaired glucose tolerance ## Management To establish the extent of disease and needs in an individual diagnosed with Assessment by pediatric endocrinologist Blood glucose monitoring (during fasting & after feeding) or continuous glucose monitoring Measurement of insulin & C-peptide levels Thyroid function tests Ovarian ultrasound (in females) Eval by pediatric cardiologist Echocardiography Cardiac MRI if indicated To assess for hypertrophic cardiomyopathy Note: Novel blood biomarkers incl BNP, NT-proBNP, hs-CRP, hs-cTnT, & uric acid are currently being evaluated. Eval by pediatric nephrologist Serum electrolytes 24-hour urinary calcium Renal ultrasound Liver function tests per gastroenterologist Abdominal ultrasound to assess liver/spleen Eval by pediatric gastroenterologist Community or Social work involvement for parental support Home nursing referral BNP = brain natriuretic peptide; GI = gastrointestinal; hs-CRP = high-sensitivity C-reactive protein; hs-cTnT = high-sensitivity cardiac troponin T; Medical geneticist, certified genetic counselor, certified advanced genetic nurse There is no cure for First-line therapy is insulin sensitizers, which ↓ the levels of HbA1c. When hyperglycemia persists, insulin is started, usually in high doses. When doses >200 units/day are required, the U500 (500 units/mL) concentration of soluble human insulin is recommended as part of a multiple-injection regime. The effect of insulin sensitizers diminishes over time, often requiring dose adjustments & multidrug therapy. In many persons, this treatment is well tolerated & permits large incremental increases in dose w/o excessive discomfort. U500 can also be administrated continuously by subcutaneous insulin pump. Oral contraceptives & antiandrogens such as flutamide & spironolactone as well as finasteride, a 5-alphareductase inhibitor that ↓ conversion of testosterone to dihydrotestosterone A GnRH agonist to suppress gonadotrophins is also likely to be beneficial. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, medications, & supplies. GnRH = gonadotropin-releasing hormone; HbA1c = glycosylated hemoglobin; RMS = Rabson-Mendenhall syndrome To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in HbA1c Insulin & C-peptide levels Thyroid function tests Endocrinology lab assessment for hyperandrogenism Echocardiography Cardiac MRI Urine calcium to assess for hypercalciuria Kidney ultrasound to assess for nephrocalcinosis HbA1c = glycosylated hemoglobin In individuals with Donohue syndrome, avoid the following: Agents that cause hypoglycemia Prolonged fasting Contact with persons with a contagious disease In individuals with RMS, avoid the following: Agents that cause hyperglycemia High-carbohydrate diet Contact with persons with a contagious disease See There are no controlled trials in The rationale for using rhIGF-1 to treat severe insulin resistance syndromes is based on observations of its direct effects on carbohydrate metabolism. In humans, infusion of rhIGF-1 suppresses hepatic glucose production, stimulates peripheral glucose uptake in muscle, and – despite a significant reduction in circulating insulin levels – causes hypoglycemia. The insulin-like growth factor 1 receptor (IGF1R) and the insulin receptor (INSR) share 60% homology and very similar intracellular activity [ Three treatment regimens for rhIGF-1 therapy in children with severe insulin resistance were reported: subcutaneous injections two to four times a day, continuous subcutaneous infusion via insulin pump, and intravenous infusion [ The metabolic state improved and levels of glucose, insulin, and glycosylated hemoglobin decreased. Growth parameters improved [ Renal tubular dysfunction improved [ In some children treated with rhIGF-1, the degree of cardiomyopathy improved and survival was prolonged [ Given a lack of evidence, it is unclear whether the following two instances were side effects of the treatment or the hyperinsulinemia itself: Endometrial carcinoma in a woman age 24 years treated with rhIGF-1 for severe insulin resistance (called Donohue syndrome by the authors, but clinically more likely RMS) [ Granulosa cell tumor of the ovary in a girl age 35 months with severe insulin resistance treated with rhIGF-1 for 16 months [ To summarize the experience with rhIGF-1 treatment in severe insulin resistance syndromes: (1) its benefit is not well established; and (2) it is more likely to be effective in individuals with less severe insulin resistance, as the few individuals with prolonged survival with rhIGF-1 treatment had milder phenotypes [ Metreleptin is approved by the FDA for treatment of congenital or acquired generalized lipodystrophy. Leptin replacement normalized blood lipids (i.e., reduced triglycerides and increased high-density lipoproteins [HDL]) and reduced insulin and glucose levels in syndromes with leptin deficiency. Syndromes with leptin deficiency are characterized by insulin resistance, hyperglycemia, dyslipidemia, endocrine disruptions, and fatty liver disease [ After one year of treatment with metreleptin (along with other medications including insulin, metformin, and pioglitazone), individuals with RMS showed improvement in all of the following: serum glucose levels, glycosylated hemoglobin (HbA1c) levels, insulinemia, insulin dose required, caloric intake, and body fat mass [ Metreleptin alters the natural history of rising HbA1c in RMS, leading to lower HbA1c throughout long-term follow up. Improved glycemia with metreleptin is likely attributable to appetite suppression and lower body mass index (BMI). Lower BMI after metreleptin may also worsen growth hormone resistance in RMS, resulting in a null effect on IGF-1 and growth despite improved glycemia [ Search • Assessment by pediatric endocrinologist • Blood glucose monitoring (during fasting & after feeding) or continuous glucose monitoring • Measurement of insulin & C-peptide levels • Thyroid function tests • Ovarian ultrasound (in females) • Eval by pediatric cardiologist • Echocardiography • Cardiac MRI if indicated • To assess for hypertrophic cardiomyopathy • Note: Novel blood biomarkers incl BNP, NT-proBNP, hs-CRP, hs-cTnT, & uric acid are currently being evaluated. • Eval by pediatric nephrologist • Serum electrolytes • 24-hour urinary calcium • Renal ultrasound • Liver function tests per gastroenterologist • Abdominal ultrasound to assess liver/spleen • Eval by pediatric gastroenterologist • Community or • Social work involvement for parental support • Home nursing referral • First-line therapy is insulin sensitizers, which ↓ the levels of HbA1c. • When hyperglycemia persists, insulin is started, usually in high doses. • When doses >200 units/day are required, the U500 (500 units/mL) concentration of soluble human insulin is recommended as part of a multiple-injection regime. • The effect of insulin sensitizers diminishes over time, often requiring dose adjustments & multidrug therapy. • In many persons, this treatment is well tolerated & permits large incremental increases in dose w/o excessive discomfort. • U500 can also be administrated continuously by subcutaneous insulin pump. • Oral contraceptives & antiandrogens such as flutamide & spironolactone as well as finasteride, a 5-alphareductase inhibitor that ↓ conversion of testosterone to dihydrotestosterone • A GnRH agonist to suppress gonadotrophins is also likely to be beneficial. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, medications, & supplies. • HbA1c • Insulin & C-peptide levels • Thyroid function tests • Endocrinology lab assessment for hyperandrogenism • Echocardiography • Cardiac MRI • Urine calcium to assess for hypercalciuria • Kidney ultrasound to assess for nephrocalcinosis • Agents that cause hypoglycemia • Prolonged fasting • Contact with persons with a contagious disease • Agents that cause hyperglycemia • High-carbohydrate diet • Contact with persons with a contagious disease • The metabolic state improved and levels of glucose, insulin, and glycosylated hemoglobin decreased. • Growth parameters improved [ • Renal tubular dysfunction improved [ • Endometrial carcinoma in a woman age 24 years treated with rhIGF-1 for severe insulin resistance (called Donohue syndrome by the authors, but clinically more likely RMS) [ • Granulosa cell tumor of the ovary in a girl age 35 months with severe insulin resistance treated with rhIGF-1 for 16 months [ ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Assessment by pediatric endocrinologist Blood glucose monitoring (during fasting & after feeding) or continuous glucose monitoring Measurement of insulin & C-peptide levels Thyroid function tests Ovarian ultrasound (in females) Eval by pediatric cardiologist Echocardiography Cardiac MRI if indicated To assess for hypertrophic cardiomyopathy Note: Novel blood biomarkers incl BNP, NT-proBNP, hs-CRP, hs-cTnT, & uric acid are currently being evaluated. Eval by pediatric nephrologist Serum electrolytes 24-hour urinary calcium Renal ultrasound Liver function tests per gastroenterologist Abdominal ultrasound to assess liver/spleen Eval by pediatric gastroenterologist Community or Social work involvement for parental support Home nursing referral BNP = brain natriuretic peptide; GI = gastrointestinal; hs-CRP = high-sensitivity C-reactive protein; hs-cTnT = high-sensitivity cardiac troponin T; Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Assessment by pediatric endocrinologist • Blood glucose monitoring (during fasting & after feeding) or continuous glucose monitoring • Measurement of insulin & C-peptide levels • Thyroid function tests • Ovarian ultrasound (in females) • Eval by pediatric cardiologist • Echocardiography • Cardiac MRI if indicated • To assess for hypertrophic cardiomyopathy • Note: Novel blood biomarkers incl BNP, NT-proBNP, hs-CRP, hs-cTnT, & uric acid are currently being evaluated. • Eval by pediatric nephrologist • Serum electrolytes • 24-hour urinary calcium • Renal ultrasound • Liver function tests per gastroenterologist • Abdominal ultrasound to assess liver/spleen • Eval by pediatric gastroenterologist • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations There is no cure for First-line therapy is insulin sensitizers, which ↓ the levels of HbA1c. When hyperglycemia persists, insulin is started, usually in high doses. When doses >200 units/day are required, the U500 (500 units/mL) concentration of soluble human insulin is recommended as part of a multiple-injection regime. The effect of insulin sensitizers diminishes over time, often requiring dose adjustments & multidrug therapy. In many persons, this treatment is well tolerated & permits large incremental increases in dose w/o excessive discomfort. U500 can also be administrated continuously by subcutaneous insulin pump. Oral contraceptives & antiandrogens such as flutamide & spironolactone as well as finasteride, a 5-alphareductase inhibitor that ↓ conversion of testosterone to dihydrotestosterone A GnRH agonist to suppress gonadotrophins is also likely to be beneficial. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, medications, & supplies. GnRH = gonadotropin-releasing hormone; HbA1c = glycosylated hemoglobin; RMS = Rabson-Mendenhall syndrome • First-line therapy is insulin sensitizers, which ↓ the levels of HbA1c. • When hyperglycemia persists, insulin is started, usually in high doses. • When doses >200 units/day are required, the U500 (500 units/mL) concentration of soluble human insulin is recommended as part of a multiple-injection regime. • The effect of insulin sensitizers diminishes over time, often requiring dose adjustments & multidrug therapy. • In many persons, this treatment is well tolerated & permits large incremental increases in dose w/o excessive discomfort. • U500 can also be administrated continuously by subcutaneous insulin pump. • Oral contraceptives & antiandrogens such as flutamide & spironolactone as well as finasteride, a 5-alphareductase inhibitor that ↓ conversion of testosterone to dihydrotestosterone • A GnRH agonist to suppress gonadotrophins is also likely to be beneficial. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, medications, & supplies. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in HbA1c Insulin & C-peptide levels Thyroid function tests Endocrinology lab assessment for hyperandrogenism Echocardiography Cardiac MRI Urine calcium to assess for hypercalciuria Kidney ultrasound to assess for nephrocalcinosis HbA1c = glycosylated hemoglobin • HbA1c • Insulin & C-peptide levels • Thyroid function tests • Endocrinology lab assessment for hyperandrogenism • Echocardiography • Cardiac MRI • Urine calcium to assess for hypercalciuria • Kidney ultrasound to assess for nephrocalcinosis ## Agents/Circumstances to Avoid In individuals with Donohue syndrome, avoid the following: Agents that cause hypoglycemia Prolonged fasting Contact with persons with a contagious disease In individuals with RMS, avoid the following: Agents that cause hyperglycemia High-carbohydrate diet Contact with persons with a contagious disease • Agents that cause hypoglycemia • Prolonged fasting • Contact with persons with a contagious disease • Agents that cause hyperglycemia • High-carbohydrate diet • Contact with persons with a contagious disease ## Evaluation of Relatives at Risk See ## Therapies Under Investigation There are no controlled trials in The rationale for using rhIGF-1 to treat severe insulin resistance syndromes is based on observations of its direct effects on carbohydrate metabolism. In humans, infusion of rhIGF-1 suppresses hepatic glucose production, stimulates peripheral glucose uptake in muscle, and – despite a significant reduction in circulating insulin levels – causes hypoglycemia. The insulin-like growth factor 1 receptor (IGF1R) and the insulin receptor (INSR) share 60% homology and very similar intracellular activity [ Three treatment regimens for rhIGF-1 therapy in children with severe insulin resistance were reported: subcutaneous injections two to four times a day, continuous subcutaneous infusion via insulin pump, and intravenous infusion [ The metabolic state improved and levels of glucose, insulin, and glycosylated hemoglobin decreased. Growth parameters improved [ Renal tubular dysfunction improved [ In some children treated with rhIGF-1, the degree of cardiomyopathy improved and survival was prolonged [ Given a lack of evidence, it is unclear whether the following two instances were side effects of the treatment or the hyperinsulinemia itself: Endometrial carcinoma in a woman age 24 years treated with rhIGF-1 for severe insulin resistance (called Donohue syndrome by the authors, but clinically more likely RMS) [ Granulosa cell tumor of the ovary in a girl age 35 months with severe insulin resistance treated with rhIGF-1 for 16 months [ To summarize the experience with rhIGF-1 treatment in severe insulin resistance syndromes: (1) its benefit is not well established; and (2) it is more likely to be effective in individuals with less severe insulin resistance, as the few individuals with prolonged survival with rhIGF-1 treatment had milder phenotypes [ Metreleptin is approved by the FDA for treatment of congenital or acquired generalized lipodystrophy. Leptin replacement normalized blood lipids (i.e., reduced triglycerides and increased high-density lipoproteins [HDL]) and reduced insulin and glucose levels in syndromes with leptin deficiency. Syndromes with leptin deficiency are characterized by insulin resistance, hyperglycemia, dyslipidemia, endocrine disruptions, and fatty liver disease [ After one year of treatment with metreleptin (along with other medications including insulin, metformin, and pioglitazone), individuals with RMS showed improvement in all of the following: serum glucose levels, glycosylated hemoglobin (HbA1c) levels, insulinemia, insulin dose required, caloric intake, and body fat mass [ Metreleptin alters the natural history of rising HbA1c in RMS, leading to lower HbA1c throughout long-term follow up. Improved glycemia with metreleptin is likely attributable to appetite suppression and lower body mass index (BMI). Lower BMI after metreleptin may also worsen growth hormone resistance in RMS, resulting in a null effect on IGF-1 and growth despite improved glycemia [ Search • The metabolic state improved and levels of glucose, insulin, and glycosylated hemoglobin decreased. • Growth parameters improved [ • Renal tubular dysfunction improved [ • Endometrial carcinoma in a woman age 24 years treated with rhIGF-1 for severe insulin resistance (called Donohue syndrome by the authors, but clinically more likely RMS) [ • Granulosa cell tumor of the ovary in a girl age 35 months with severe insulin resistance treated with rhIGF-1 for 16 months [ ## Recombinant Human Insulin-like Growth Factor 1 (rhIGF-1) The rationale for using rhIGF-1 to treat severe insulin resistance syndromes is based on observations of its direct effects on carbohydrate metabolism. In humans, infusion of rhIGF-1 suppresses hepatic glucose production, stimulates peripheral glucose uptake in muscle, and – despite a significant reduction in circulating insulin levels – causes hypoglycemia. The insulin-like growth factor 1 receptor (IGF1R) and the insulin receptor (INSR) share 60% homology and very similar intracellular activity [ Three treatment regimens for rhIGF-1 therapy in children with severe insulin resistance were reported: subcutaneous injections two to four times a day, continuous subcutaneous infusion via insulin pump, and intravenous infusion [ The metabolic state improved and levels of glucose, insulin, and glycosylated hemoglobin decreased. Growth parameters improved [ Renal tubular dysfunction improved [ In some children treated with rhIGF-1, the degree of cardiomyopathy improved and survival was prolonged [ Given a lack of evidence, it is unclear whether the following two instances were side effects of the treatment or the hyperinsulinemia itself: Endometrial carcinoma in a woman age 24 years treated with rhIGF-1 for severe insulin resistance (called Donohue syndrome by the authors, but clinically more likely RMS) [ Granulosa cell tumor of the ovary in a girl age 35 months with severe insulin resistance treated with rhIGF-1 for 16 months [ To summarize the experience with rhIGF-1 treatment in severe insulin resistance syndromes: (1) its benefit is not well established; and (2) it is more likely to be effective in individuals with less severe insulin resistance, as the few individuals with prolonged survival with rhIGF-1 treatment had milder phenotypes [ • The metabolic state improved and levels of glucose, insulin, and glycosylated hemoglobin decreased. • Growth parameters improved [ • Renal tubular dysfunction improved [ • Endometrial carcinoma in a woman age 24 years treated with rhIGF-1 for severe insulin resistance (called Donohue syndrome by the authors, but clinically more likely RMS) [ • Granulosa cell tumor of the ovary in a girl age 35 months with severe insulin resistance treated with rhIGF-1 for 16 months [ ## Metreleptin (Recombinant Human Leptin) Metreleptin is approved by the FDA for treatment of congenital or acquired generalized lipodystrophy. Leptin replacement normalized blood lipids (i.e., reduced triglycerides and increased high-density lipoproteins [HDL]) and reduced insulin and glucose levels in syndromes with leptin deficiency. Syndromes with leptin deficiency are characterized by insulin resistance, hyperglycemia, dyslipidemia, endocrine disruptions, and fatty liver disease [ After one year of treatment with metreleptin (along with other medications including insulin, metformin, and pioglitazone), individuals with RMS showed improvement in all of the following: serum glucose levels, glycosylated hemoglobin (HbA1c) levels, insulinemia, insulin dose required, caloric intake, and body fat mass [ Metreleptin alters the natural history of rising HbA1c in RMS, leading to lower HbA1c throughout long-term follow up. Improved glycemia with metreleptin is likely attributable to appetite suppression and lower body mass index (BMI). Lower BMI after metreleptin may also worsen growth hormone resistance in RMS, resulting in a null effect on IGF-1 and growth despite improved glycemia [ 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 are usually asymptomatic but may have features of the allelic disorder type A insulin resistance (see If both parents are known to be heterozygous for an Heterozygotes are usually asymptomatic but may have features of the allelic disorder type A insulin resistance (see Heterozygote testing for at-risk relatives requires prior identification of the Heterozygotes are usually asymptomatic but may have features of the allelic disorder type A insulin resistance. Females who are heterozygous for an The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are heterozygous or are at risk of being heterozygous. Heterozygote testing should be considered for the reproductive partners of known heterozygotes, particularly if both partners are of the same ancestry. The prevalence of heterozygotes for the pathogenic variant Females who are heterozygous for 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 deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual 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 are usually asymptomatic but may have features of the allelic disorder type A insulin resistance (see • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual 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 are usually asymptomatic but may have features of the allelic disorder type A insulin resistance (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 heterozygous or are at risk of being heterozygous. • Heterozygote testing should be considered for the reproductive partners of known heterozygotes, particularly if both partners are of the same ancestry. The prevalence of heterozygotes for the pathogenic variant • Females who are heterozygous for an ## 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 are usually asymptomatic but may have features of the allelic disorder type A insulin resistance (see If both parents are known to be heterozygous for an Heterozygotes are usually asymptomatic but may have features of the allelic disorder type A insulin resistance (see • 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 are usually asymptomatic but may have features of the allelic disorder type A insulin resistance (see • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual 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 are usually asymptomatic but may have features of the allelic disorder type A insulin resistance (see ## Heterozygote Detection Heterozygote testing for at-risk relatives requires prior identification of the Heterozygotes are usually asymptomatic but may have features of the allelic disorder type A insulin resistance. Females who are heterozygous for an ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are heterozygous or are at risk of being heterozygous. Heterozygote testing should be considered for the reproductive partners of known heterozygotes, particularly if both partners are of the same ancestry. The prevalence of heterozygotes for the pathogenic variant Females who are heterozygous for an • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are heterozygous or are at risk of being heterozygous. • Heterozygote testing should be considered for the reproductive partners of known heterozygotes, particularly if both partners are of the same ancestry. The prevalence of heterozygotes for the pathogenic variant • Females who are heterozygous for 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 INSR-Related Severe Insulin Resistance Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for INSR-Related Severe Insulin Resistance Syndrome ( When insulin binds to the alpha subunit, the beta subunit undergoes autophosphorylation, which activates the insulin-signaling pathway regulating glucose uptake and release as well as the synthesis and storage of carbohydrates, lipids, and protein. Impair synthesis of the receptors; Impair transport of receptors to the cell membrane; Decrease receptor affinity for insulin; Reduce the tyrosine kinase activity of the receptor intracellular domain; Accelerate receptor degradation [ In severe insulin resistance, reduced intracellular insulin signaling causes hyperglycemia. The hypoglycemia in Notable Variants listed in the table have been provided by the authors. • Impair synthesis of the receptors; • Impair transport of receptors to the cell membrane; • Decrease receptor affinity for insulin; • Reduce the tyrosine kinase activity of the receptor intracellular domain; • Accelerate receptor degradation [ ## Molecular Pathogenesis When insulin binds to the alpha subunit, the beta subunit undergoes autophosphorylation, which activates the insulin-signaling pathway regulating glucose uptake and release as well as the synthesis and storage of carbohydrates, lipids, and protein. Impair synthesis of the receptors; Impair transport of receptors to the cell membrane; Decrease receptor affinity for insulin; Reduce the tyrosine kinase activity of the receptor intracellular domain; Accelerate receptor degradation [ In severe insulin resistance, reduced intracellular insulin signaling causes hyperglycemia. The hypoglycemia in Notable Variants listed in the table have been provided by the authors. • Impair synthesis of the receptors; • Impair transport of receptors to the cell membrane; • Decrease receptor affinity for insulin; • Reduce the tyrosine kinase activity of the receptor intracellular domain; • Accelerate receptor degradation [ ## Chapter Notes Author research interests: Searching for genes responsible for various rare genetic disorders and investigating the clinical, biochemical, and molecular basis for each disorder by studying the related protein function and biologic pathway. Diseases currently of particular interest include neurogenetic diseases, aplasia of distal phalanges with juvenile breast hypertrophy (MDN), osteogenesis imperfecta, and hereditary spastic paraparesis and cardiomyopathies. Identification of new pathogenic variants, genes, and proteins involved in NER-type DNA repair mechanisms and understanding their cellular function and their role in premature aging and cancer. In addition, the establishment of new diagnostic procedures for the screening of causative pathogenic variants in affected individuals in Israel and the Middle East. Development of methods of genetic counseling tailored to kindreds at high risk for genetic disorders, in an attempt to raise awareness and to prevent and minimize the births of affected individuals. Also, early identification of affected newborns is critical for provision of prompt and effective treatment. Genetics of pain. Our interest in this field is manifested in the study of women with vulvodynia (pain during sexual intercourse). This phenomenon is evident within families, and genetic associations have been found. With the collaboration of Professor J Bornstein, we are studying possible genetic associations that relate to biochemical pathways involved in pain regulation among a large cohort of women affected with vulvodynia. Dr Falik Zaccai's Shani Ben Harouch, MD; Bar-Ilan University (2018-2024)Tzipora C Falik Zaccai, MD (2018-present)Aharon Klar, MD (2018-present)Aviv Mesika (2024-present) 25 April 2024 (sw) Comprehensive updated posted live 25 January 2018 (bp) Review posted live 14 March 2016 (sbh) Original submission • Searching for genes responsible for various rare genetic disorders and investigating the clinical, biochemical, and molecular basis for each disorder by studying the related protein function and biologic pathway. Diseases currently of particular interest include neurogenetic diseases, aplasia of distal phalanges with juvenile breast hypertrophy (MDN), osteogenesis imperfecta, and hereditary spastic paraparesis and cardiomyopathies. • Identification of new pathogenic variants, genes, and proteins involved in NER-type DNA repair mechanisms and understanding their cellular function and their role in premature aging and cancer. In addition, the establishment of new diagnostic procedures for the screening of causative pathogenic variants in affected individuals in Israel and the Middle East. • Development of methods of genetic counseling tailored to kindreds at high risk for genetic disorders, in an attempt to raise awareness and to prevent and minimize the births of affected individuals. Also, early identification of affected newborns is critical for provision of prompt and effective treatment. • Genetics of pain. Our interest in this field is manifested in the study of women with vulvodynia (pain during sexual intercourse). This phenomenon is evident within families, and genetic associations have been found. With the collaboration of Professor J Bornstein, we are studying possible genetic associations that relate to biochemical pathways involved in pain regulation among a large cohort of women affected with vulvodynia. • 25 April 2024 (sw) Comprehensive updated posted live • 25 January 2018 (bp) Review posted live • 14 March 2016 (sbh) Original submission ## Author Notes Author research interests: Searching for genes responsible for various rare genetic disorders and investigating the clinical, biochemical, and molecular basis for each disorder by studying the related protein function and biologic pathway. Diseases currently of particular interest include neurogenetic diseases, aplasia of distal phalanges with juvenile breast hypertrophy (MDN), osteogenesis imperfecta, and hereditary spastic paraparesis and cardiomyopathies. Identification of new pathogenic variants, genes, and proteins involved in NER-type DNA repair mechanisms and understanding their cellular function and their role in premature aging and cancer. In addition, the establishment of new diagnostic procedures for the screening of causative pathogenic variants in affected individuals in Israel and the Middle East. Development of methods of genetic counseling tailored to kindreds at high risk for genetic disorders, in an attempt to raise awareness and to prevent and minimize the births of affected individuals. Also, early identification of affected newborns is critical for provision of prompt and effective treatment. Genetics of pain. Our interest in this field is manifested in the study of women with vulvodynia (pain during sexual intercourse). This phenomenon is evident within families, and genetic associations have been found. With the collaboration of Professor J Bornstein, we are studying possible genetic associations that relate to biochemical pathways involved in pain regulation among a large cohort of women affected with vulvodynia. Dr Falik Zaccai's • Searching for genes responsible for various rare genetic disorders and investigating the clinical, biochemical, and molecular basis for each disorder by studying the related protein function and biologic pathway. Diseases currently of particular interest include neurogenetic diseases, aplasia of distal phalanges with juvenile breast hypertrophy (MDN), osteogenesis imperfecta, and hereditary spastic paraparesis and cardiomyopathies. • Identification of new pathogenic variants, genes, and proteins involved in NER-type DNA repair mechanisms and understanding their cellular function and their role in premature aging and cancer. In addition, the establishment of new diagnostic procedures for the screening of causative pathogenic variants in affected individuals in Israel and the Middle East. • Development of methods of genetic counseling tailored to kindreds at high risk for genetic disorders, in an attempt to raise awareness and to prevent and minimize the births of affected individuals. Also, early identification of affected newborns is critical for provision of prompt and effective treatment. • Genetics of pain. Our interest in this field is manifested in the study of women with vulvodynia (pain during sexual intercourse). This phenomenon is evident within families, and genetic associations have been found. With the collaboration of Professor J Bornstein, we are studying possible genetic associations that relate to biochemical pathways involved in pain regulation among a large cohort of women affected with vulvodynia. ## Author History Shani Ben Harouch, MD; Bar-Ilan University (2018-2024)Tzipora C Falik Zaccai, MD (2018-present)Aharon Klar, MD (2018-present)Aviv Mesika (2024-present) ## Revision History 25 April 2024 (sw) Comprehensive updated posted live 25 January 2018 (bp) Review posted live 14 March 2016 (sbh) Original submission • 25 April 2024 (sw) Comprehensive updated posted live • 25 January 2018 (bp) Review posted live • 14 March 2016 (sbh) Original submission ## References ## Literature Cited Characteristic dysmorphism seen in neonate with Donohue syndrome: gingival overgrowth; large, low-set, posteriorly rotated ears; infraorbital folds; proptosis; thick vermilion of the upper and lower lips Hypertrichosis is a feature in all individuals with Donohue syndrome. Reproduced from Prominent nipples are a typical finding in neonates with Donohue syndrome. A and B. Abdominal distention B. Labial hypertrophy and clitoromegaly in a girl age four months with Donohue syndrome Rectal hypertrophy and prolapse in an infant with Donohue syndrome.	[]	25/1/2018	25/4/2024		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
ipa	ipa	[ "AH receptor-interacting protein", "AIP", "AIP Familial Isolated Pituitary Adenomas" ]		Márta Korbonits, Laura C Hernández-Ramírez	Summary The diagnosis of In symptomatic individuals: annual clinical assessment and pituitary function tests (serum IGF-1, spot GH, prolactin, estradiol/testosterone, LH, FSH, TSH, thyroxine, and morning cortisol); if indicated, annual dynamic testing to evaluate for hormone excess or deficiency (e.g., glucose tolerance test, insulin tolerance test); pituitary MRI with frequency depending on clinical status, previous extent of the tumor, and treatment modality. Clinical monitoring of secondary complications of the tumor and/or its treatment (e.g., diabetes mellitus, hypertension, osteoarthritis, hypogonadism, osteoporosis); in those with acromegaly, colonoscopy at age 40 years and repeated every three to ten years depending on the number of colorectal lesions and IGF-1 levels.	## Diagnosis A pituitary neuroendocrine tumor (PitNET) diagnosed before age 18 years, especially a growth hormone (GH)-secreting PitNET, regardless of family history A pituitary macroadenoma (tumor >10 mm in diameter) diagnosed before age 30 years, especially a GH-secreting PitNET, regardless of family history A prolactin-secreting pituitary macroadenoma (tumor >10 mm in diameter) diagnosed before age 30 years, regardless of family history. A single individual with clinically presenting childhood-onset microadenoma (tumor <10 mm) has been identified in this setting [ Note: (1) A germline A family history of more than one individual with a PitNET. Note: (1) A germline Absence of clinical features of other syndromic disorders associated with PitNETs such as The GH secreting (somatotropinoma) Note: Somatotroph (GH-secreting) cell hyperplasia has also been described in individuals with Prolactin secreting (prolactinoma) GH and prolactin cosecreting (somatomammotropinoma) Clinically nonfunctioning PitNETs (NF-PitNETs) Note: Most Thyrotropinoma (thyroid-stimulating hormone [TSH] secreting) (rare; 1 individual described) Multihormonal (i.e., secreting >1 pituitary hormone) (extremely rare apart from tumors secreting GH and prolactin) Note: No unequivocal cases of corticotropinomas have been described in individuals with 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: Targeted analysis for pathogenic variants can be performed first in individuals of Finnish ancestry (see For an introduction to multigene panels click When the phenotype is indistinguishable from other inherited disorders characterized by pituitary tumors, 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 One promoter variant has been reported (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 gene-targeted array-based comparative genomic hybridization assays designed to detect single-exon deletions or duplications. Short read-based NGS panels and exome and genome sequencing may be able to detect deletions/duplications using read depth; however, sensitivity is variable and might be lower than that of other methods. To date, five individuals/families with exon or multiexon deletions and two families with whole-gene deletions have been reported in the literature. Five more intragenic large deletions have been reported by clinical laboratories in ClinVar [ • A pituitary neuroendocrine tumor (PitNET) diagnosed before age 18 years, especially a growth hormone (GH)-secreting PitNET, regardless of family history • A pituitary macroadenoma (tumor >10 mm in diameter) diagnosed before age 30 years, especially a GH-secreting PitNET, regardless of family history • A prolactin-secreting pituitary macroadenoma (tumor >10 mm in diameter) diagnosed before age 30 years, regardless of family history. A single individual with clinically presenting childhood-onset microadenoma (tumor <10 mm) has been identified in this setting [ • Note: (1) A germline • A family history of more than one individual with a PitNET. • Note: (1) A germline • Absence of clinical features of other syndromic disorders associated with PitNETs such as • GH secreting (somatotropinoma) • Note: Somatotroph (GH-secreting) cell hyperplasia has also been described in individuals with • Prolactin secreting (prolactinoma) • GH and prolactin cosecreting (somatomammotropinoma) • Clinically nonfunctioning PitNETs (NF-PitNETs) • Note: Most • Thyrotropinoma (thyroid-stimulating hormone [TSH] secreting) (rare; 1 individual described) • Multihormonal (i.e., secreting >1 pituitary hormone) (extremely rare apart from tumors secreting GH and prolactin) • Note: No unequivocal cases of corticotropinomas have been described in individuals with ## Suggestive Findings A pituitary neuroendocrine tumor (PitNET) diagnosed before age 18 years, especially a growth hormone (GH)-secreting PitNET, regardless of family history A pituitary macroadenoma (tumor >10 mm in diameter) diagnosed before age 30 years, especially a GH-secreting PitNET, regardless of family history A prolactin-secreting pituitary macroadenoma (tumor >10 mm in diameter) diagnosed before age 30 years, regardless of family history. A single individual with clinically presenting childhood-onset microadenoma (tumor <10 mm) has been identified in this setting [ Note: (1) A germline A family history of more than one individual with a PitNET. Note: (1) A germline Absence of clinical features of other syndromic disorders associated with PitNETs such as The GH secreting (somatotropinoma) Note: Somatotroph (GH-secreting) cell hyperplasia has also been described in individuals with Prolactin secreting (prolactinoma) GH and prolactin cosecreting (somatomammotropinoma) Clinically nonfunctioning PitNETs (NF-PitNETs) Note: Most Thyrotropinoma (thyroid-stimulating hormone [TSH] secreting) (rare; 1 individual described) Multihormonal (i.e., secreting >1 pituitary hormone) (extremely rare apart from tumors secreting GH and prolactin) Note: No unequivocal cases of corticotropinomas have been described in individuals with • A pituitary neuroendocrine tumor (PitNET) diagnosed before age 18 years, especially a growth hormone (GH)-secreting PitNET, regardless of family history • A pituitary macroadenoma (tumor >10 mm in diameter) diagnosed before age 30 years, especially a GH-secreting PitNET, regardless of family history • A prolactin-secreting pituitary macroadenoma (tumor >10 mm in diameter) diagnosed before age 30 years, regardless of family history. A single individual with clinically presenting childhood-onset microadenoma (tumor <10 mm) has been identified in this setting [ • Note: (1) A germline • A family history of more than one individual with a PitNET. • Note: (1) A germline • Absence of clinical features of other syndromic disorders associated with PitNETs such as • GH secreting (somatotropinoma) • Note: Somatotroph (GH-secreting) cell hyperplasia has also been described in individuals with • Prolactin secreting (prolactinoma) • GH and prolactin cosecreting (somatomammotropinoma) • Clinically nonfunctioning PitNETs (NF-PitNETs) • Note: Most • Thyrotropinoma (thyroid-stimulating hormone [TSH] secreting) (rare; 1 individual described) • Multihormonal (i.e., secreting >1 pituitary hormone) (extremely rare apart from tumors secreting GH and prolactin) • Note: No unequivocal cases of corticotropinomas have been described in individuals with ## 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: Targeted analysis for pathogenic variants can be performed first in individuals of Finnish ancestry (see For an introduction to multigene panels click When the phenotype is indistinguishable from other inherited disorders characterized by pituitary tumors, 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 One promoter variant has been reported (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 gene-targeted array-based comparative genomic hybridization assays designed to detect single-exon deletions or duplications. Short read-based NGS panels and exome and genome sequencing may be able to detect deletions/duplications using read depth; however, sensitivity is variable and might be lower than that of other methods. To date, five individuals/families with exon or multiexon deletions and two families with whole-gene deletions have been reported in the literature. Five more intragenic large deletions have been reported by clinical laboratories in ClinVar [ ## Option 1 Note: Targeted analysis for pathogenic variants can be performed first in individuals of Finnish ancestry (see For an introduction to multigene panels click ## Option 2 When the phenotype is indistinguishable from other inherited disorders characterized by pituitary tumors, 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 One promoter variant has been reported (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 gene-targeted array-based comparative genomic hybridization assays designed to detect single-exon deletions or duplications. Short read-based NGS panels and exome and genome sequencing may be able to detect deletions/duplications using read depth; however, sensitivity is variable and might be lower than that of other methods. To date, five individuals/families with exon or multiexon deletions and two families with whole-gene deletions have been reported in the literature. Five more intragenic large deletions have been reported by clinical laboratories in ClinVar [ ## Clinical Characteristics Pituitary Neuroendocrine Tumors in Individuals with Based on GH = growth hormone; PitNET = pituitary neuroendocrine tumor; TSH = thyroid-stimulating hormone If acromegaly starts in childhood/adolescence, it can lead to pituitary gigantism. One third of all individuals with a germline NF-PitNETs are usually diagnosed due to the local effects of the tumor, such as bitemporal hemianopia or hypogonadism. It is unclear why these silent tumors do not release hormones at a clinically recognizable level; however, there is likely to be a continuum between fully functional and completely silent PitNETs [ In Larger pituitary tumors may autoinfarct, resulting in pituitary apoplexy (sudden onset of severe headache, visual disturbance, cranial nerve palsies, hypoglycemia, and hypotensive shock). Pituitary apoplexy has been described in individuals with Individuals with Studies on large families with Previously, pituitary adenoma predisposition (PAP) syndrome was used to refer to individuals who had an The exact prevalence of • If acromegaly starts in childhood/adolescence, it can lead to pituitary gigantism. • One third of all individuals with a germline ## Clinical Description Pituitary Neuroendocrine Tumors in Individuals with Based on GH = growth hormone; PitNET = pituitary neuroendocrine tumor; TSH = thyroid-stimulating hormone If acromegaly starts in childhood/adolescence, it can lead to pituitary gigantism. One third of all individuals with a germline NF-PitNETs are usually diagnosed due to the local effects of the tumor, such as bitemporal hemianopia or hypogonadism. It is unclear why these silent tumors do not release hormones at a clinically recognizable level; however, there is likely to be a continuum between fully functional and completely silent PitNETs [ In Larger pituitary tumors may autoinfarct, resulting in pituitary apoplexy (sudden onset of severe headache, visual disturbance, cranial nerve palsies, hypoglycemia, and hypotensive shock). Pituitary apoplexy has been described in individuals with • If acromegaly starts in childhood/adolescence, it can lead to pituitary gigantism. • One third of all individuals with a germline ## Genotype-Phenotype Correlations Individuals with ## Penetrance Studies on large families with ## Nomenclature Previously, pituitary adenoma predisposition (PAP) syndrome was used to refer to individuals who had an ## Prevalence The exact prevalence of ## Genetically Related (Allelic) Disorders Children with biallelic germline pathogenic No phenotypes other than those discussed in this Somatic pathogenic ## Differential Diagnosis In children more often than in adults, pituitary neuroendocrine tumors (PitNETs) may be a manifestation of a genetic condition. PitNETs of genetic origin can be divided into isolated and syndromic categories. FIPA is defined as a hereditary condition associated with PitNETs and no other features of a syndrome known to be associated with these tumors. Families with FIPA of known or unknown cause can have homogeneous PitNET phenotypes (i.e., pituitary tumors of the same type) or heterogeneous phenotypes (i.e., pituitary tumors of different types). Aspects of FIPA that tend to differ between families with or without germline Comparison of Findings in Persons with Isolated PitNETs by Family History and Presence/Absence of a Germline FIPA = familial isolated pituitary adenoma; NA = not applicable Simplex case, a single occurrence in a family Genetic Syndromes Associated with Pituitary Tumors ACTH = adrenocorticotropic hormone; AD = autosomal dominant; GH = growth hormone; MOI = mode of inheritance Reviewed in One individual with Carney complex (<1% of families with Carney complex) had a germline rearrangement resulting in four copies of Hereditary paraganglioma-pheochromocytoma syndromes are also caused by pathogenic variants in Reviewed in Lynch syndrome is also caused by deletions in Note: Autopsy and radiologic studies suggest that 14%-22% of the population may have a PitNET, most of these being asymptomatic [ In addition to PitNETs, numerous space-occupying lesions can occur in the pituitary fossa, including germ cell tumors, hamartomas, Rathke cleft cysts, arachnoid cysts, meningiomas, optic pathway gliomas, sellar lymphomas, metastatic lesions, cavernous sinus venous malformations, aneurysms, and craniopharyngiomas, among others [ ## Familial Isolated Pituitary Adenomas (FIPA) FIPA is defined as a hereditary condition associated with PitNETs and no other features of a syndrome known to be associated with these tumors. Families with FIPA of known or unknown cause can have homogeneous PitNET phenotypes (i.e., pituitary tumors of the same type) or heterogeneous phenotypes (i.e., pituitary tumors of different types). Aspects of FIPA that tend to differ between families with or without germline Comparison of Findings in Persons with Isolated PitNETs by Family History and Presence/Absence of a Germline FIPA = familial isolated pituitary adenoma; NA = not applicable Simplex case, a single occurrence in a family ## Genetic Syndromes Associated with Pituitary Tumors Genetic Syndromes Associated with Pituitary Tumors ACTH = adrenocorticotropic hormone; AD = autosomal dominant; GH = growth hormone; MOI = mode of inheritance Reviewed in One individual with Carney complex (<1% of families with Carney complex) had a germline rearrangement resulting in four copies of Hereditary paraganglioma-pheochromocytoma syndromes are also caused by pathogenic variants in Reviewed in Lynch syndrome is also caused by deletions in Note: Autopsy and radiologic studies suggest that 14%-22% of the population may have a PitNET, most of these being asymptomatic [ ## Other Space-Occupying Lesions In addition to PitNETs, numerous space-occupying lesions can occur in the pituitary fossa, including germ cell tumors, hamartomas, Rathke cleft cysts, arachnoid cysts, meningiomas, optic pathway gliomas, sellar lymphomas, metastatic lesions, cavernous sinus venous malformations, aneurysms, and craniopharyngiomas, among others [ ## Management Recent clinical practice guidelines for pediatric pituitary neuroendocrine tumors (PitNETs), as well as acromegaly and prolactinoma, include management suggestions for hereditary pituitary tumors [ To establish the extent of disease and needs of an individual diagnosed with LH, FSH, testosterone/estradiol Visual field eval Consultation w/endocrinologist Evaluate for signs/symptoms of GH excess (e.g., stature, change in facial appearance, change in shoe size, ↑ ring size, headache, excessive sweating, joint pains, carpal tunnel syndrome). Spot serum GH, IGF-1 Review of serial photographs for acromegalic changes Measurement of parental heights OGTT in persons w/findings of acromegaly ACTH reserve if needed Evaluate for manifestations of prolactin excess (e.g., menstrual history, galactorrhea, infertility, low libido, impotence). Serum prolactin ACTH = adrenocorticotropic hormone; DXA = dual-energy x-ray absorptiometry; FIPA = familial isolated pituitary adenoma; FSH = follicle-stimulating hormone; GH = growth hormone; IGF-1 = insulin-like growth factor 1; LH = luteinizing hormone; OGTT = oral glucose tolerance test; MOI = mode of inheritance; NF = nonfunctioning; PitNET = pituitary neuroendocrine tumor; TSH = thyroid-stimulating hormone Recommendations for treatment for The following recommendations are based on those of Radiotherapy (conventional or radiosurgery) for large tumors, for which repeat surgery is unlikely to control hormone levels Standard treatment of cardiovascular & rheumatologic/orthopedic complications for those w/acromegaly Dopamine agonist therapy (e.g., cabergoline) Surgical treatment often used for macroprolactinoma (diameter >10 mm) GH = growth hormone; NF = nonfunctioning; PitNETs = pituitary neuroendocrine tumors; SRLs = somatostatin receptor ligands No formal guidelines regarding surveillance of persons with Measure height & weight; calculate height velocity. Evaluate for signs/symptoms of PitNET & evaluate pubertal development. Annually from age 4 to 30 yrs; to date, no secreting PitNETs have developed after age 30 in those w/normal findings at age 30 yrs. Blood tests if symptomatic after age 30 yrs Baseline at age 10 yrs unless indicated earlier due to clinical findings Repeat MRI every 5 yrs until age 30 yrs (if clinical & pituitary function tests remain normal) If clinical or biochemical abnormality: MRI can be performed between ages 30 & 50 yrs FSH = follicle-stimulating hormone; IGF-1 = insulin-like growth factor 1; LH = luteinizing hormone; PitNETs = pituitary neuroendocrine tumors; TSH = thyroid-stimulating hormone In children between ages four and ten years, it may be difficult to get annual blood samples. In these cases, monitoring symptoms and growth may be an acceptable alternative, as non-GH-secreting PitNETs before age ten years are rare. Clinical assessment Serum IGF-1, spot GH, prolactin, estradiol/testosterone, LH, FSH, TSH, free thyroxine, morning cortisol If necessary, dynamic testing (e.g., glucose tolerance test, insulin tolerance test) to evaluate for hormone excess or deficiency At age 40 yrs Repeat every 3-10 yrs depending on # of colorectal lesions on initial colonoscopy & IGF-1 levels. DXA = dual-energy x-ray absorptiometry; FSH = follicle-stimulating hormone; GH = growth hormone; IGF-1 = insulin-like growth factor 1; LH = luteinizing hormone; PitNETs = pituitary neuroendocrine tumors; TSH = thyroid-stimulating hormone It is appropriate to clarify the genetic status of all at-risk relatives of an affected individual by molecular genetic testing for the familial Apparently asymptomatic individuals found to be heterozygous for a familial As PitNET surveillance for those at risk for See Pregnancy may increase the size of a growth hormone (GH)-secreting PitNET or a prolactin-secreting PitNET (especially macroadenomas); thus, a pregnant woman with pituitary macroadenoma is at risk of developing visual field defects. In each trimester it is appropriate to inquire about headaches and perform visual field testing. Medical therapies are stopped during pregnancy. See The Genetics of Endocrine Tumours - Familial Isolated Pituitary Adenoma – FIPA study is actively recruiting individuals with FIPA or childhood-onset PitNET ( GH receptor antagonists block the action of endogenous GH, thereby controlling disease manifestations such as headaches, soft tissue enlargement, diabetes mellitus, hypertension, and high insulin-like growth factor 1 (IGF-1) levels. In two individuals with The GH receptor antagonist pegvisomant has been used in at least eight persons with acromegaly and pituitary gigantism and confirmed Search • LH, FSH, testosterone/estradiol • Visual field eval • Consultation w/endocrinologist • Evaluate for signs/symptoms of GH excess (e.g., stature, change in facial appearance, change in shoe size, ↑ ring size, headache, excessive sweating, joint pains, carpal tunnel syndrome). • Spot serum GH, IGF-1 • Review of serial photographs for acromegalic changes • Measurement of parental heights • OGTT in persons w/findings of acromegaly • ACTH reserve if needed • Evaluate for manifestations of prolactin excess (e.g., menstrual history, galactorrhea, infertility, low libido, impotence). • Serum prolactin • Radiotherapy (conventional or radiosurgery) for large tumors, for which repeat surgery is unlikely to control hormone levels • Standard treatment of cardiovascular & rheumatologic/orthopedic complications for those w/acromegaly • Dopamine agonist therapy (e.g., cabergoline) • Surgical treatment often used for macroprolactinoma (diameter >10 mm) • Measure height & weight; calculate height velocity. • Evaluate for signs/symptoms of PitNET & evaluate pubertal development. • Annually from age 4 to 30 yrs; to date, no secreting PitNETs have developed after age 30 in those w/normal findings at age 30 yrs. • Blood tests if symptomatic after age 30 yrs • Baseline at age 10 yrs unless indicated earlier due to clinical findings • Repeat MRI every 5 yrs until age 30 yrs (if clinical & pituitary function tests remain normal) • If clinical or biochemical abnormality: MRI can be performed between ages 30 & 50 yrs • Clinical assessment • Serum IGF-1, spot GH, prolactin, estradiol/testosterone, LH, FSH, TSH, free thyroxine, morning cortisol • If necessary, dynamic testing (e.g., glucose tolerance test, insulin tolerance test) to evaluate for hormone excess or deficiency • At age 40 yrs • Repeat every 3-10 yrs depending on # of colorectal lesions on initial colonoscopy & IGF-1 levels. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with LH, FSH, testosterone/estradiol Visual field eval Consultation w/endocrinologist Evaluate for signs/symptoms of GH excess (e.g., stature, change in facial appearance, change in shoe size, ↑ ring size, headache, excessive sweating, joint pains, carpal tunnel syndrome). Spot serum GH, IGF-1 Review of serial photographs for acromegalic changes Measurement of parental heights OGTT in persons w/findings of acromegaly ACTH reserve if needed Evaluate for manifestations of prolactin excess (e.g., menstrual history, galactorrhea, infertility, low libido, impotence). Serum prolactin ACTH = adrenocorticotropic hormone; DXA = dual-energy x-ray absorptiometry; FIPA = familial isolated pituitary adenoma; FSH = follicle-stimulating hormone; GH = growth hormone; IGF-1 = insulin-like growth factor 1; LH = luteinizing hormone; OGTT = oral glucose tolerance test; MOI = mode of inheritance; NF = nonfunctioning; PitNET = pituitary neuroendocrine tumor; TSH = thyroid-stimulating hormone • LH, FSH, testosterone/estradiol • Visual field eval • Consultation w/endocrinologist • Evaluate for signs/symptoms of GH excess (e.g., stature, change in facial appearance, change in shoe size, ↑ ring size, headache, excessive sweating, joint pains, carpal tunnel syndrome). • Spot serum GH, IGF-1 • Review of serial photographs for acromegalic changes • Measurement of parental heights • OGTT in persons w/findings of acromegaly • ACTH reserve if needed • Evaluate for manifestations of prolactin excess (e.g., menstrual history, galactorrhea, infertility, low libido, impotence). • Serum prolactin ## Treatment of Manifestations Recommendations for treatment for The following recommendations are based on those of Radiotherapy (conventional or radiosurgery) for large tumors, for which repeat surgery is unlikely to control hormone levels Standard treatment of cardiovascular & rheumatologic/orthopedic complications for those w/acromegaly Dopamine agonist therapy (e.g., cabergoline) Surgical treatment often used for macroprolactinoma (diameter >10 mm) GH = growth hormone; NF = nonfunctioning; PitNETs = pituitary neuroendocrine tumors; SRLs = somatostatin receptor ligands • Radiotherapy (conventional or radiosurgery) for large tumors, for which repeat surgery is unlikely to control hormone levels • Standard treatment of cardiovascular & rheumatologic/orthopedic complications for those w/acromegaly • Dopamine agonist therapy (e.g., cabergoline) • Surgical treatment often used for macroprolactinoma (diameter >10 mm) ## Surveillance No formal guidelines regarding surveillance of persons with Measure height & weight; calculate height velocity. Evaluate for signs/symptoms of PitNET & evaluate pubertal development. Annually from age 4 to 30 yrs; to date, no secreting PitNETs have developed after age 30 in those w/normal findings at age 30 yrs. Blood tests if symptomatic after age 30 yrs Baseline at age 10 yrs unless indicated earlier due to clinical findings Repeat MRI every 5 yrs until age 30 yrs (if clinical & pituitary function tests remain normal) If clinical or biochemical abnormality: MRI can be performed between ages 30 & 50 yrs FSH = follicle-stimulating hormone; IGF-1 = insulin-like growth factor 1; LH = luteinizing hormone; PitNETs = pituitary neuroendocrine tumors; TSH = thyroid-stimulating hormone In children between ages four and ten years, it may be difficult to get annual blood samples. In these cases, monitoring symptoms and growth may be an acceptable alternative, as non-GH-secreting PitNETs before age ten years are rare. Clinical assessment Serum IGF-1, spot GH, prolactin, estradiol/testosterone, LH, FSH, TSH, free thyroxine, morning cortisol If necessary, dynamic testing (e.g., glucose tolerance test, insulin tolerance test) to evaluate for hormone excess or deficiency At age 40 yrs Repeat every 3-10 yrs depending on # of colorectal lesions on initial colonoscopy & IGF-1 levels. DXA = dual-energy x-ray absorptiometry; FSH = follicle-stimulating hormone; GH = growth hormone; IGF-1 = insulin-like growth factor 1; LH = luteinizing hormone; PitNETs = pituitary neuroendocrine tumors; TSH = thyroid-stimulating hormone • Measure height & weight; calculate height velocity. • Evaluate for signs/symptoms of PitNET & evaluate pubertal development. • Annually from age 4 to 30 yrs; to date, no secreting PitNETs have developed after age 30 in those w/normal findings at age 30 yrs. • Blood tests if symptomatic after age 30 yrs • Baseline at age 10 yrs unless indicated earlier due to clinical findings • Repeat MRI every 5 yrs until age 30 yrs (if clinical & pituitary function tests remain normal) • If clinical or biochemical abnormality: MRI can be performed between ages 30 & 50 yrs • Clinical assessment • Serum IGF-1, spot GH, prolactin, estradiol/testosterone, LH, FSH, TSH, free thyroxine, morning cortisol • If necessary, dynamic testing (e.g., glucose tolerance test, insulin tolerance test) to evaluate for hormone excess or deficiency • At age 40 yrs • Repeat every 3-10 yrs depending on # of colorectal lesions on initial colonoscopy & IGF-1 levels. ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of all at-risk relatives of an affected individual by molecular genetic testing for the familial Apparently asymptomatic individuals found to be heterozygous for a familial As PitNET surveillance for those at risk for See ## Pregnancy Management Pregnancy may increase the size of a growth hormone (GH)-secreting PitNET or a prolactin-secreting PitNET (especially macroadenomas); thus, a pregnant woman with pituitary macroadenoma is at risk of developing visual field defects. In each trimester it is appropriate to inquire about headaches and perform visual field testing. Medical therapies are stopped during pregnancy. See ## Therapies Under Investigation The Genetics of Endocrine Tumours - Familial Isolated Pituitary Adenoma – FIPA study is actively recruiting individuals with FIPA or childhood-onset PitNET ( GH receptor antagonists block the action of endogenous GH, thereby controlling disease manifestations such as headaches, soft tissue enlargement, diabetes mellitus, hypertension, and high insulin-like growth factor 1 (IGF-1) levels. In two individuals with The GH receptor antagonist pegvisomant has been used in at least eight persons with acromegaly and pituitary gigantism and confirmed Search ## Genetic Counseling Almost all individuals reported to date with Reports of unequivocally 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 assess their need for PitNET surveillance. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members due to a milder phenotypic presentation or reduced penetrance. 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 or is known to have the If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [ If the parents have not been tested for the 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 use of prenatal and preimplantation genetic testing is a personal decision, discussion of these issues may be helpful. • Almost all individuals reported to date with • Reports of unequivocally • 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 assess their need for PitNET surveillance. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members due to a milder phenotypic presentation or reduced penetrance. 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 or is known to have the • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [ • If the parents have not been tested for the • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is 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 Almost all individuals reported to date with Reports of unequivocally 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 assess their need for PitNET surveillance. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members due to a milder phenotypic presentation or reduced penetrance. 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 or is known to have the If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [ If the parents have not been tested for the • Almost all individuals reported to date with • Reports of unequivocally • 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 assess their need for PitNET surveillance. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members due to a milder phenotypic presentation or reduced penetrance. 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 or is known to have the • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [ • If the parents have not been tested for the ## 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 use of prenatal and preimplantation genetic testing is a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom Association for Multiple Endocrine Neoplasia Disorders United Kingdom • • United Kingdom • • • Association for Multiple Endocrine Neoplasia Disorders • United Kingdom • • • • ## Molecular Genetics AIP Familial Isolated Pituitary Adenomas : Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for AIP Familial Isolated Pituitary Adenomas ( The majority (75%) of Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis The majority (75%) of Variants listed in the table have been provided by the authors. ## Chapter Notes Website: The FIPA Patients website, established by Dr Korbonits in collaboration with the The authors welcome comments and inquiries: We are grateful to referring colleagues and patients for providing information on this disease. Our research is supported by departmental funding from the Coordination of Scientific Research from the National Autonomous University of Mexico (UNAM), and grants from UNAM's Support Program for Research Projects and Technological, the Mexican Society of Nutrition and Endocrinology, and the United Kingdom's Society for Endocrinology as well as UK's Medical Research Council, Barts Charity, and the Rosehills Trust. Márta Korbonits, MD, PhD (2012-present)Ajith V Kumar, MD; Great Ormond Street Hospital (2012-2025)Laura C Hernández-Ramírez, MD, PhD (2025-present) 16 January 2025 (sw) Comprehensive update posted live 16 April 2020 (sw) Comprehensive update posted live 21 June 2012 (me) Review posted live 3 February 2011 (mk) Original submission • 16 January 2025 (sw) Comprehensive update posted live • 16 April 2020 (sw) Comprehensive update posted live • 21 June 2012 (me) Review posted live • 3 February 2011 (mk) Original submission ## Author Notes Website: The FIPA Patients website, established by Dr Korbonits in collaboration with the The authors welcome comments and inquiries: ## Acknowledgments We are grateful to referring colleagues and patients for providing information on this disease. Our research is supported by departmental funding from the Coordination of Scientific Research from the National Autonomous University of Mexico (UNAM), and grants from UNAM's Support Program for Research Projects and Technological, the Mexican Society of Nutrition and Endocrinology, and the United Kingdom's Society for Endocrinology as well as UK's Medical Research Council, Barts Charity, and the Rosehills Trust. ## Author History Márta Korbonits, MD, PhD (2012-present)Ajith V Kumar, MD; Great Ormond Street Hospital (2012-2025)Laura C Hernández-Ramírez, MD, PhD (2025-present) ## Revision History 16 January 2025 (sw) Comprehensive update posted live 16 April 2020 (sw) Comprehensive update posted live 21 June 2012 (me) Review posted live 3 February 2011 (mk) Original submission • 16 January 2025 (sw) Comprehensive update posted live • 16 April 2020 (sw) Comprehensive update posted live • 21 June 2012 (me) Review posted live • 3 February 2011 (mk) Original submission ## References Giustina A, Barkan A, Beckers A, Biermasz N, Biller BMK, Boguszewski C, Bolanowski M, Bonert V, Bronstein MD, Casanueva FF, Clemmons D, Colao A, Ferone D, Fleseriu M, Frara S, Gadelha MR, Ghigo E, Gurnell M, Heaney AP, Ho K, Ioachimescu A, Katznelson L, Kelestimur F, Kopchick J, Krsek M, Lamberts S, Losa M, Luger A, Maffei P, Marazuela M, Mazziotti G, Mercado M, Mortini P, Neggers S, Pereira AM, Petersenn S, Puig-Domingo M, Salvatori R, Shimon I, Strasburger C, Tsagarakis S, van der Lely AJ, Wass J, Zatelli MC, Melmed S. A consensus on the diagnosis and treatment of acromegaly comorbidities: an update. J Clin Endocrinol Metab. 2020;105:dgz096. [ Giustina A, Biermasz N, Casanueva FF, Fleseriu M, Mortini P, Strasburger C, van der Lely AJ, Wass J, Melmed S; Acromegaly Consensus G. Consensus on criteria for acromegaly diagnosis and remission. Pituitary. 2024;27:7-22. [ Katznelson L, Laws ER, Jr., Melmed S, Molitch ME, Murad MH, Utz A, Wass JA, Endocrine S. Acromegaly: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99:3933-51. [ Korbonits M, Blair JC, Boguslawska A, Ayuk J, Davies JH, Druce MR, Evanson J, Flanagan D, Glynn N, Higham CE, Jacques TS, Sinha S, Simmons I, Thorp N, Swords FM, Storr HL, Spoudeas HA. Consensus guideline for the diagnosis and management of pituitary adenomas in childhood and adolescence: part 1, general recommendations. Nat Rev Endocrinol. 2024a;20:278-89. [ Korbonits M, Blair JC, Boguslawska A, Ayuk J, Davies JH, Druce MR, Evanson J, Flanagan D, Glynn N, Higham CE, Jacques TS, Sinha S, Simmons I, Thorp N, Swords FM, Storr HL, Spoudeas HA. Consensus guideline for the diagnosis and management of pituitary adenomas in childhood and adolescence: part 2, specific diseases. Nat Rev Endocrinol. 2024b;20:290-309. [ Petersenn S, Fleseriu M, Casanueva FF, Giustina A, Biermasz N, Biller BMK, Bronstein M, Chanson P, Fukuoka H, Gadelha M, Greenman Y, Gurnell M, Ho KKY, Honegger J, Ioachimescu AG, Kaiser UB, Karavitaki N, Katznelson L, Lodish M, Maiter D, Marcus HJ, McCormack A, Molitch M, Muir CA, Neggers S, Pereira AM, Pivonello R, Post K, Raverot G, Salvatori R, Samson SL, Shimon I, Spencer-Segal J, Vila G, Wass J, Melmed S. Diagnosis and management of prolactin-secreting pituitary adenomas: a Pituitary Society international Consensus Statement. Nat Rev Endocrinol. 2023;19:722-40. [ • Giustina A, Barkan A, Beckers A, Biermasz N, Biller BMK, Boguszewski C, Bolanowski M, Bonert V, Bronstein MD, Casanueva FF, Clemmons D, Colao A, Ferone D, Fleseriu M, Frara S, Gadelha MR, Ghigo E, Gurnell M, Heaney AP, Ho K, Ioachimescu A, Katznelson L, Kelestimur F, Kopchick J, Krsek M, Lamberts S, Losa M, Luger A, Maffei P, Marazuela M, Mazziotti G, Mercado M, Mortini P, Neggers S, Pereira AM, Petersenn S, Puig-Domingo M, Salvatori R, Shimon I, Strasburger C, Tsagarakis S, van der Lely AJ, Wass J, Zatelli MC, Melmed S. A consensus on the diagnosis and treatment of acromegaly comorbidities: an update. J Clin Endocrinol Metab. 2020;105:dgz096. [ • Giustina A, Biermasz N, Casanueva FF, Fleseriu M, Mortini P, Strasburger C, van der Lely AJ, Wass J, Melmed S; Acromegaly Consensus G. Consensus on criteria for acromegaly diagnosis and remission. Pituitary. 2024;27:7-22. [ • Katznelson L, Laws ER, Jr., Melmed S, Molitch ME, Murad MH, Utz A, Wass JA, Endocrine S. Acromegaly: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99:3933-51. [ • Korbonits M, Blair JC, Boguslawska A, Ayuk J, Davies JH, Druce MR, Evanson J, Flanagan D, Glynn N, Higham CE, Jacques TS, Sinha S, Simmons I, Thorp N, Swords FM, Storr HL, Spoudeas HA. Consensus guideline for the diagnosis and management of pituitary adenomas in childhood and adolescence: part 1, general recommendations. Nat Rev Endocrinol. 2024a;20:278-89. [ • Korbonits M, Blair JC, Boguslawska A, Ayuk J, Davies JH, Druce MR, Evanson J, Flanagan D, Glynn N, Higham CE, Jacques TS, Sinha S, Simmons I, Thorp N, Swords FM, Storr HL, Spoudeas HA. Consensus guideline for the diagnosis and management of pituitary adenomas in childhood and adolescence: part 2, specific diseases. Nat Rev Endocrinol. 2024b;20:290-309. [ • Petersenn S, Fleseriu M, Casanueva FF, Giustina A, Biermasz N, Biller BMK, Bronstein M, Chanson P, Fukuoka H, Gadelha M, Greenman Y, Gurnell M, Ho KKY, Honegger J, Ioachimescu AG, Kaiser UB, Karavitaki N, Katznelson L, Lodish M, Maiter D, Marcus HJ, McCormack A, Molitch M, Muir CA, Neggers S, Pereira AM, Pivonello R, Post K, Raverot G, Salvatori R, Samson SL, Shimon I, Spencer-Segal J, Vila G, Wass J, Melmed S. Diagnosis and management of prolactin-secreting pituitary adenomas: a Pituitary Society international Consensus Statement. Nat Rev Endocrinol. 2023;19:722-40. [ ## Published Guidelines / Consensus Statements Giustina A, Barkan A, Beckers A, Biermasz N, Biller BMK, Boguszewski C, Bolanowski M, Bonert V, Bronstein MD, Casanueva FF, Clemmons D, Colao A, Ferone D, Fleseriu M, Frara S, Gadelha MR, Ghigo E, Gurnell M, Heaney AP, Ho K, Ioachimescu A, Katznelson L, Kelestimur F, Kopchick J, Krsek M, Lamberts S, Losa M, Luger A, Maffei P, Marazuela M, Mazziotti G, Mercado M, Mortini P, Neggers S, Pereira AM, Petersenn S, Puig-Domingo M, Salvatori R, Shimon I, Strasburger C, Tsagarakis S, van der Lely AJ, Wass J, Zatelli MC, Melmed S. A consensus on the diagnosis and treatment of acromegaly comorbidities: an update. J Clin Endocrinol Metab. 2020;105:dgz096. [ Giustina A, Biermasz N, Casanueva FF, Fleseriu M, Mortini P, Strasburger C, van der Lely AJ, Wass J, Melmed S; Acromegaly Consensus G. Consensus on criteria for acromegaly diagnosis and remission. Pituitary. 2024;27:7-22. [ Katznelson L, Laws ER, Jr., Melmed S, Molitch ME, Murad MH, Utz A, Wass JA, Endocrine S. Acromegaly: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99:3933-51. [ Korbonits M, Blair JC, Boguslawska A, Ayuk J, Davies JH, Druce MR, Evanson J, Flanagan D, Glynn N, Higham CE, Jacques TS, Sinha S, Simmons I, Thorp N, Swords FM, Storr HL, Spoudeas HA. Consensus guideline for the diagnosis and management of pituitary adenomas in childhood and adolescence: part 1, general recommendations. Nat Rev Endocrinol. 2024a;20:278-89. [ Korbonits M, Blair JC, Boguslawska A, Ayuk J, Davies JH, Druce MR, Evanson J, Flanagan D, Glynn N, Higham CE, Jacques TS, Sinha S, Simmons I, Thorp N, Swords FM, Storr HL, Spoudeas HA. Consensus guideline for the diagnosis and management of pituitary adenomas in childhood and adolescence: part 2, specific diseases. Nat Rev Endocrinol. 2024b;20:290-309. [ Petersenn S, Fleseriu M, Casanueva FF, Giustina A, Biermasz N, Biller BMK, Bronstein M, Chanson P, Fukuoka H, Gadelha M, Greenman Y, Gurnell M, Ho KKY, Honegger J, Ioachimescu AG, Kaiser UB, Karavitaki N, Katznelson L, Lodish M, Maiter D, Marcus HJ, McCormack A, Molitch M, Muir CA, Neggers S, Pereira AM, Pivonello R, Post K, Raverot G, Salvatori R, Samson SL, Shimon I, Spencer-Segal J, Vila G, Wass J, Melmed S. Diagnosis and management of prolactin-secreting pituitary adenomas: a Pituitary Society international Consensus Statement. Nat Rev Endocrinol. 2023;19:722-40. [ • Giustina A, Barkan A, Beckers A, Biermasz N, Biller BMK, Boguszewski C, Bolanowski M, Bonert V, Bronstein MD, Casanueva FF, Clemmons D, Colao A, Ferone D, Fleseriu M, Frara S, Gadelha MR, Ghigo E, Gurnell M, Heaney AP, Ho K, Ioachimescu A, Katznelson L, Kelestimur F, Kopchick J, Krsek M, Lamberts S, Losa M, Luger A, Maffei P, Marazuela M, Mazziotti G, Mercado M, Mortini P, Neggers S, Pereira AM, Petersenn S, Puig-Domingo M, Salvatori R, Shimon I, Strasburger C, Tsagarakis S, van der Lely AJ, Wass J, Zatelli MC, Melmed S. A consensus on the diagnosis and treatment of acromegaly comorbidities: an update. J Clin Endocrinol Metab. 2020;105:dgz096. [ • Giustina A, Biermasz N, Casanueva FF, Fleseriu M, Mortini P, Strasburger C, van der Lely AJ, Wass J, Melmed S; Acromegaly Consensus G. Consensus on criteria for acromegaly diagnosis and remission. Pituitary. 2024;27:7-22. [ • Katznelson L, Laws ER, Jr., Melmed S, Molitch ME, Murad MH, Utz A, Wass JA, Endocrine S. Acromegaly: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99:3933-51. [ • Korbonits M, Blair JC, Boguslawska A, Ayuk J, Davies JH, Druce MR, Evanson J, Flanagan D, Glynn N, Higham CE, Jacques TS, Sinha S, Simmons I, Thorp N, Swords FM, Storr HL, Spoudeas HA. Consensus guideline for the diagnosis and management of pituitary adenomas in childhood and adolescence: part 1, general recommendations. Nat Rev Endocrinol. 2024a;20:278-89. [ • Korbonits M, Blair JC, Boguslawska A, Ayuk J, Davies JH, Druce MR, Evanson J, Flanagan D, Glynn N, Higham CE, Jacques TS, Sinha S, Simmons I, Thorp N, Swords FM, Storr HL, Spoudeas HA. Consensus guideline for the diagnosis and management of pituitary adenomas in childhood and adolescence: part 2, specific diseases. Nat Rev Endocrinol. 2024b;20:290-309. [ • Petersenn S, Fleseriu M, Casanueva FF, Giustina A, Biermasz N, Biller BMK, Bronstein M, Chanson P, Fukuoka H, Gadelha M, Greenman Y, Gurnell M, Ho KKY, Honegger J, Ioachimescu AG, Kaiser UB, Karavitaki N, Katznelson L, Lodish M, Maiter D, Marcus HJ, McCormack A, Molitch M, Muir CA, Neggers S, Pereira AM, Pivonello R, Post K, Raverot G, Salvatori R, Samson SL, Shimon I, Spencer-Segal J, Vila G, Wass J, Melmed S. Diagnosis and management of prolactin-secreting pituitary adenomas: a Pituitary Society international Consensus Statement. Nat Rev Endocrinol. 2023;19:722-40. [ ## Literature Cited	[]	21/6/2012	16/1/2025		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
ipex	ipex	[ "Immunodeficiency, Polyendocrinopathy, and Enteropathy X-Linked Syndrome", "Immunodeficiency, Polyendocrinopathy, and Enteropathy X-Linked Syndrome", "Forkhead box protein P3", "FOXP3", "IPEX Syndrome" ]	IPEX Syndrome	Queenie K-G Tan, Raymond J Louie, John W Sleasman	Summary IPEX ( The diagnosis is established in a male proband with typical clinical findings, absent regulatory T cells (Treg) in blood or tissues, decreased numbers of FOXP3-expressing T cells in peripheral blood determined by flow cytometry (although FOXP3 levels in Treg can be normal in some individuals), and a hemizygous pathogenic variant in IPEX syndrome is inherited in an X-linked manner. The risk to sibs of the proband depends on the genetic status of the mother. If the mother of the proband has a	## Diagnosis The term "IPEX" is an acronym for IPEX syndrome Elevated serum concentration of immunoglobulin E (IgE), and in some individuals elevated serum concentration of IgA Eosinophilia Autoimmune anemia, thrombocytopenia, and/or neutropenia Autoantibodies to pancreatic islet antigens, thyroid antigens, small bowel mucosa, and other autoantigens Decreased numbers of FOXP3-expressing T cells in peripheral blood determined by flow cytometry – although FOXP3 levels in regulatory T cells (Treg) can be normal in some individuals Note: Standard lymphocyte enumeration of T cells, B cells, and NK cells as well as T cell function measured by mitogen proliferation is generally normal and not helpful for 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 Note: Pathogenic variants have been reported in the 5' UTR ( For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in IPEX 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. A deletion of the noncoding exon 1 has been reported [ • Elevated serum concentration of immunoglobulin E (IgE), and in some individuals elevated serum concentration of IgA • Eosinophilia • Autoimmune anemia, thrombocytopenia, and/or neutropenia • Autoantibodies to pancreatic islet antigens, thyroid antigens, small bowel mucosa, and other autoantigens • Decreased numbers of FOXP3-expressing T cells in peripheral blood determined by flow cytometry – although FOXP3 levels in regulatory T cells (Treg) can be normal in some individuals ## Suggestive Findings IPEX syndrome Elevated serum concentration of immunoglobulin E (IgE), and in some individuals elevated serum concentration of IgA Eosinophilia Autoimmune anemia, thrombocytopenia, and/or neutropenia Autoantibodies to pancreatic islet antigens, thyroid antigens, small bowel mucosa, and other autoantigens Decreased numbers of FOXP3-expressing T cells in peripheral blood determined by flow cytometry – although FOXP3 levels in regulatory T cells (Treg) can be normal in some individuals Note: Standard lymphocyte enumeration of T cells, B cells, and NK cells as well as T cell function measured by mitogen proliferation is generally normal and not helpful for diagnosis. • Elevated serum concentration of immunoglobulin E (IgE), and in some individuals elevated serum concentration of IgA • Eosinophilia • Autoimmune anemia, thrombocytopenia, and/or neutropenia • Autoantibodies to pancreatic islet antigens, thyroid antigens, small bowel mucosa, and other autoantigens • Decreased numbers of FOXP3-expressing T cells in peripheral blood determined by flow cytometry – although FOXP3 levels in regulatory T cells (Treg) can be normal in some individuals ## 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 Note: Pathogenic variants have been reported in the 5' UTR ( For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in IPEX 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. A deletion of the noncoding exon 1 has been reported [ ## Option 1 Note: Pathogenic variants have been reported in the 5' UTR ( For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in IPEX 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. A deletion of the noncoding exon 1 has been reported [ ## Clinical Characteristics IPEX syndrome is generally considered to be a syndrome of neonatal enteropathy [ Early hematopoietic stem cell transplantation (HSCT) can cure IPEX syndrome; some survivors are now more than ten years post transplant and doing well. If individuals develop diabetes or thyroiditis prior to HSCT, these aspects of the disorder usually persist, but the other signs of IPEX syndrome resolve. Survival and long-term outcomes are improved if HSCT occurs at an earlier age, prior to the individual developing irreversible organ damage related to the extensive, systemic autoimmunity present in virtually all individuals with IPEX syndrome [ Heterozygous females have not been reported to have IPEX syndrome. Note: Recurrent miscarriage of male fetuses, including fetal hydrops and abnormal findings on fetal ultrasound, have been reported and are associated with fetal rather than maternal factors [ There are currently no genotype-phenotype correlations. The same genotype can present with variable severity in different individuals, even within the same family [ IPEX syndrome may also be referred to as X-linked autoimmunity-allergic dysregulation (XLAAD) syndrome or X-linked syndrome of polyendocrinopathy, immune dysfunction, and diarrhea (XPID). IPEX syndrome is rare: fewer than 300 affected individuals have been identified worldwide. No accurate estimates of prevalence have been published. ## Clinical Description IPEX syndrome is generally considered to be a syndrome of neonatal enteropathy [ Early hematopoietic stem cell transplantation (HSCT) can cure IPEX syndrome; some survivors are now more than ten years post transplant and doing well. If individuals develop diabetes or thyroiditis prior to HSCT, these aspects of the disorder usually persist, but the other signs of IPEX syndrome resolve. Survival and long-term outcomes are improved if HSCT occurs at an earlier age, prior to the individual developing irreversible organ damage related to the extensive, systemic autoimmunity present in virtually all individuals with IPEX syndrome [ Heterozygous females have not been reported to have IPEX syndrome. Note: Recurrent miscarriage of male fetuses, including fetal hydrops and abnormal findings on fetal ultrasound, have been reported and are associated with fetal rather than maternal factors [ ## Males IPEX syndrome is generally considered to be a syndrome of neonatal enteropathy [ Early hematopoietic stem cell transplantation (HSCT) can cure IPEX syndrome; some survivors are now more than ten years post transplant and doing well. If individuals develop diabetes or thyroiditis prior to HSCT, these aspects of the disorder usually persist, but the other signs of IPEX syndrome resolve. Survival and long-term outcomes are improved if HSCT occurs at an earlier age, prior to the individual developing irreversible organ damage related to the extensive, systemic autoimmunity present in virtually all individuals with IPEX syndrome [ ## Heterozygous Females Heterozygous females have not been reported to have IPEX syndrome. Note: Recurrent miscarriage of male fetuses, including fetal hydrops and abnormal findings on fetal ultrasound, have been reported and are associated with fetal rather than maternal factors [ ## Genotype-Phenotype Correlations There are currently no genotype-phenotype correlations. The same genotype can present with variable severity in different individuals, even within the same family [ ## Nomenclature IPEX syndrome may also be referred to as X-linked autoimmunity-allergic dysregulation (XLAAD) syndrome or X-linked syndrome of polyendocrinopathy, immune dysfunction, and diarrhea (XPID). ## Prevalence IPEX syndrome is rare: fewer than 300 affected individuals have been identified worldwide. No accurate estimates of prevalence have been published. ## Genetically Related (Allelic) Disorders No other phenotypes other than those discussed in this ## Differential Diagnosis IPEX syndrome is classified by the International Union of Immunological Societies (IUIS) as an inborn error of immunity that results in immune dysregulation due to absent or defective regulatory T cells (Treg) [ In addition to immune dysregulation disorders, monogenic forms of neonatal diabetes that are clinically evident soon after birth can present similarly to IPEX syndrome. These conditions are most commonly associated with pancreatic defects and lack autoimmune manifestations [ See Syndromes of Known Genetic Cause to Consider in the Differential Diagnosis of IPEX Syndrome Low Treg numbers, immune deficiency, & autoimmune disease Distinguished from IPEX syndrome by low B cell numbers Identified in 3 persons w/IPEX syndrome-like clinical phenotype. In addition to autoimmunity, however, these persons had features of severe cellular immunodeficiency w/susceptibility to severe cytomegalovirus infections. Distinguished from IPEX syndrome by normal IgE & absence of CD25 expression on T cells Enteropathy, type 1 diabetes mellitus, autoimmune cytopenias Distinguished from IPEX syndrome by short stature Low T & NK cell numbers Distinguished from IPEX syndrome by dwarfism & GH resistance Endocrinopathy, enteropathy Distinguished from IPEX syndrome by chronic mucocutaneous candidiasis & ectodermal dysplasia (dental enamel hypoplasia, keratopathy) Type I diabetes mellitus, thyroiditis, enteropathy Distinguished from IPEX syndrome by facial dysmorphisms Enteropathy Distinguished from IPEX syndrome by intestinal atresias (variably present) AD = autosomal dominant; AR = autosomal recessive; GH = growth hormone; GOF = gain of function; Ig = immunoglobulin; IL = Interleukin; MOI = mode of inheritance; Treg = regulatory T cell(s); XL = X-linked Individuals with STAT5B deficiency also have a form of dwarfism related to the fact that growth hormone mediates its effects through STAT5. Inheritance of autoimmune lymphoproliferative syndrome (ALPS)-CASP10, most instances of ALPS-FAS, and some instances of ALPS-FASLG is autosomal dominant. ALPS-FAS can also be the result of somatic mosaicism. Somatic pathogenic variants have not been reported in ALPS-FASLG or ALPS-CASP10 to date. Omenn syndrome is also known as familial reticuloendotheliosis with eosinophilia or severe combined immunodeficiency (SCID) with hypereosinophilia. The mode of inheritance of permanent neonatal diabetes mellitus (PNDM) is autosomal dominant for See Pancreatic beta cell agenesis with neonatal diabetes mellitus (OMIM Autoimmune polyendocrine syndrome, type II (OMIM • Low Treg numbers, immune deficiency, & autoimmune disease • Distinguished from IPEX syndrome by low B cell numbers • Identified in 3 persons w/IPEX syndrome-like clinical phenotype. In addition to autoimmunity, however, these persons had features of severe cellular immunodeficiency w/susceptibility to severe cytomegalovirus infections. • Distinguished from IPEX syndrome by normal IgE & absence of CD25 expression on T cells • Enteropathy, type 1 diabetes mellitus, autoimmune cytopenias • Distinguished from IPEX syndrome by short stature • Low T & NK cell numbers • Distinguished from IPEX syndrome by dwarfism & GH resistance • Endocrinopathy, enteropathy • Distinguished from IPEX syndrome by chronic mucocutaneous candidiasis & ectodermal dysplasia (dental enamel hypoplasia, keratopathy) • Type I diabetes mellitus, thyroiditis, enteropathy • Distinguished from IPEX syndrome by facial dysmorphisms • Enteropathy • Distinguished from IPEX syndrome by intestinal atresias (variably present) • Pancreatic beta cell agenesis with neonatal diabetes mellitus (OMIM • Autoimmune polyendocrine syndrome, type II (OMIM ## Management To establish the extent of disease in an individual diagnosed with IPEX syndrome, the evaluations summarized in IPEX Syndrome: Recommended Evaluations Following Initial Diagnosis Glucose tolerance test Hemoglobin A1c Thyroid function tests Autoantibodies to pancreatic islet antigens & thyroid antigens Serum IgG, IgM, IgA, & IgE concentrations Lymphocyte enumeration by flow cytometry Lymphocyte response to mitogens Complete blood count & differential Coombs test Eval of autoimmune hypercoagulability (anti-phospholipid antibodies, lupus anticoagulant) BUN, creatinine Urinalysis Community or Social work involvement for parental support Home nursing referral ALT = alanine transferase; AST = aspartate transferase; BUN = blood urea nitrogen; GGT = gamma-glutamyl transferase; HSCT = hematopoietic stem cell transplantation; Ig = immunoglobulin; MOI = mode of inheritance; TPN = total parenteral nutrition; Treg = regulatory T cell(s) 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 IPEX Syndrome: Treatment of Manifestations T cell-directed immune suppression (i.e., sirolimus, cyclosporin A, or tacrolimus), either alone or in combination w/steroids Sirolimus (rapamycin) as monotherapy or in combination w/other drugs Toxicity, tachyphylaxis, & ↑ susceptibility to infection related to chronic use of these agents reduce their potential for long-term amelioration of symptoms in most persons. Sirolimus & tacrolimus are nephrotoxic & require close renal monitoring & plasma drug levels. Sirolimus has been used successfully in persons for whom tacrolimus was either ineffective or toxic. The ability of sirolimus to suppress effector T cell function while allowing Treg cells to continue to develop & function offers some theoretic advantages for its use. Standard treatment of type 1 insulin-dependent diabetes mellitus w/insulin & carbohydrate mgmt Standard treatment of autoimmune thyroid disease Systemic T cell-directed immune suppression Topical therapies (e.g., steroids, tacrolimus, emollients) can also be beneficial. For autoimmune neutropenia: G-CSF can improve neutrophil counts. For pemphigus nodularis & other autoantibody-mediated disease: rituximab has been effective. . Persons w/autoimmune neutropenia or recurrent infections due to severe eczema may benefit from prophylactic antibiotic therapy to ↓ risk of severe infectious complications. Aggressive mgmt of dermatitis w/topical steroids & anti-inflammatory agents can help prevent infections from pathogens that enter as a result of the poor barrier function of the skin. Standard antimicrobial therapy when indicated G-CSF = granulocyte colony-stimulating factor; TPN = total parenteral nutrition; Treg = regulatory T cell(s) To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in IPEX Syndrome: Recommended Surveillance Glucose tolerance test Hemoglobin A1c Thyroid function tests Complete blood count BUN, creatinine Urinalysis Serum AST, ALT ALT = alanine transferase; AST = aspartate transferase; BUN = blood urea nitrogen Immune activation (e.g., by immunizations or severe infections) has been reported to cause worsening or exacerbation of disease symptoms [ It is appropriate to clarify the genetic status of at-risk males either prenatally or immediately after birth to enable early diagnosis and HSCT and/or steroid treatment in affected males before significant organ damage occurs. See HSCT carries the risk of significant morbidity and mortality, and suitable donors are not always available. For these and other reasons, IPEX syndrome is an excellent candidate for treatment with gene therapy. However, one major hurdle is the need to regulate the expression of Search • Glucose tolerance test • Hemoglobin A1c • Thyroid function tests • Autoantibodies to pancreatic islet antigens & thyroid antigens • Serum IgG, IgM, IgA, & IgE concentrations • Lymphocyte enumeration by flow cytometry • Lymphocyte response to mitogens • Complete blood count & differential • Coombs test • Eval of autoimmune hypercoagulability (anti-phospholipid antibodies, lupus anticoagulant) • BUN, creatinine • Urinalysis • Community or • Social work involvement for parental support • Home nursing referral • T cell-directed immune suppression (i.e., sirolimus, cyclosporin A, or tacrolimus), either alone or in combination w/steroids • Sirolimus (rapamycin) as monotherapy or in combination w/other drugs • Toxicity, tachyphylaxis, & ↑ susceptibility to infection related to chronic use of these agents reduce their potential for long-term amelioration of symptoms in most persons. • Sirolimus & tacrolimus are nephrotoxic & require close renal monitoring & plasma drug levels. • Sirolimus has been used successfully in persons for whom tacrolimus was either ineffective or toxic. • The ability of sirolimus to suppress effector T cell function while allowing Treg cells to continue to develop & function offers some theoretic advantages for its use. • Standard treatment of type 1 insulin-dependent diabetes mellitus w/insulin & carbohydrate mgmt • Standard treatment of autoimmune thyroid disease • Systemic T cell-directed immune suppression • Topical therapies (e.g., steroids, tacrolimus, emollients) can also be beneficial. • For autoimmune neutropenia: G-CSF can improve neutrophil counts. • For pemphigus nodularis & other autoantibody-mediated disease: rituximab has been effective. . • Persons w/autoimmune neutropenia or recurrent infections due to severe eczema may benefit from prophylactic antibiotic therapy to ↓ risk of severe infectious complications. • Aggressive mgmt of dermatitis w/topical steroids & anti-inflammatory agents can help prevent infections from pathogens that enter as a result of the poor barrier function of the skin. • Standard antimicrobial therapy when indicated • Glucose tolerance test • Hemoglobin A1c • Thyroid function tests • Complete blood count • BUN, creatinine • Urinalysis • Serum AST, ALT ## Evaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with IPEX syndrome, the evaluations summarized in IPEX Syndrome: Recommended Evaluations Following Initial Diagnosis Glucose tolerance test Hemoglobin A1c Thyroid function tests Autoantibodies to pancreatic islet antigens & thyroid antigens Serum IgG, IgM, IgA, & IgE concentrations Lymphocyte enumeration by flow cytometry Lymphocyte response to mitogens Complete blood count & differential Coombs test Eval of autoimmune hypercoagulability (anti-phospholipid antibodies, lupus anticoagulant) BUN, creatinine Urinalysis Community or Social work involvement for parental support Home nursing referral ALT = alanine transferase; AST = aspartate transferase; BUN = blood urea nitrogen; GGT = gamma-glutamyl transferase; HSCT = hematopoietic stem cell transplantation; Ig = immunoglobulin; MOI = mode of inheritance; TPN = total parenteral nutrition; Treg = regulatory T cell(s) Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Glucose tolerance test • Hemoglobin A1c • Thyroid function tests • Autoantibodies to pancreatic islet antigens & thyroid antigens • Serum IgG, IgM, IgA, & IgE concentrations • Lymphocyte enumeration by flow cytometry • Lymphocyte response to mitogens • Complete blood count & differential • Coombs test • Eval of autoimmune hypercoagulability (anti-phospholipid antibodies, lupus anticoagulant) • BUN, creatinine • Urinalysis • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see IPEX Syndrome: Treatment of Manifestations T cell-directed immune suppression (i.e., sirolimus, cyclosporin A, or tacrolimus), either alone or in combination w/steroids Sirolimus (rapamycin) as monotherapy or in combination w/other drugs Toxicity, tachyphylaxis, & ↑ susceptibility to infection related to chronic use of these agents reduce their potential for long-term amelioration of symptoms in most persons. Sirolimus & tacrolimus are nephrotoxic & require close renal monitoring & plasma drug levels. Sirolimus has been used successfully in persons for whom tacrolimus was either ineffective or toxic. The ability of sirolimus to suppress effector T cell function while allowing Treg cells to continue to develop & function offers some theoretic advantages for its use. Standard treatment of type 1 insulin-dependent diabetes mellitus w/insulin & carbohydrate mgmt Standard treatment of autoimmune thyroid disease Systemic T cell-directed immune suppression Topical therapies (e.g., steroids, tacrolimus, emollients) can also be beneficial. For autoimmune neutropenia: G-CSF can improve neutrophil counts. For pemphigus nodularis & other autoantibody-mediated disease: rituximab has been effective. . Persons w/autoimmune neutropenia or recurrent infections due to severe eczema may benefit from prophylactic antibiotic therapy to ↓ risk of severe infectious complications. Aggressive mgmt of dermatitis w/topical steroids & anti-inflammatory agents can help prevent infections from pathogens that enter as a result of the poor barrier function of the skin. Standard antimicrobial therapy when indicated G-CSF = granulocyte colony-stimulating factor; TPN = total parenteral nutrition; Treg = regulatory T cell(s) • T cell-directed immune suppression (i.e., sirolimus, cyclosporin A, or tacrolimus), either alone or in combination w/steroids • Sirolimus (rapamycin) as monotherapy or in combination w/other drugs • Toxicity, tachyphylaxis, & ↑ susceptibility to infection related to chronic use of these agents reduce their potential for long-term amelioration of symptoms in most persons. • Sirolimus & tacrolimus are nephrotoxic & require close renal monitoring & plasma drug levels. • Sirolimus has been used successfully in persons for whom tacrolimus was either ineffective or toxic. • The ability of sirolimus to suppress effector T cell function while allowing Treg cells to continue to develop & function offers some theoretic advantages for its use. • Standard treatment of type 1 insulin-dependent diabetes mellitus w/insulin & carbohydrate mgmt • Standard treatment of autoimmune thyroid disease • Systemic T cell-directed immune suppression • Topical therapies (e.g., steroids, tacrolimus, emollients) can also be beneficial. • For autoimmune neutropenia: G-CSF can improve neutrophil counts. • For pemphigus nodularis & other autoantibody-mediated disease: rituximab has been effective. . • Persons w/autoimmune neutropenia or recurrent infections due to severe eczema may benefit from prophylactic antibiotic therapy to ↓ risk of severe infectious complications. • Aggressive mgmt of dermatitis w/topical steroids & anti-inflammatory agents can help prevent infections from pathogens that enter as a result of the poor barrier function of the skin. • Standard antimicrobial therapy when indicated ## Targeted Therapies ## Supportive Care Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see IPEX Syndrome: Treatment of Manifestations T cell-directed immune suppression (i.e., sirolimus, cyclosporin A, or tacrolimus), either alone or in combination w/steroids Sirolimus (rapamycin) as monotherapy or in combination w/other drugs Toxicity, tachyphylaxis, & ↑ susceptibility to infection related to chronic use of these agents reduce their potential for long-term amelioration of symptoms in most persons. Sirolimus & tacrolimus are nephrotoxic & require close renal monitoring & plasma drug levels. Sirolimus has been used successfully in persons for whom tacrolimus was either ineffective or toxic. The ability of sirolimus to suppress effector T cell function while allowing Treg cells to continue to develop & function offers some theoretic advantages for its use. Standard treatment of type 1 insulin-dependent diabetes mellitus w/insulin & carbohydrate mgmt Standard treatment of autoimmune thyroid disease Systemic T cell-directed immune suppression Topical therapies (e.g., steroids, tacrolimus, emollients) can also be beneficial. For autoimmune neutropenia: G-CSF can improve neutrophil counts. For pemphigus nodularis & other autoantibody-mediated disease: rituximab has been effective. . Persons w/autoimmune neutropenia or recurrent infections due to severe eczema may benefit from prophylactic antibiotic therapy to ↓ risk of severe infectious complications. Aggressive mgmt of dermatitis w/topical steroids & anti-inflammatory agents can help prevent infections from pathogens that enter as a result of the poor barrier function of the skin. Standard antimicrobial therapy when indicated G-CSF = granulocyte colony-stimulating factor; TPN = total parenteral nutrition; Treg = regulatory T cell(s) • T cell-directed immune suppression (i.e., sirolimus, cyclosporin A, or tacrolimus), either alone or in combination w/steroids • Sirolimus (rapamycin) as monotherapy or in combination w/other drugs • Toxicity, tachyphylaxis, & ↑ susceptibility to infection related to chronic use of these agents reduce their potential for long-term amelioration of symptoms in most persons. • Sirolimus & tacrolimus are nephrotoxic & require close renal monitoring & plasma drug levels. • Sirolimus has been used successfully in persons for whom tacrolimus was either ineffective or toxic. • The ability of sirolimus to suppress effector T cell function while allowing Treg cells to continue to develop & function offers some theoretic advantages for its use. • Standard treatment of type 1 insulin-dependent diabetes mellitus w/insulin & carbohydrate mgmt • Standard treatment of autoimmune thyroid disease • Systemic T cell-directed immune suppression • Topical therapies (e.g., steroids, tacrolimus, emollients) can also be beneficial. • For autoimmune neutropenia: G-CSF can improve neutrophil counts. • For pemphigus nodularis & other autoantibody-mediated disease: rituximab has been effective. . • Persons w/autoimmune neutropenia or recurrent infections due to severe eczema may benefit from prophylactic antibiotic therapy to ↓ risk of severe infectious complications. • Aggressive mgmt of dermatitis w/topical steroids & anti-inflammatory agents can help prevent infections from pathogens that enter as a result of the poor barrier function of the skin. • Standard antimicrobial therapy when indicated ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in IPEX Syndrome: Recommended Surveillance Glucose tolerance test Hemoglobin A1c Thyroid function tests Complete blood count BUN, creatinine Urinalysis Serum AST, ALT ALT = alanine transferase; AST = aspartate transferase; BUN = blood urea nitrogen • Glucose tolerance test • Hemoglobin A1c • Thyroid function tests • Complete blood count • BUN, creatinine • Urinalysis • Serum AST, ALT ## Agents/Circumstances to Avoid Immune activation (e.g., by immunizations or severe infections) has been reported to cause worsening or exacerbation of disease symptoms [ ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of at-risk males either prenatally or immediately after birth to enable early diagnosis and HSCT and/or steroid treatment in affected males before significant organ damage occurs. See ## Therapies Under Investigation HSCT carries the risk of significant morbidity and mortality, and suitable donors are not always available. For these and other reasons, IPEX syndrome is an excellent candidate for treatment with gene therapy. However, one major hurdle is the need to regulate the expression of Search ## Genetic Counseling IPEX 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 In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), the affected male may have a Molecular genetic testing of the mother is recommended to evaluate her genetic status and inform recurrence risk assessment. If the mother of the proband has a Males who inherit the pathogenic variant will be affected. Male sibs with the same Females who inherit the pathogenic variant will be heterozygous (carriers). To date, IPEX syndrome has not been reported in females who are heterozygous for a If the proband represents a simplex case and if the Identification of female heterozygotes requires prior identification of the X-chromosome inactivation is skewed only in regulatory T cells [ 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 father of an affected male will not have the disorder, nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), the affected male may have a • Molecular genetic testing of the mother is recommended to evaluate her genetic status and inform recurrence risk assessment. • If the mother of the proband has a • Males who inherit the pathogenic variant will be affected. Male sibs with the same • Females who inherit the pathogenic variant will be heterozygous (carriers). To date, IPEX syndrome has not been reported in females who are heterozygous for a • Males who inherit the pathogenic variant will be affected. Male sibs with the same • Females who inherit the pathogenic variant will be heterozygous (carriers). To date, IPEX syndrome has not been reported in females who are heterozygous for a • If the proband represents a simplex case and if the • Males who inherit the pathogenic variant will be affected. Male sibs with the same • Females who inherit the pathogenic variant will be heterozygous (carriers). To date, IPEX syndrome has not been reported in females who are 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 IPEX 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 In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), the affected male may have a Molecular genetic testing of the mother is recommended to evaluate her genetic status and inform recurrence risk assessment. If the mother of the proband has a Males who inherit the pathogenic variant will be affected. Male sibs with the same Females who inherit the pathogenic variant will be heterozygous (carriers). To date, IPEX syndrome has not been reported in females who are heterozygous for a If the proband represents a simplex case and if the • The father of an affected male will not have the disorder, nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), the affected male may have a • Molecular genetic testing of the mother is recommended to evaluate her genetic status and inform recurrence risk assessment. • If the mother of the proband has a • Males who inherit the pathogenic variant will be affected. Male sibs with the same • Females who inherit the pathogenic variant will be heterozygous (carriers). To date, IPEX syndrome has not been reported in females who are heterozygous for a • Males who inherit the pathogenic variant will be affected. Male sibs with the same • Females who inherit the pathogenic variant will be heterozygous (carriers). To date, IPEX syndrome has not been reported in females who are heterozygous for a • If the proband represents a simplex case and if the • Males who inherit the pathogenic variant will be affected. Male sibs with the same • Females who inherit the pathogenic variant will be heterozygous (carriers). To date, IPEX syndrome has not been reported in females who are heterozygous for a ## Carrier Detection Identification of female heterozygotes requires prior identification of the X-chromosome inactivation is skewed only in regulatory T cells [ ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom United Kingdom • • • • United Kingdom • • • United Kingdom • • • • • • • ## Molecular Genetics IPEX Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for IPEX Syndrome ( An N-terminal proline-rich domain, which is essential for the gene-suppressive function of FOXP3 and for interaction with other key transcription factors including RORα and RORγt [ A C2H2 zinc finger and leucine zipper (both conserved structural motifs involved in protein-protein interactions) in the central portion; A forkhead DNA-binding domain at the C terminus, from which it derives its name (forkhead box) [ Proteins bearing forkhead DNA-binding motifs comprise a large family of related DNA-binding proteins that play diverse roles in enhancing or suppressing transcription from specific binding sites. Several members of this protein family are involved in patterning and development [ The majority of pathogenic variants in Variants listed in the table have been provided by the authors. • An N-terminal proline-rich domain, which is essential for the gene-suppressive function of FOXP3 and for interaction with other key transcription factors including RORα and RORγt [ • A C2H2 zinc finger and leucine zipper (both conserved structural motifs involved in protein-protein interactions) in the central portion; • A forkhead DNA-binding domain at the C terminus, from which it derives its name (forkhead box) [ ## Molecular Pathogenesis An N-terminal proline-rich domain, which is essential for the gene-suppressive function of FOXP3 and for interaction with other key transcription factors including RORα and RORγt [ A C2H2 zinc finger and leucine zipper (both conserved structural motifs involved in protein-protein interactions) in the central portion; A forkhead DNA-binding domain at the C terminus, from which it derives its name (forkhead box) [ Proteins bearing forkhead DNA-binding motifs comprise a large family of related DNA-binding proteins that play diverse roles in enhancing or suppressing transcription from specific binding sites. Several members of this protein family are involved in patterning and development [ The majority of pathogenic variants in Variants listed in the table have been provided by the authors. • An N-terminal proline-rich domain, which is essential for the gene-suppressive function of FOXP3 and for interaction with other key transcription factors including RORα and RORγt [ • A C2H2 zinc finger and leucine zipper (both conserved structural motifs involved in protein-protein interactions) in the central portion; • A forkhead DNA-binding domain at the C terminus, from which it derives its name (forkhead box) [ ## Chapter Notes Supported in part by an award from the Jeffrey Modell Foundation (JS). Mark C Hannibal, MD, PhD; University of Michigan Medical School (2004-2018)Raymond J Louie, PhD (2018-present)John W Sleasman, MD (2018-present)Queenie K-G Tan, MD, PhD (2018-present)Troy Torgerson, MD, PhD; University of Washington, Seattle (2004-2018) 1 February 2024 (sw) Comprehensive update posted live 19 July 2018 (ha) Comprehensive update posted live 27 January 2011 (me) Comprehensive update posted live 12 December 2007 (me) Comprehensive update posted live 19 October 2004 (me) Review posted live 11 February 2004 (mh) Original submission • 1 February 2024 (sw) Comprehensive update posted live • 19 July 2018 (ha) Comprehensive update posted live • 27 January 2011 (me) Comprehensive update posted live • 12 December 2007 (me) Comprehensive update posted live • 19 October 2004 (me) Review posted live • 11 February 2004 (mh) Original submission ## Acknowledgments Supported in part by an award from the Jeffrey Modell Foundation (JS). ## Author History Mark C Hannibal, MD, PhD; University of Michigan Medical School (2004-2018)Raymond J Louie, PhD (2018-present)John W Sleasman, MD (2018-present)Queenie K-G Tan, MD, PhD (2018-present)Troy Torgerson, MD, PhD; University of Washington, Seattle (2004-2018) ## Revision History 1 February 2024 (sw) Comprehensive update posted live 19 July 2018 (ha) Comprehensive update posted live 27 January 2011 (me) Comprehensive update posted live 12 December 2007 (me) Comprehensive update posted live 19 October 2004 (me) Review posted live 11 February 2004 (mh) Original submission • 1 February 2024 (sw) Comprehensive update posted live • 19 July 2018 (ha) Comprehensive update posted live • 27 January 2011 (me) Comprehensive update posted live • 12 December 2007 (me) Comprehensive update posted live • 19 October 2004 (me) Review posted live • 11 February 2004 (mh) Original submission ## Key Sections in this ## References ## Literature Cited Intrauterine ultrasound at 32 weeks' gestation of fetus with IPEX syndrome showing desquamation with dense, echogenic amniotic fluid with particulate appearance and sediment layering, as well as echogenic debris in the stomach. Reprinted with permission from Typical erythematous rash seen in individuals with IPEX syndrome.	[]	19/10/2004	1/2/2024	27/4/2006	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
irf2bpl-dis	irf2bpl-dis	[ "NEDAMSS (Neurodevelopmental Disorder With Regression, Abnormal Movements, Loss of Speech, and Seizures)", "IRF2BPL Mutation Syndrome", "NEDAMSS (Neurodevelopmental Disorder With Regression, Abnormal Movements, Loss of Speech, and Seizures)", "IRF2BPL Mutation Syndrome", "Probable E3 ubiquitin-protein ligase IRF2BPL", "IRF2BPL", "IRF2BPL-Related Disorder" ]		Tomas Vanagunas, Elizabeth Ulm Seiwert, Travis R Larsh, Paul C Marcogliese, Loren DM Pena	Summary The diagnosis of	## Diagnosis Mild-to-profound developmental delay (Developmental regression has been described in 50% of individuals.) Intellectual disability Epilepsy (generalized tonic-clonic, myoclonic [with photoparoxsymal response], absence, focal tonic-clonic, complex partial, infantile spasms, and/or atonic seizures) Movement disorders (ataxia, dystonia, tremor, and parkinsonism; less commonly, athetosis, chorea, and myoclonus) Neurobehavioral/psychiatric manifestations (autism spectrum disorder, autistic features, anxiety, depression, and psychosis) Ophthalmologic manifestations (dysconjugate gaze, ophthalmoplegia, gaze palsy, slow saccades; less commonly, keratoconus, cataracts, and retinal pigmentary anomalies) Epilepsy (generalized tonic-clonic, myoclonic, absence, and focal tonic-clonic seizures) Movement disorders (dystonia with or without dysarthria, ataxia, choreoathetosis) Cognitive decline Anarthria, aphonia Psychiatric manifestations (recurrent psychosis) Ophthalmologic manifestations (macular degeneration, gaze palsy, and abnormal saccades) Note: Presentation can be as late as the sixth decade. Focal or diffuse cortical and/or subcortical atrophy Cerebellar atrophy (particularly of the vermis) Brain stem atrophy Corpus callosum abnormalities (thinning/atrophy, thickening) Note: Brain MRI can be normal, particularly in early childhood. 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. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. To date, a large deletion including • Mild-to-profound developmental delay (Developmental regression has been described in 50% of individuals.) • Intellectual disability • Epilepsy (generalized tonic-clonic, myoclonic [with photoparoxsymal response], absence, focal tonic-clonic, complex partial, infantile spasms, and/or atonic seizures) • Movement disorders (ataxia, dystonia, tremor, and parkinsonism; less commonly, athetosis, chorea, and myoclonus) • Neurobehavioral/psychiatric manifestations (autism spectrum disorder, autistic features, anxiety, depression, and psychosis) • Ophthalmologic manifestations (dysconjugate gaze, ophthalmoplegia, gaze palsy, slow saccades; less commonly, keratoconus, cataracts, and retinal pigmentary anomalies) • Epilepsy (generalized tonic-clonic, myoclonic, absence, and focal tonic-clonic seizures) • Movement disorders (dystonia with or without dysarthria, ataxia, choreoathetosis) • Cognitive decline • Anarthria, aphonia • Psychiatric manifestations (recurrent psychosis) • Ophthalmologic manifestations (macular degeneration, gaze palsy, and abnormal saccades) • Focal or diffuse cortical and/or subcortical atrophy • Cerebellar atrophy (particularly of the vermis) • Brain stem atrophy • Corpus callosum abnormalities (thinning/atrophy, thickening) • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings Mild-to-profound developmental delay (Developmental regression has been described in 50% of individuals.) Intellectual disability Epilepsy (generalized tonic-clonic, myoclonic [with photoparoxsymal response], absence, focal tonic-clonic, complex partial, infantile spasms, and/or atonic seizures) Movement disorders (ataxia, dystonia, tremor, and parkinsonism; less commonly, athetosis, chorea, and myoclonus) Neurobehavioral/psychiatric manifestations (autism spectrum disorder, autistic features, anxiety, depression, and psychosis) Ophthalmologic manifestations (dysconjugate gaze, ophthalmoplegia, gaze palsy, slow saccades; less commonly, keratoconus, cataracts, and retinal pigmentary anomalies) Epilepsy (generalized tonic-clonic, myoclonic, absence, and focal tonic-clonic seizures) Movement disorders (dystonia with or without dysarthria, ataxia, choreoathetosis) Cognitive decline Anarthria, aphonia Psychiatric manifestations (recurrent psychosis) Ophthalmologic manifestations (macular degeneration, gaze palsy, and abnormal saccades) Note: Presentation can be as late as the sixth decade. Focal or diffuse cortical and/or subcortical atrophy Cerebellar atrophy (particularly of the vermis) Brain stem atrophy Corpus callosum abnormalities (thinning/atrophy, thickening) Note: Brain MRI can be normal, particularly in early childhood. • Mild-to-profound developmental delay (Developmental regression has been described in 50% of individuals.) • Intellectual disability • Epilepsy (generalized tonic-clonic, myoclonic [with photoparoxsymal response], absence, focal tonic-clonic, complex partial, infantile spasms, and/or atonic seizures) • Movement disorders (ataxia, dystonia, tremor, and parkinsonism; less commonly, athetosis, chorea, and myoclonus) • Neurobehavioral/psychiatric manifestations (autism spectrum disorder, autistic features, anxiety, depression, and psychosis) • Ophthalmologic manifestations (dysconjugate gaze, ophthalmoplegia, gaze palsy, slow saccades; less commonly, keratoconus, cataracts, and retinal pigmentary anomalies) • Epilepsy (generalized tonic-clonic, myoclonic, absence, and focal tonic-clonic seizures) • Movement disorders (dystonia with or without dysarthria, ataxia, choreoathetosis) • Cognitive decline • Anarthria, aphonia • Psychiatric manifestations (recurrent psychosis) • Ophthalmologic manifestations (macular degeneration, gaze palsy, and abnormal saccades) • Focal or diffuse cortical and/or subcortical atrophy • Cerebellar atrophy (particularly of the vermis) • Brain stem atrophy • Corpus callosum abnormalities (thinning/atrophy, thickening) ## 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. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. To date, a large deletion including • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics Select Features of Percentages are from a completed but unpublished clinical study that collected self-reported features in 32 individuals with Some individuals have progressive loss of gross motor, fine motor, and self-help skills. Early signs of developmental regression can include dysarthria, dysphagia, and dysconjugate gaze. Lack of balance and coordination with frequent falls is also described. Increased difficulty with walking and/or sitting is reported in 38% of individuals, increased falls in 25%, progressive articulation difficulties in 19%, and loss of speech in 6%. Regression has been described as early as age eight months and can occur throughout early adulthood. Additional cerebellar signs include eye movement abnormalities and dysdiadochokinesia. Pathogenic variants (including missense and nonsense) located downstream of the nuclear localization signal may be associated with a less severe phenotype without a progressive loss of milestones or movement disorder. However, the precise genomic location for this genotype-phenotype correlation is currently unknown. To date, three variants have been associated with a concordant phenotype of NEDAMSS (neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures) reported in at least three different families ( Penetrance for Prevalence is unknown. To date, more than 60 affected individuals have been described. ## Clinical Description Select Features of Percentages are from a completed but unpublished clinical study that collected self-reported features in 32 individuals with Some individuals have progressive loss of gross motor, fine motor, and self-help skills. Early signs of developmental regression can include dysarthria, dysphagia, and dysconjugate gaze. Lack of balance and coordination with frequent falls is also described. Increased difficulty with walking and/or sitting is reported in 38% of individuals, increased falls in 25%, progressive articulation difficulties in 19%, and loss of speech in 6%. Regression has been described as early as age eight months and can occur throughout early adulthood. Additional cerebellar signs include eye movement abnormalities and dysdiadochokinesia. ## Genotype-Phenotype Correlations Pathogenic variants (including missense and nonsense) located downstream of the nuclear localization signal may be associated with a less severe phenotype without a progressive loss of milestones or movement disorder. However, the precise genomic location for this genotype-phenotype correlation is currently unknown. To date, three variants have been associated with a concordant phenotype of NEDAMSS (neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures) reported in at least three different families ( ## Penetrance Penetrance for ## Prevalence Prevalence is unknown. To date, more than 60 affected individuals have been described. ## Genetically Related (Allelic) Disorders ## Differential Diagnosis Because OMIM Phenotypic Series: Selected disorders with a high degree of clinical overlap are listed in Selected Disorders in the Differential Diagnosis of Global DD Speech impairment Ataxia Seizures Regression Ataxia Seizures Short stature Acquired microcephaly Hand stereotypies Global DD Seizures Ataxia Microcephaly Hearing loss Cardiomyopathy Global DD Movement disorder Seizure Speech impairment Seizures Ataxia DD/ID Characteristic craniofacial features Microcephaly Unique behavior w/apparent happy demeanor AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; NDD = neurodevelopmental disorder The risk to sibs of a proband with Angelman syndrome depends on the genetic mechanism leading to the loss of • OMIM Phenotypic Series: • • • • • • • • • • • • • • • • • Global DD • Speech impairment • Ataxia • Seizures • Regression • Ataxia • Seizures • Short stature • Acquired microcephaly • Hand stereotypies • Global DD • Seizures • Ataxia • Microcephaly • Hearing loss • Cardiomyopathy • Global DD • Movement disorder • Seizure • Speech impairment • Seizures • Ataxia • DD/ID • Characteristic craniofacial features • Microcephaly • Unique behavior w/apparent happy demeanor ## 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 For persons age >5 yrs: consider baseline neurocognitive eval To incl brain MRI Consider EEG if seizures are a concern. Note: Abnormal EEG may precede clinical seizures. Consider dedicated movement disorder eval. Gross motor & fine motor skills Contractures Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) To incl eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. Community or Social work involvement for parental support Home nursing referral ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PFT = pulmonary function test; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Many 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. Treatment per ophthalmologist for vision deficits Treatment per ophthalmic subspecialists for more complex findings (e.g., cataract, retinal changes) 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 therapist; PT = physical therapist 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. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Assess cognitive function. Assess for new or increasing seizures. Assess for new manifestations such as movement disorders &/or spasticity. Physical medicine, OT/PT assessment of mobility, self-help skills Assess for contractures. Measurement of growth parameters Eval of nutritional status & safety of oral intake Assessment for gastrointestinal dysmotility ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PFT = pulmonary function test; PT = physical therapy See Search • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • For persons age >5 yrs: consider baseline neurocognitive eval • To incl brain MRI • Consider EEG if seizures are a concern. Note: Abnormal EEG may precede clinical seizures. • Consider dedicated movement disorder eval. • Gross motor & fine motor skills • Contractures • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • To incl eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. • Community or • Social work involvement for parental support • Home nursing referral • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Treatment per ophthalmologist for vision deficits • Treatment per ophthalmic subspecialists for more complex findings (e.g., cataract, retinal changes) • 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 baclofen, tizanidine, Botox • Assess cognitive function. • Assess for new or increasing seizures. • Assess for new manifestations such as movement disorders &/or spasticity. • Physical medicine, OT/PT assessment of mobility, self-help skills • Assess for contractures. • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Assessment for gastrointestinal dysmotility ## 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 For persons age >5 yrs: consider baseline neurocognitive eval To incl brain MRI Consider EEG if seizures are a concern. Note: Abnormal EEG may precede clinical seizures. Consider dedicated movement disorder eval. Gross motor & fine motor skills Contractures Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) To incl eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. Community or Social work involvement for parental support Home nursing referral ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PFT = pulmonary function test; 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 • For persons age >5 yrs: consider baseline neurocognitive eval • To incl brain MRI • Consider EEG if seizures are a concern. Note: Abnormal EEG may precede clinical seizures. • Consider dedicated movement disorder eval. • Gross motor & fine motor skills • Contractures • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • To incl eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations 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 Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Treatment per ophthalmologist for vision deficits Treatment per ophthalmic subspecialists for more complex findings (e.g., cataract, retinal changes) 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 therapist; PT = physical therapist 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. • 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. • Treatment per ophthalmologist for vision deficits • Treatment per ophthalmic subspecialists for more complex findings (e.g., cataract, retinal changes) • 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 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 Assess cognitive function. Assess for new or increasing seizures. Assess for new manifestations such as movement disorders &/or spasticity. Physical medicine, OT/PT assessment of mobility, self-help skills Assess for contractures. Measurement of growth parameters Eval of nutritional status & safety of oral intake Assessment for gastrointestinal dysmotility ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PFT = pulmonary function test; PT = physical therapy • Assess cognitive function. • Assess for new or increasing seizures. • Assess for new manifestations such as movement disorders &/or spasticity. • Physical medicine, OT/PT assessment of mobility, self-help skills • Assess for contractures. • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Assessment for gastrointestinal dysmotility ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling The majority of individuals diagnosed with Approximately 9% of individuals with If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. * A parent with somatic and gonadal mosaicism for an 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%. While penetrance for If the If the parents are clinically unaffected but their genetic status is unknown, sibs are still presumed to be at increased risk for The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is 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. • The majority of individuals diagnosed with • Approximately 9% of individuals with • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * A parent with somatic and gonadal mosaicism for an • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * A parent with somatic and gonadal mosaicism for an • The family history of some individuals diagnosed with • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * A parent with somatic and gonadal mosaicism for 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%. • While penetrance for • If the • If the parents are clinically unaffected but their genetic status is unknown, sibs are still presumed to be at increased risk for • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance ## Risk to Family Members The majority of individuals diagnosed with Approximately 9% of individuals with If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. * A parent with somatic and gonadal mosaicism for an 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%. While penetrance for If the If the parents are clinically unaffected but their genetic status is unknown, sibs are still presumed to be at increased risk for • The majority of individuals diagnosed with • Approximately 9% of individuals with • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * A parent with somatic and gonadal mosaicism for an • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * A parent with somatic and gonadal mosaicism for an • The family history of some individuals diagnosed with • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * A parent with somatic and gonadal mosaicism for 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%. • While penetrance for • If the • If the parents are clinically unaffected but their genetic status is unknown, sibs are still presumed to be at increased risk for ## 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 • • • • • • ## Molecular Genetics IRF2BPL-Related Disorder: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for IRF2BPL-Related Disorder ( To date, all seven pathogenic frameshift or nonsense variants (six lead to truncation prior to the nuclear localization signal [NLS], and one leads to truncation after the NLS) in Although no clear genotype-phenotype correlation has been confirmed, pathogenic variants causing truncation proximal to the polyglutamine tract (amino acids 103-127) may be associated with increased severity, and pathogenic variants causing truncation downstream of the NLS (amino acids 542-545) display more variability with milder presentation and/or later onset. ## Molecular Pathogenesis To date, all seven pathogenic frameshift or nonsense variants (six lead to truncation prior to the nuclear localization signal [NLS], and one leads to truncation after the NLS) in Although no clear genotype-phenotype correlation has been confirmed, pathogenic variants causing truncation proximal to the polyglutamine tract (amino acids 103-127) may be associated with increased severity, and pathogenic variants causing truncation downstream of the NLS (amino acids 542-545) display more variability with milder presentation and/or later onset. ## Chapter Notes Contact Dr Paul Marcogliese ( The authors would like to gratefully acknowledge the families and affected individuals for their interest, support, and participation in research initiatives to understand the scope of the phenotypes and the function of the IRF2BPL gene product. 21 November 2024 (sw) Review posted live 31 May 2024 (ldmp/pm) Original submission • 21 November 2024 (sw) Review posted live • 31 May 2024 (ldmp/pm) Original submission ## Author Notes Contact Dr Paul Marcogliese ( ## Acknowledgments The authors would like to gratefully acknowledge the families and affected individuals for their interest, support, and participation in research initiatives to understand the scope of the phenotypes and the function of the IRF2BPL gene product. ## Revision History 21 November 2024 (sw) Review posted live 31 May 2024 (ldmp/pm) Original submission • 21 November 2024 (sw) Review posted live • 31 May 2024 (ldmp/pm) Original submission ## References ## Literature Cited	[]	21/11/2024			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
isca1-mmds	isca1-mmds	[ "Multiple Mitochondrial Dysfunctions Syndrome 5", "Multiple Mitochondrial Dysfunctions Syndrome 5", "Iron-sulfur cluster assembly 1 homolog, mitochondrial", "ISCA1", "ISCA1-Related Multiple Mitochondrial Dysfunctions Syndrome" ]		Anju Shukla, Dhanya Lakshmi Narayanan, Parneet Kaur, Katta Mohan Girisha	Summary The diagnosis of	## Diagnosis Early-infantile onset and progressive neurologic deterioration Early-onset seizures, often developing before age six months Incessant cry Spasticity Exaggerated deep tendon reflexes Early death Nystagmus Pigmentary retinopathy Diffuse bilateral symmetric signal abnormality in the deep cerebral and cerebellar white matter; white matter abnormalities may also involve the corpus callosum, pons, and spinal cord. Pachygyria Ventriculomegaly Elevated lipid-lactate peak on MR spectroscopy Elevated plasma lactate Elevated serum creatinine phosphokinase The diagnosis of 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 A possible founder variant has been identified in four families (3 families reported in the literature and 1 family with unpublished data) from southwestern India [ Molecular Genetic Testing Used in See See The pathogenic c.259G>A (p.Glu87Lys) variant has been proposed as a founder variant in individuals of southwestern Indian descent. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and 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. • Early-infantile onset and progressive neurologic deterioration • Early-onset seizures, often developing before age six months • Incessant cry • Spasticity • Exaggerated deep tendon reflexes • Early death • Nystagmus • Pigmentary retinopathy • Diffuse bilateral symmetric signal abnormality in the deep cerebral and cerebellar white matter; white matter abnormalities may also involve the corpus callosum, pons, and spinal cord. • Pachygyria • Ventriculomegaly • Elevated lipid-lactate peak on MR spectroscopy • Elevated plasma lactate • Elevated serum creatinine phosphokinase • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings Early-infantile onset and progressive neurologic deterioration Early-onset seizures, often developing before age six months Incessant cry Spasticity Exaggerated deep tendon reflexes Early death Nystagmus Pigmentary retinopathy Diffuse bilateral symmetric signal abnormality in the deep cerebral and cerebellar white matter; white matter abnormalities may also involve the corpus callosum, pons, and spinal cord. Pachygyria Ventriculomegaly Elevated lipid-lactate peak on MR spectroscopy Elevated plasma lactate Elevated serum creatinine phosphokinase • Early-infantile onset and progressive neurologic deterioration • Early-onset seizures, often developing before age six months • Incessant cry • Spasticity • Exaggerated deep tendon reflexes • Early death • Nystagmus • Pigmentary retinopathy • Diffuse bilateral symmetric signal abnormality in the deep cerebral and cerebellar white matter; white matter abnormalities may also involve the corpus callosum, pons, and spinal cord. • Pachygyria • Ventriculomegaly • Elevated lipid-lactate peak on MR spectroscopy • Elevated plasma lactate • Elevated serum creatinine phosphokinase ## Establishing the Diagnosis The diagnosis of 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 A possible founder variant has been identified in four families (3 families reported in the literature and 1 family with unpublished data) from southwestern India [ Molecular Genetic Testing Used in See See The pathogenic c.259G>A (p.Glu87Lys) variant has been proposed as a founder variant in individuals of southwestern Indian descent. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and 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 ## Further Testing to Consider A possible founder variant has been identified in four families (3 families reported in the literature and 1 family with unpublished data) from southwestern India [ Molecular Genetic Testing Used in See See The pathogenic c.259G>A (p.Glu87Lys) variant has been proposed as a founder variant in individuals of southwestern Indian descent. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and 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 Frequency of Clinical Features Observed in Individuals with Six of the seven affected individuals either did not attain any developmental milestone or showed very early loss of achieved milestones. One individual reported by The proband lost head control at age three months. He regained head control and was able to sit with support at 18 months. He achieved the ability to sit without support by age four years. At age six years, he could speak in sentences. Occipitofrontal circumference ranged from normal to -6 SD at the time of evaluation [ Progressive microcephaly was noted in only one individual for whom head circumference at birth was available. His head circumference was noted to be normal at birth and fell to -2 SD at six months [ Six of the seven individuals developed seizures between age two and four months. Clinical examination revealed spasticity and exaggerated deep tendon reflexes. Two of seven had incessant cry. Nystagmus was observed in two individuals [ Pigmentary retinopathy was seen in one individual. Elevated blood lactate was observed in six of the seven individuals. In one individual, elevated creatine phosphokinase level was observed [ Respiratory chain enzyme analysis on fibroblasts revealed deficient levels of mitochondrial complex I and II enzymes [ Note: More invasive testing that requires a skin biopsy sample may be bypassed in favor of molecular genetic testing on a peripheral blood sample. Extensive cerebral and cerebellar deep white matter hyperintensities were noted in all individuals. Marked dilatation of the cerebral ventricles and pachygyria were seen in four families (see Elevated lipid-lactate peak was seen on brain MR spectroscopy [ Radiologic Features of Individuals with MRS = magnetic resonance spectroscopy Though very few individuals are reported with this condition, there appears to be striking similarity in clinical and brain imaging features in individuals with the c.259G>A variant. In four families with biallelic The individual reported by One affected individual homozygous for the c.29T>G missense variant showed milder clinical as well as radiologic features and succumbed to this condition at age 11 years [ The prevalence of • Six of the seven affected individuals either did not attain any developmental milestone or showed very early loss of achieved milestones. • One individual reported by • The proband lost head control at age three months. • He regained head control and was able to sit with support at 18 months. • He achieved the ability to sit without support by age four years. • At age six years, he could speak in sentences. • The proband lost head control at age three months. • He regained head control and was able to sit with support at 18 months. • He achieved the ability to sit without support by age four years. • At age six years, he could speak in sentences. • The proband lost head control at age three months. • He regained head control and was able to sit with support at 18 months. • He achieved the ability to sit without support by age four years. • At age six years, he could speak in sentences. • Occipitofrontal circumference ranged from normal to -6 SD at the time of evaluation [ • Progressive microcephaly was noted in only one individual for whom head circumference at birth was available. His head circumference was noted to be normal at birth and fell to -2 SD at six months [ • Six of the seven individuals developed seizures between age two and four months. • Clinical examination revealed spasticity and exaggerated deep tendon reflexes. • Two of seven had incessant cry. • Nystagmus was observed in two individuals [ • Pigmentary retinopathy was seen in one individual. • Elevated blood lactate was observed in six of the seven individuals. • In one individual, elevated creatine phosphokinase level was observed [ • Respiratory chain enzyme analysis on fibroblasts revealed deficient levels of mitochondrial complex I and II enzymes [ • Extensive cerebral and cerebellar deep white matter hyperintensities were noted in all individuals. • Marked dilatation of the cerebral ventricles and pachygyria were seen in four families (see • Elevated lipid-lactate peak was seen on brain MR spectroscopy [ • In four families with biallelic • The individual reported by ## Clinical Description Frequency of Clinical Features Observed in Individuals with Six of the seven affected individuals either did not attain any developmental milestone or showed very early loss of achieved milestones. One individual reported by The proband lost head control at age three months. He regained head control and was able to sit with support at 18 months. He achieved the ability to sit without support by age four years. At age six years, he could speak in sentences. Occipitofrontal circumference ranged from normal to -6 SD at the time of evaluation [ Progressive microcephaly was noted in only one individual for whom head circumference at birth was available. His head circumference was noted to be normal at birth and fell to -2 SD at six months [ Six of the seven individuals developed seizures between age two and four months. Clinical examination revealed spasticity and exaggerated deep tendon reflexes. Two of seven had incessant cry. Nystagmus was observed in two individuals [ Pigmentary retinopathy was seen in one individual. Elevated blood lactate was observed in six of the seven individuals. In one individual, elevated creatine phosphokinase level was observed [ Respiratory chain enzyme analysis on fibroblasts revealed deficient levels of mitochondrial complex I and II enzymes [ Note: More invasive testing that requires a skin biopsy sample may be bypassed in favor of molecular genetic testing on a peripheral blood sample. Extensive cerebral and cerebellar deep white matter hyperintensities were noted in all individuals. Marked dilatation of the cerebral ventricles and pachygyria were seen in four families (see Elevated lipid-lactate peak was seen on brain MR spectroscopy [ Radiologic Features of Individuals with MRS = magnetic resonance spectroscopy • Six of the seven affected individuals either did not attain any developmental milestone or showed very early loss of achieved milestones. • One individual reported by • The proband lost head control at age three months. • He regained head control and was able to sit with support at 18 months. • He achieved the ability to sit without support by age four years. • At age six years, he could speak in sentences. • The proband lost head control at age three months. • He regained head control and was able to sit with support at 18 months. • He achieved the ability to sit without support by age four years. • At age six years, he could speak in sentences. • The proband lost head control at age three months. • He regained head control and was able to sit with support at 18 months. • He achieved the ability to sit without support by age four years. • At age six years, he could speak in sentences. • Occipitofrontal circumference ranged from normal to -6 SD at the time of evaluation [ • Progressive microcephaly was noted in only one individual for whom head circumference at birth was available. His head circumference was noted to be normal at birth and fell to -2 SD at six months [ • Six of the seven individuals developed seizures between age two and four months. • Clinical examination revealed spasticity and exaggerated deep tendon reflexes. • Two of seven had incessant cry. • Nystagmus was observed in two individuals [ • Pigmentary retinopathy was seen in one individual. • Elevated blood lactate was observed in six of the seven individuals. • In one individual, elevated creatine phosphokinase level was observed [ • Respiratory chain enzyme analysis on fibroblasts revealed deficient levels of mitochondrial complex I and II enzymes [ • Extensive cerebral and cerebellar deep white matter hyperintensities were noted in all individuals. • Marked dilatation of the cerebral ventricles and pachygyria were seen in four families (see • Elevated lipid-lactate peak was seen on brain MR spectroscopy [ ## Genotype-Phenotype Correlations Though very few individuals are reported with this condition, there appears to be striking similarity in clinical and brain imaging features in individuals with the c.259G>A variant. In four families with biallelic The individual reported by One affected individual homozygous for the c.29T>G missense variant showed milder clinical as well as radiologic features and succumbed to this condition at age 11 years [ • In four families with biallelic • The individual reported by ## Prevalence The prevalence of ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The differential diagnosis of neurologic regression with white matter disease in infancy is extensive. Diagnostic algorithms for genetic leukodystrophy disorders have been published. In Disorders to Consider in the Differential Diagnosis of Feeding difficulties, muscle weakness, decreasing responsiveness, neurologic regression WM lesions on brain MRI Pulmonary hypertension, obstructive vasculopathy Spongiform degeneration, WM necrosis Visual impairment, spasticity Leukodystrophy Onset in infancy Cardiomyopathy, hepatomegaly Extrapyramidal signs, ataxia, myoclonus Onset in utero, IUGR Microcephaly, dysmorphic features (retrognathia, high-arched palate, widely spaced nipples), arthrogryposis, severe hypotonia Hypoplasia of corpus callosum & medulla oblongata Loss of developmental milestones, spasticity, nystagmus WM abnormalities Lactic acidosis Neurologic regression Leukodystrophy Spasticity Neurologic regression, spasticity Leukodystrophy Spotty or confluent cerebral WM changes w/relative sparing of subcortical WM Involvement of dorsal columns, lateral corticospinal tracts, & medial lemniscus in medulla oblongata Neurologic regression, spasticity Leukodystrophy Unsteady gait bilateral symmetric diffuse changes in cerebral hemispheres isointense w/CSF; cystic breakdown of WM on proton density or FLAIR images; mild-to-severe cerebellar atrophy Ovarian dysgenesis in females Neurologic regression Leukodystrophy Macrocephaly symmetric & diffuse WM changes in cerebral cortex & subcortical region; less marked involvement of cerebellum & brain stem ↑ N-acetyl-L-aspartate in urine Neurologic regression, spasticity Leukodystrophy Macrocephaly cerebral WM abnormalities w/frontal predominance; basal ganglia & thalami may incl atrophy &/or altered signal intensity; medulla & midbrain involvement Neurologic regression ↑ lactate in MR spectroscopy Hypertrophic cardiomyopathy Hypertrichosis Renal tubulopathy Liver involvement basal ganglia involvement; bilateral symmetric T AD = autosomal dominant; AR = autosomal recessive; CSF = cerebrospinal fluid; IUGR = intrauterine growth restriction; MOI = mode of inheritance; mt = mitochondrial; WM = white matter; XL = X-linked See • Feeding difficulties, muscle weakness, decreasing responsiveness, neurologic regression • WM lesions on brain MRI • Pulmonary hypertension, obstructive vasculopathy • Spongiform degeneration, WM necrosis • Visual impairment, spasticity • Leukodystrophy • Onset in infancy • Cardiomyopathy, hepatomegaly • Extrapyramidal signs, ataxia, myoclonus • Onset in utero, IUGR • Microcephaly, dysmorphic features (retrognathia, high-arched palate, widely spaced nipples), arthrogryposis, severe hypotonia • Hypoplasia of corpus callosum & medulla oblongata • Loss of developmental milestones, spasticity, nystagmus • WM abnormalities • Lactic acidosis • Neurologic regression • Leukodystrophy • Spasticity • Neurologic regression, spasticity • Leukodystrophy • Spotty or confluent cerebral WM changes w/relative sparing of subcortical WM • Involvement of dorsal columns, lateral corticospinal tracts, & medial lemniscus in medulla oblongata • Neurologic regression, spasticity • Leukodystrophy • Unsteady gait • bilateral symmetric diffuse changes in cerebral hemispheres isointense w/CSF; • cystic breakdown of WM on proton density or FLAIR images; • mild-to-severe cerebellar atrophy • Ovarian dysgenesis in females • Neurologic regression • Leukodystrophy • Macrocephaly • symmetric & diffuse WM changes in cerebral cortex & subcortical region; • less marked involvement of cerebellum & brain stem • ↑ N-acetyl-L-aspartate in urine • Neurologic regression, spasticity • Leukodystrophy • Macrocephaly • cerebral WM abnormalities w/frontal predominance; • basal ganglia & thalami may incl atrophy &/or altered signal intensity; • medulla & midbrain involvement • Neurologic regression • ↑ lactate in MR spectroscopy • Hypertrophic cardiomyopathy • Hypertrichosis • Renal tubulopathy • Liver involvement • basal ganglia involvement; • bilateral symmetric T ## Management To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with Swallowing study. Eval for gastric tube placement in those w/dysphagia &/or aspiration risk. Use of community or online resources (e.g., Parent to Parent). Need for social work involvement for parental support. Need for home nursing referral. The mainstay of treatment is supportive and is best provided by a multidisciplinary team including a geneticist, pediatric neurologist or neurologist, and dietician. The following recommendations are based on the experience from a small number of affected individuals. The spectrum of disease may evolve with reports of additional affected people. Treatment options should be considered based on the observed phenotype. Treatment of Manifestations in Individuals with PT & rehabilitation therapy. Need for positioning & mobility devices, disability parking placard. PT = physical therapy With the progression of the disease, constipation can be a problem. Adequate hydration, stool softeners, and laxatives may help in avoiding severe constipation. Recommended Surveillance for Individuals with Monitor developmental progress & educational needs. Meaurement of growth parameters See Search • Swallowing study. • Eval for gastric tube placement in those w/dysphagia &/or aspiration risk. • Use of community or online resources (e.g., Parent to Parent). • Need for social work involvement for parental support. • Need for home nursing referral. • PT & rehabilitation therapy. • Need for positioning & mobility devices, disability parking placard. • Monitor developmental progress & educational needs. • Meaurement of growth parameters ## 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 Swallowing study. Eval for gastric tube placement in those w/dysphagia &/or aspiration risk. Use of community or online resources (e.g., Parent to Parent). Need for social work involvement for parental support. Need for home nursing referral. • Swallowing study. • Eval for gastric tube placement in those w/dysphagia &/or aspiration risk. • Use of community or online resources (e.g., Parent to Parent). • Need for social work involvement for parental support. • Need for home nursing referral. ## Treatment of Manifestations The mainstay of treatment is supportive and is best provided by a multidisciplinary team including a geneticist, pediatric neurologist or neurologist, and dietician. The following recommendations are based on the experience from a small number of affected individuals. The spectrum of disease may evolve with reports of additional affected people. Treatment options should be considered based on the observed phenotype. Treatment of Manifestations in Individuals with PT & rehabilitation therapy. Need for positioning & mobility devices, disability parking placard. PT = physical therapy • PT & rehabilitation therapy. • Need for positioning & mobility devices, disability parking placard. ## Prevention of Secondary Complications With the progression of the disease, constipation can be a problem. Adequate hydration, stool softeners, and laxatives may help in avoiding severe constipation. ## Surveillance Recommended Surveillance for Individuals with Monitor developmental progress & educational needs. Meaurement of growth parameters • Monitor developmental progress & educational needs. • Meaurement of growth parameters ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling The parents of an affected child are obligate heterozygotes (i.e., carriers of one Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Carrier testing for at-risk relatives requires prior identification of the The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected child are obligate heterozygotes (i.e., carriers of one • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. ## Mode of Inheritance The parents of an affected child are obligate heterozygotes (i.e., carriers of one Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The parents of an affected child are obligate heterozygotes (i.e., carriers of one • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources Australia Italy United Kingdom • • Australia • • • • Italy • • • United Kingdom • • • • • ## Molecular Genetics ISCA1-Related Multiple Mitochondrial Dysfunctions Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for ISCA1-Related Multiple Mitochondrial Dysfunctions Syndrome ( One pathogenic possible founder variant has been reported in four families to date [ Functional studies by Notable Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis One pathogenic possible founder variant has been reported in four families to date [ Functional studies by Notable Variants listed in the table have been provided by the authors. ## Chapter Notes Department of Health Research, Ministry of Health and Family Welfare, Government of India for funding the project entitled "Clinical and Molecular Characterization of Leukodystrophies in Indian Children" (V.25011/379/2015-GIA/HR) 3 October 2019 (ma) Review posted live 3 January 2019 (as) Original submission • 3 October 2019 (ma) Review posted live • 3 January 2019 (as) Original submission ## Acknowledgments Department of Health Research, Ministry of Health and Family Welfare, Government of India for funding the project entitled "Clinical and Molecular Characterization of Leukodystrophies in Indian Children" (V.25011/379/2015-GIA/HR) ## Revision History 3 October 2019 (ma) Review posted live 3 January 2019 (as) Original submission • 3 October 2019 (ma) Review posted live • 3 January 2019 (as) Original submission ## References ## Literature Cited	[ "AD Sheftel, C Wilbrecht, O Stehling, B Niggemeyer, HP Elsasser, U Muhlenhoff, R Lill. The human mitochondrial ISCA1, ISCA2, and IBA57 proteins are required for [4Fe-4S] protein maturation.. Molec Biol Cell. 2012;23:1157-66", "A Shukla, M Hebbar, A Srivastava, R Kadavigere, P Upadhyai, A Kanthi, O Brandau, S Bielas, KM Girisha. Homozygous p.(Glu8Lys) variant in ISCA1 is associated with a multiple mitochondrial dysfunctions syndrome.. J Hum Genet. 2017;62:723-7", "A Shukla, P Kaur, KM Girisha. Report of the third family with multiple mitochondrial dysfunctions syndrome 5 caused by the founder variant p.(Glu87Lys) in ISCA1.. J Pediatr Genet. 2018;7:130-3", "A Torraco, O Stehling, C Stümpfig, R Rösser, D De Rasmo, G Fiermonte, D Verrigni, T Rizza, A Vozza, M Di Nottia, D Diodato, D Martinelli, F Piemonte, C Dionisi-Vici, E Bertini, R Lill, R. Carrozzo. ISCA1 mutation in a patient with infantile-onset leukodystrophy causes defects in mitochondrial [4Fe-4S] proteins.. Hum Mol Genet. 2018;27:3650" ]	3/10/2019			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
isca2-mt-dis	isca2-mt-dis	[ "Multiple Mitochondrial Dysfunction Syndrome 4", "Multiple Mitochondrial Dysfunction Syndrome 4", "Iron-sulfur cluster assembly 2 homolog, mitochondrial", "ISCA2", "ISCA2-Related Mitochondrial Disorder" ]		Zuhair N Al-Hassnan, Namik Kaya	Summary Infants with The diagnosis of	## Diagnosis IRMD Progressive loss of developmental milestones, typically beginning between ages three and seven months Spasticity Impaired speech Optic atrophy Nystagmus Diffuse bilateral symmetric signal abnormality in cerebral white matter In some cases, signal abnormalities in the corpus callosum, internal capsule, midbrain, middle cerebellar peduncles, and cervical spinal cord Serum and CSF lactate may be elevated, but this is not a consistent finding. Plasma and CSF glycine levels are usually elevated [ Plasma acylcarnitine and urine organic acids analyses are usually unremarkable [ Note: (1) Respiratory chain enzyme analysis is not required to make the diagnosis. (2) More invasive testing that requires a skin or muscle biopsy sample may be bypassed in favor of molecular genetic testing on a peripheral blood sample (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 use of a Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of IRMD is similar to a wide range of neurodegenerative conditions, genomic testing is typically pursued first. For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See One pathogenic founder variant has been reported [ Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and 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. • Progressive loss of developmental milestones, typically beginning between ages three and seven months • Spasticity • Impaired speech • Optic atrophy • Nystagmus • Diffuse bilateral symmetric signal abnormality in cerebral white matter • In some cases, signal abnormalities in the corpus callosum, internal capsule, midbrain, middle cerebellar peduncles, and cervical spinal cord • • Serum and CSF lactate may be elevated, but this is not a consistent finding. • Plasma and CSF glycine levels are usually elevated [ • Plasma acylcarnitine and urine organic acids analyses are usually unremarkable [ • Serum and CSF lactate may be elevated, but this is not a consistent finding. • Plasma and CSF glycine levels are usually elevated [ • Plasma acylcarnitine and urine organic acids analyses are usually unremarkable [ • Serum and CSF lactate may be elevated, but this is not a consistent finding. • Plasma and CSF glycine levels are usually elevated [ • Plasma acylcarnitine and urine organic acids analyses are usually unremarkable [ ## Suggestive Findings IRMD Progressive loss of developmental milestones, typically beginning between ages three and seven months Spasticity Impaired speech Optic atrophy Nystagmus Diffuse bilateral symmetric signal abnormality in cerebral white matter In some cases, signal abnormalities in the corpus callosum, internal capsule, midbrain, middle cerebellar peduncles, and cervical spinal cord Serum and CSF lactate may be elevated, but this is not a consistent finding. Plasma and CSF glycine levels are usually elevated [ Plasma acylcarnitine and urine organic acids analyses are usually unremarkable [ Note: (1) Respiratory chain enzyme analysis is not required to make the diagnosis. (2) More invasive testing that requires a skin or muscle biopsy sample may be bypassed in favor of molecular genetic testing on a peripheral blood sample (see • Progressive loss of developmental milestones, typically beginning between ages three and seven months • Spasticity • Impaired speech • Optic atrophy • Nystagmus • Diffuse bilateral symmetric signal abnormality in cerebral white matter • In some cases, signal abnormalities in the corpus callosum, internal capsule, midbrain, middle cerebellar peduncles, and cervical spinal cord • • Serum and CSF lactate may be elevated, but this is not a consistent finding. • Plasma and CSF glycine levels are usually elevated [ • Plasma acylcarnitine and urine organic acids analyses are usually unremarkable [ • Serum and CSF lactate may be elevated, but this is not a consistent finding. • Plasma and CSF glycine levels are usually elevated [ • Plasma acylcarnitine and urine organic acids analyses are usually unremarkable [ • Serum and CSF lactate may be elevated, but this is not a consistent finding. • Plasma and CSF glycine levels are usually elevated [ • Plasma acylcarnitine and urine organic acids analyses are usually unremarkable [ ## 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 use of a Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of IRMD is similar to a wide range of neurodegenerative conditions, genomic testing is typically pursued first. For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See One pathogenic founder variant has been reported [ Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and 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 Genomic Testing For an introduction to multigene panels click For an introduction to comprehensive genomic testing click ## Further Testing to Consider Molecular Genetic Testing Used in See See One pathogenic founder variant has been reported [ Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and 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 Only 20 individuals with this condition have been reported [ Dysmorphic features (low-set ears, broad nasal bridge, short fourth metacarpals, cutaneous toe syndactyly) have been rarely observed (2/18) [ A rapidly progressive severe course with neonatal leukoencephalopathy and death at age three months was reported in a single affected individual who had biallelic novel (non-founder) pathogenic Since so few cases have been identified, understanding of the clinical phenotypic spectrum and natural history continues to evolve. One affected infant who had diffuse hypotonia, a rapidly progressive course, and no optic atrophy was found to have biallelic novel (non-founder) pathogenic The prevalence of IRMD is unknown. Twenty affected individuals from 18 families have been reported in the literature [ ## Clinical Description Only 20 individuals with this condition have been reported [ Dysmorphic features (low-set ears, broad nasal bridge, short fourth metacarpals, cutaneous toe syndactyly) have been rarely observed (2/18) [ A rapidly progressive severe course with neonatal leukoencephalopathy and death at age three months was reported in a single affected individual who had biallelic novel (non-founder) pathogenic Since so few cases have been identified, understanding of the clinical phenotypic spectrum and natural history continues to evolve. ## Genotype-Phenotype Correlations One affected infant who had diffuse hypotonia, a rapidly progressive course, and no optic atrophy was found to have biallelic novel (non-founder) pathogenic ## Prevalence The prevalence of IRMD is unknown. Twenty affected individuals from 18 families have been reported in the literature [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The differential diagnosis of neurologic regression with white matter disease in infancy is extensive. Diagnostic algorithms for genetic leukodystrophy disorders have been published. In Disorders to Consider in the Differential Diagnosis of Feeding difficulties Muscle weakness Decreasing responsiveness Neurologic regression White matter lesions on brain MRI Lactic acidosis ↓ activity of mt respiratory complexes Pulmonary hypertension Obstructive vasculopathy Spongiform degeneration & white matter necrosis Onset soon after birth Optic atrophy Visual impairment Spasticity Leukodystrophy Spinal cord lesions Lactic acidosis Onset in infancy ↓ activity of mt respiratory complexes Cardiomyopathy Hepatomegaly Extrapyramidal signs Ataxia Myoclonus White matter abnormalities Lactic acidosis ↓ activity of mt respiratory complexes Onset in utero Intrauterine growth restriction Microcephaly Dysmorphic features (retrognathia, high-arched palate, widely spaced nipples) Arthrogryposis Severe hypotonia Polymicrogyria Hypoplasia of the corpus callosum Hypoplasia of the medulla oblongata Neurologic regression White matter abnormalities Lactic acidosis Neurologic regression Leukodystrophy Spasticity Optic atrophy Neurologic regression Leukodystrophy Spasticity Optic atrophy Neurologic regression ↑ lactate in serum & MR spectroscopy Neurologic regression Leukodystrophy Spasticity Optic atrophy Unsteady gait Pattern of MRI findings Ovarian dysgenesis in females Neurologic regression Leukodystrophy Optic atrophy Macrocephaly Pattern of MRI findings Increased N-acetyl-L-aspartate in urine Neurologic regression Leukodystrophy Spasticity Optic atrophy Macrocephaly Pattern of MRI findings Neurologic regression ↑ lactate in serum & MR spectroscopy Hypertrophic cardiomyopathy Hypertrichosis Renal tubulopathy Liver involvement Bilateral symmetric T Basal ganglia involvement AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; mt = mitochondrial; XL = X-linked See • Feeding difficulties • Muscle weakness • Decreasing responsiveness • Neurologic regression • White matter lesions on brain MRI • Lactic acidosis • ↓ activity of mt respiratory complexes • Pulmonary hypertension • Obstructive vasculopathy • Spongiform degeneration & white matter necrosis • Onset soon after birth • Optic atrophy • Visual impairment • Spasticity • Leukodystrophy • Spinal cord lesions • Lactic acidosis • Onset in infancy • ↓ activity of mt respiratory complexes • Cardiomyopathy • Hepatomegaly • Extrapyramidal signs • Ataxia • Myoclonus • White matter abnormalities • Lactic acidosis • ↓ activity of mt respiratory complexes • Onset in utero • Intrauterine growth restriction • Microcephaly • Dysmorphic features (retrognathia, high-arched palate, widely spaced nipples) • Arthrogryposis • Severe hypotonia • Polymicrogyria • Hypoplasia of the corpus callosum • Hypoplasia of the medulla oblongata • Neurologic regression • White matter abnormalities • Lactic acidosis • Neurologic regression • Leukodystrophy • Spasticity • Optic atrophy • Neurologic regression • Leukodystrophy • Spasticity • Optic atrophy • Neurologic regression • ↑ lactate in serum & MR spectroscopy • Neurologic regression • Leukodystrophy • Spasticity • Optic atrophy • Unsteady gait • Pattern of MRI findings • Ovarian dysgenesis in females • Neurologic regression • Leukodystrophy • Optic atrophy • Macrocephaly • Pattern of MRI findings • Increased N-acetyl-L-aspartate in urine • Neurologic regression • Leukodystrophy • Spasticity • Optic atrophy • Macrocephaly • Pattern of MRI findings • Neurologic regression • ↑ lactate in serum & MR spectroscopy • Hypertrophic cardiomyopathy • Hypertrichosis • Renal tubulopathy • Liver involvement • Bilateral symmetric T • Basal ganglia involvement ## Management To establish the extent of disease and needs in an individual diagnosed with Neurologic evaluation to assess for tone and spasticity Ophthalmologic examination to assess for optic atrophy Brain MRI and MRS Assessment of feeding problems, with consideration of a swallowing study Assessment of nutritional status by monitoring growth parameters and serum chemistries, such as albumin and total protein Consultation with a clinical geneticist and/or genetic counselor The mainstay of treatment is supportive and is best provided by a multidisciplinary team including a geneticist, neurologist, and dietician. Feeding via nasogastric tube or gastrostomy will be required in most cases. Standard treatment for epilepsy is indicated for those who have seizures. Recurrent chest infections may require ventilator support in addition to antimicrobial 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. Explore private supportive therapies based on the affected individual's needs. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. In the US: Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility. Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). With the progression of the disease, constipation can be a problem. Adequate hydration, stool softeners, and laxatives may help in avoiding severe constipation. Periodic evaluation of swallowing function is suggested. Abnormal swallowing may prompt consideration of placement of a feeding tube. See Search • Neurologic evaluation to assess for tone and spasticity • Ophthalmologic examination to assess for optic atrophy • Brain MRI and MRS • Assessment of feeding problems, with consideration of a swallowing study • Assessment of nutritional status by monitoring growth parameters and serum chemistries, such as albumin and total protein • Consultation with a clinical geneticist and/or genetic counselor • Explore private supportive therapies based on the affected individual's needs. 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. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Neurologic evaluation to assess for tone and spasticity Ophthalmologic examination to assess for optic atrophy Brain MRI and MRS Assessment of feeding problems, with consideration of a swallowing study Assessment of nutritional status by monitoring growth parameters and serum chemistries, such as albumin and total protein Consultation with a clinical geneticist and/or genetic counselor • Neurologic evaluation to assess for tone and spasticity • Ophthalmologic examination to assess for optic atrophy • Brain MRI and MRS • Assessment of feeding problems, with consideration of a swallowing study • Assessment of nutritional status by monitoring growth parameters and serum chemistries, such as albumin and total protein • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations The mainstay of treatment is supportive and is best provided by a multidisciplinary team including a geneticist, neurologist, and dietician. Feeding via nasogastric tube or gastrostomy will be required in most cases. Standard treatment for epilepsy is indicated for those who have seizures. Recurrent chest infections may require ventilator support in addition to antimicrobial 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. Explore private supportive therapies based on the affected individual's needs. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. In the US: Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility. Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • Explore private supportive therapies based on the affected individual's needs. 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. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. ## 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. Explore private supportive therapies based on the affected individual's needs. 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. • Explore private supportive therapies based on the affected individual's needs. 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. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. ## Gross Motor Dysfunction Physical therapy is recommended to maximize mobility. Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## Prevention of Secondary Complications With the progression of the disease, constipation can be a problem. Adequate hydration, stool softeners, and laxatives may help in avoiding severe constipation. ## Surveillance Periodic evaluation of swallowing function is suggested. Abnormal swallowing may prompt consideration of placement of a feeding tube. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling The parents of an affected child are obligate heterozygotes (i.e., carriers of one Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Carrier testing for at-risk relatives requires prior identification of the The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected child are obligate heterozygotes (i.e., carriers of one • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. ## Mode of Inheritance ## Risk to Family Members The parents of an affected child are obligate heterozygotes (i.e., carriers of one Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The parents of an affected child are obligate heterozygotes (i.e., carriers of one • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources Australia United Kingdom • • Australia • • • United Kingdom • • • • • ## Molecular Genetics ISCA2-Related Mitochondrial Disorder: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for ISCA2-Related Mitochondrial Disorder ( Variants listed in the table have been provided by the authors. ## Chapter Notes 22 February 2018 (ma) Review posted live 31 July 2017 (znah) Original submission • 22 February 2018 (ma) Review posted live • 31 July 2017 (znah) Original submission ## Revision History 22 February 2018 (ma) Review posted live 31 July 2017 (znah) Original submission • 22 February 2018 (ma) Review posted live • 31 July 2017 (znah) Original submission ## References ## Literature Cited	[ "JT Alaimo, A Besse, CL Alston, K Pang, V Appadurai, M Samanta, P Smpokou, R McFarland, RW Taylor, PE Bonnen. Loss-of-function mutations in ISCA2 disrupt 4Fe-4S cluster machinery and cause a fatal leukodystrophy with hyperglycinemia and mtDNA depletion.. Hum Mutat. 2018;39:537-49", "AM Alazami, N Patel, HE Shamseldin, S Anazi, MS Al-Dosari, F Alzahrani, H Hijazi, M Alshammari, MA Aldahmesh, MA Salih, E Faqeih, A Alhashem, FA Bashiri, M Al-Owain, AY Kentab, S Sogaty, S Al Tala, MH Temsah, M Tulbah, RF Aljelaify, SA Alshahwan, MZ Seidahmed, AA Alhadid, H Aldhalaan, F AlQallaf, W Kurdi, M Alfadhel, Z Babay, M Alsogheer, N Kaya, ZN Al-Hassnan, GM Abdel-Salam, N Al-Sannaa, F Al Mutairi, HY El Khashab, S Bohlega, X Jia, HC Nguyen, R Hammami, N Adly, JY Mohamed, F Abdulwahab, N Ibrahim, EA Naim, B Al-Younes, BF Meyer, M Hashem, R Shaheen, Y Xiong, M Abouelhoda, AA Aldeeri, DM Monies, FS Alkuraya. Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families.. Cell Rep. 2015;10:148-61", "M Alfadhel, M Nashabat, MT Alrifai, H Alshaalan, F Al Mutairi, SA Al-Shahrani, B Plecko, R Almass, M Alsagob, FB Almutairi, A Al-Rumayyan, W Al-Twaijri, M Al-Owain, RW Taylor, N Kaya. Further delineation of the phenotypic spectrum of ISCA2 defect: a report of ten new cases.. Eur J Paediatr Neurol. 2018;22:46-55", "ZN Al-Hassnan, M Al-Dosary, M Alfadhel, EA Faqeih, M Alsagob, R Kenana, R Almass, OS Al-Harazi, H Al-Hindi, OI Malibari, FB Almutari, S Tulbah, F Alhadeq, T Al-Sheddi, R Alamro, A AlAsmari, M Almuntashri, H Alshaalan, FA Al-Mohanna, D Colak, N Kaya. ISCA2 mutation causes infantile neurodegenerative mitochondrial disorder.. J Med Genet. 2015;52:186-94", "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", "I Toldo, M Nosadini, C Boscardin, G Talenti, R Manara, E Lamantea, A Legati, D Ghezzi, G Perilongo, S Sartori. Neonatal mitochondrial leukoencephalopathy with brain and spinal involvement and high lactate: expanding the phenotype of ISCA2 gene mutations.. Metab Brain Dis. 2018;33:805-12" ]	22/2/2018			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
iso-def	iso-def	[ "Sulfocysteinuria", "Sulfocysteinuria", "Sulfite oxidase, mitochondrial", "SUOX", "Isolated Sulfite Oxidase Deficiency" ]	Isolated Sulfite Oxidase Deficiency	Parayil Sankaran Bindu, Madhu Nagappa, Rose Dawn Bharath, Arun B Taly	Summary The spectrum of isolated sulfite oxidase deficiency ranges from classic early-onset (severe) disease to late-onset (mild) disease. Laboratory findings that suggest the diagnosis of ISOD are dipstick positive for urinary sulfite, elevated urinary thiosulfate and S-sulfocysteine, low urinary organic sulfate, and markedly reduced plasma levels of total homocysteine. The diagnosis is confirmed by identification of biallelic pathogenic variants in ISOD is inherited in an autosomal recessive manner. The parents of an affected child are asymptomatic obligate heterozygotes (i.e., carriers of one	## Diagnosis Intractable seizures and feeding difficulties in the first few hours to days of life Progressive encephalopathy manifest as abnormal tone (especially opisthotonus, spastic quadriplegia, and pyramidal signs) Progressive microcephaly Profound intellectual disability Dysmorphic facial features: long face, narrow bifrontal diameter, deep and widely set eyes, elongated palpebral fissures, puffy cheeks, small nose, long philtrum, and thick lips ( Lens subluxation or dislocation (ectopia lentis) after the newborn period Family history consistent with autosomal recessive inheritance Onset usually between age six and 18 months, often precipitated by febrile illness Ectopia lentis (variably present) Developmental regression Episodic encephalopathy, ataxia, choreoathetosis, and dystonia Acute hemiparesis as a result of metabolic stroke During the first week, loss of gray-white matter differentiation and edema in the cerebral cortex and basal ganglia During the ensuing weeks, development of the following: Cystic encephalomalacia in the subcortical white matter, external capsules, and basal ganglia Ventriculomegaly and diffuse cerebral atrophy, which may be consistent with ulegyria Thinning of the corpus callosum Of note: Marked cerebellar hypoplasia and the progressive cystic and atrophic changes seen ISOD help differentiate it from mild-to-moderate hypoxic ischemic encephalopathy, in which the cerebellum, brain stem, and deep gray matter structures are usually spared [ Note: (1) Urinary sulfite is very unstable and disappears rapidly from urine either at room temperature or even when urine is stored at 40° C; therefore, testing immediately after voiding is recommended [ Drugs containing free aliphatic sulfhydryl group such as N-acetyl cysteine, mercaptamine, dimercaprol, and mucolite drug 2-mercaptoethane sulfonate; Certain antibiotics such as cefotaxime, cefuroxime, ampicillin, and benzylpenicillin [ Bacterial degradation of urine samples as reflected by increased levels of compounds such as succinic acid, benzoic acid, 2-hydroxyglutaric acid, and uracil [ The diagnosis of ISOD 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 isolated sulfite oxidase deficiency is broad, children with the distinctive findings of classic ISOD described in When the phenotypic and laboratory findings suggest the diagnosis of ISOD, molecular genetic testing approaches can include For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited neonatal seizures, molecular genetic testing approaches can include For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Isolated Sulfite Oxidase Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. • Intractable seizures and feeding difficulties in the first few hours to days of life • Progressive encephalopathy manifest as abnormal tone (especially opisthotonus, spastic quadriplegia, and pyramidal signs) • Progressive microcephaly • Profound intellectual disability • Dysmorphic facial features: long face, narrow bifrontal diameter, deep and widely set eyes, elongated palpebral fissures, puffy cheeks, small nose, long philtrum, and thick lips ( • Lens subluxation or dislocation (ectopia lentis) after the newborn period • Family history consistent with autosomal recessive inheritance • Onset usually between age six and 18 months, often precipitated by febrile illness • Ectopia lentis (variably present) • Developmental regression • Episodic encephalopathy, ataxia, choreoathetosis, and dystonia • Acute hemiparesis as a result of metabolic stroke • During the first week, loss of gray-white matter differentiation and edema in the cerebral cortex and basal ganglia • During the ensuing weeks, development of the following: • Cystic encephalomalacia in the subcortical white matter, external capsules, and basal ganglia • Ventriculomegaly and diffuse cerebral atrophy, which may be consistent with ulegyria • Thinning of the corpus callosum • During the first week, loss of gray-white matter differentiation and edema in the cerebral cortex and basal ganglia • During the ensuing weeks, development of the following: • Cystic encephalomalacia in the subcortical white matter, external capsules, and basal ganglia • Ventriculomegaly and diffuse cerebral atrophy, which may be consistent with ulegyria • Thinning of the corpus callosum • Cystic encephalomalacia in the subcortical white matter, external capsules, and basal ganglia • Ventriculomegaly and diffuse cerebral atrophy, which may be consistent with ulegyria • Thinning of the corpus callosum • Of note: Marked cerebellar hypoplasia and the progressive cystic and atrophic changes seen ISOD help differentiate it from mild-to-moderate hypoxic ischemic encephalopathy, in which the cerebellum, brain stem, and deep gray matter structures are usually spared [ • During the first week, loss of gray-white matter differentiation and edema in the cerebral cortex and basal ganglia • During the ensuing weeks, development of the following: • Cystic encephalomalacia in the subcortical white matter, external capsules, and basal ganglia • Ventriculomegaly and diffuse cerebral atrophy, which may be consistent with ulegyria • Thinning of the corpus callosum • Cystic encephalomalacia in the subcortical white matter, external capsules, and basal ganglia • Ventriculomegaly and diffuse cerebral atrophy, which may be consistent with ulegyria • Thinning of the corpus callosum • Cystic encephalomalacia in the subcortical white matter, external capsules, and basal ganglia • Ventriculomegaly and diffuse cerebral atrophy, which may be consistent with ulegyria • Thinning of the corpus callosum • • Note: (1) Urinary sulfite is very unstable and disappears rapidly from urine either at room temperature or even when urine is stored at 40° C; therefore, testing immediately after voiding is recommended [ • Drugs containing free aliphatic sulfhydryl group such as N-acetyl cysteine, mercaptamine, dimercaprol, and mucolite drug 2-mercaptoethane sulfonate; • Certain antibiotics such as cefotaxime, cefuroxime, ampicillin, and benzylpenicillin [ • Bacterial degradation of urine samples as reflected by increased levels of compounds such as succinic acid, benzoic acid, 2-hydroxyglutaric acid, and uracil [ • Drugs containing free aliphatic sulfhydryl group such as N-acetyl cysteine, mercaptamine, dimercaprol, and mucolite drug 2-mercaptoethane sulfonate; • Certain antibiotics such as cefotaxime, cefuroxime, ampicillin, and benzylpenicillin [ • Bacterial degradation of urine samples as reflected by increased levels of compounds such as succinic acid, benzoic acid, 2-hydroxyglutaric acid, and uracil [ • Drugs containing free aliphatic sulfhydryl group such as N-acetyl cysteine, mercaptamine, dimercaprol, and mucolite drug 2-mercaptoethane sulfonate; • Certain antibiotics such as cefotaxime, cefuroxime, ampicillin, and benzylpenicillin [ • Bacterial degradation of urine samples as reflected by increased levels of compounds such as succinic acid, benzoic acid, 2-hydroxyglutaric acid, and uracil [ • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings Intractable seizures and feeding difficulties in the first few hours to days of life Progressive encephalopathy manifest as abnormal tone (especially opisthotonus, spastic quadriplegia, and pyramidal signs) Progressive microcephaly Profound intellectual disability Dysmorphic facial features: long face, narrow bifrontal diameter, deep and widely set eyes, elongated palpebral fissures, puffy cheeks, small nose, long philtrum, and thick lips ( Lens subluxation or dislocation (ectopia lentis) after the newborn period Family history consistent with autosomal recessive inheritance Onset usually between age six and 18 months, often precipitated by febrile illness Ectopia lentis (variably present) Developmental regression Episodic encephalopathy, ataxia, choreoathetosis, and dystonia Acute hemiparesis as a result of metabolic stroke During the first week, loss of gray-white matter differentiation and edema in the cerebral cortex and basal ganglia During the ensuing weeks, development of the following: Cystic encephalomalacia in the subcortical white matter, external capsules, and basal ganglia Ventriculomegaly and diffuse cerebral atrophy, which may be consistent with ulegyria Thinning of the corpus callosum Of note: Marked cerebellar hypoplasia and the progressive cystic and atrophic changes seen ISOD help differentiate it from mild-to-moderate hypoxic ischemic encephalopathy, in which the cerebellum, brain stem, and deep gray matter structures are usually spared [ Note: (1) Urinary sulfite is very unstable and disappears rapidly from urine either at room temperature or even when urine is stored at 40° C; therefore, testing immediately after voiding is recommended [ Drugs containing free aliphatic sulfhydryl group such as N-acetyl cysteine, mercaptamine, dimercaprol, and mucolite drug 2-mercaptoethane sulfonate; Certain antibiotics such as cefotaxime, cefuroxime, ampicillin, and benzylpenicillin [ Bacterial degradation of urine samples as reflected by increased levels of compounds such as succinic acid, benzoic acid, 2-hydroxyglutaric acid, and uracil [ • Intractable seizures and feeding difficulties in the first few hours to days of life • Progressive encephalopathy manifest as abnormal tone (especially opisthotonus, spastic quadriplegia, and pyramidal signs) • Progressive microcephaly • Profound intellectual disability • Dysmorphic facial features: long face, narrow bifrontal diameter, deep and widely set eyes, elongated palpebral fissures, puffy cheeks, small nose, long philtrum, and thick lips ( • Lens subluxation or dislocation (ectopia lentis) after the newborn period • Family history consistent with autosomal recessive inheritance • Onset usually between age six and 18 months, often precipitated by febrile illness • Ectopia lentis (variably present) • Developmental regression • Episodic encephalopathy, ataxia, choreoathetosis, and dystonia • Acute hemiparesis as a result of metabolic stroke • During the first week, loss of gray-white matter differentiation and edema in the cerebral cortex and basal ganglia • During the ensuing weeks, development of the following: • Cystic encephalomalacia in the subcortical white matter, external capsules, and basal ganglia • Ventriculomegaly and diffuse cerebral atrophy, which may be consistent with ulegyria • Thinning of the corpus callosum • During the first week, loss of gray-white matter differentiation and edema in the cerebral cortex and basal ganglia • During the ensuing weeks, development of the following: • Cystic encephalomalacia in the subcortical white matter, external capsules, and basal ganglia • Ventriculomegaly and diffuse cerebral atrophy, which may be consistent with ulegyria • Thinning of the corpus callosum • Cystic encephalomalacia in the subcortical white matter, external capsules, and basal ganglia • Ventriculomegaly and diffuse cerebral atrophy, which may be consistent with ulegyria • Thinning of the corpus callosum • Of note: Marked cerebellar hypoplasia and the progressive cystic and atrophic changes seen ISOD help differentiate it from mild-to-moderate hypoxic ischemic encephalopathy, in which the cerebellum, brain stem, and deep gray matter structures are usually spared [ • During the first week, loss of gray-white matter differentiation and edema in the cerebral cortex and basal ganglia • During the ensuing weeks, development of the following: • Cystic encephalomalacia in the subcortical white matter, external capsules, and basal ganglia • Ventriculomegaly and diffuse cerebral atrophy, which may be consistent with ulegyria • Thinning of the corpus callosum • Cystic encephalomalacia in the subcortical white matter, external capsules, and basal ganglia • Ventriculomegaly and diffuse cerebral atrophy, which may be consistent with ulegyria • Thinning of the corpus callosum • Cystic encephalomalacia in the subcortical white matter, external capsules, and basal ganglia • Ventriculomegaly and diffuse cerebral atrophy, which may be consistent with ulegyria • Thinning of the corpus callosum • • Note: (1) Urinary sulfite is very unstable and disappears rapidly from urine either at room temperature or even when urine is stored at 40° C; therefore, testing immediately after voiding is recommended [ • Drugs containing free aliphatic sulfhydryl group such as N-acetyl cysteine, mercaptamine, dimercaprol, and mucolite drug 2-mercaptoethane sulfonate; • Certain antibiotics such as cefotaxime, cefuroxime, ampicillin, and benzylpenicillin [ • Bacterial degradation of urine samples as reflected by increased levels of compounds such as succinic acid, benzoic acid, 2-hydroxyglutaric acid, and uracil [ • Drugs containing free aliphatic sulfhydryl group such as N-acetyl cysteine, mercaptamine, dimercaprol, and mucolite drug 2-mercaptoethane sulfonate; • Certain antibiotics such as cefotaxime, cefuroxime, ampicillin, and benzylpenicillin [ • Bacterial degradation of urine samples as reflected by increased levels of compounds such as succinic acid, benzoic acid, 2-hydroxyglutaric acid, and uracil [ • Drugs containing free aliphatic sulfhydryl group such as N-acetyl cysteine, mercaptamine, dimercaprol, and mucolite drug 2-mercaptoethane sulfonate; • Certain antibiotics such as cefotaxime, cefuroxime, ampicillin, and benzylpenicillin [ • Bacterial degradation of urine samples as reflected by increased levels of compounds such as succinic acid, benzoic acid, 2-hydroxyglutaric acid, and uracil [ ## Clinical Features Intractable seizures and feeding difficulties in the first few hours to days of life Progressive encephalopathy manifest as abnormal tone (especially opisthotonus, spastic quadriplegia, and pyramidal signs) Progressive microcephaly Profound intellectual disability Dysmorphic facial features: long face, narrow bifrontal diameter, deep and widely set eyes, elongated palpebral fissures, puffy cheeks, small nose, long philtrum, and thick lips ( Lens subluxation or dislocation (ectopia lentis) after the newborn period Family history consistent with autosomal recessive inheritance Onset usually between age six and 18 months, often precipitated by febrile illness Ectopia lentis (variably present) Developmental regression Episodic encephalopathy, ataxia, choreoathetosis, and dystonia Acute hemiparesis as a result of metabolic stroke • Intractable seizures and feeding difficulties in the first few hours to days of life • Progressive encephalopathy manifest as abnormal tone (especially opisthotonus, spastic quadriplegia, and pyramidal signs) • Progressive microcephaly • Profound intellectual disability • Dysmorphic facial features: long face, narrow bifrontal diameter, deep and widely set eyes, elongated palpebral fissures, puffy cheeks, small nose, long philtrum, and thick lips ( • Lens subluxation or dislocation (ectopia lentis) after the newborn period • Family history consistent with autosomal recessive inheritance • Onset usually between age six and 18 months, often precipitated by febrile illness • Ectopia lentis (variably present) • Developmental regression • Episodic encephalopathy, ataxia, choreoathetosis, and dystonia • Acute hemiparesis as a result of metabolic stroke ## Neuroimaging Findings During the first week, loss of gray-white matter differentiation and edema in the cerebral cortex and basal ganglia During the ensuing weeks, development of the following: Cystic encephalomalacia in the subcortical white matter, external capsules, and basal ganglia Ventriculomegaly and diffuse cerebral atrophy, which may be consistent with ulegyria Thinning of the corpus callosum Of note: Marked cerebellar hypoplasia and the progressive cystic and atrophic changes seen ISOD help differentiate it from mild-to-moderate hypoxic ischemic encephalopathy, in which the cerebellum, brain stem, and deep gray matter structures are usually spared [ • During the first week, loss of gray-white matter differentiation and edema in the cerebral cortex and basal ganglia • During the ensuing weeks, development of the following: • Cystic encephalomalacia in the subcortical white matter, external capsules, and basal ganglia • Ventriculomegaly and diffuse cerebral atrophy, which may be consistent with ulegyria • Thinning of the corpus callosum • During the first week, loss of gray-white matter differentiation and edema in the cerebral cortex and basal ganglia • During the ensuing weeks, development of the following: • Cystic encephalomalacia in the subcortical white matter, external capsules, and basal ganglia • Ventriculomegaly and diffuse cerebral atrophy, which may be consistent with ulegyria • Thinning of the corpus callosum • Cystic encephalomalacia in the subcortical white matter, external capsules, and basal ganglia • Ventriculomegaly and diffuse cerebral atrophy, which may be consistent with ulegyria • Thinning of the corpus callosum • Of note: Marked cerebellar hypoplasia and the progressive cystic and atrophic changes seen ISOD help differentiate it from mild-to-moderate hypoxic ischemic encephalopathy, in which the cerebellum, brain stem, and deep gray matter structures are usually spared [ • During the first week, loss of gray-white matter differentiation and edema in the cerebral cortex and basal ganglia • During the ensuing weeks, development of the following: • Cystic encephalomalacia in the subcortical white matter, external capsules, and basal ganglia • Ventriculomegaly and diffuse cerebral atrophy, which may be consistent with ulegyria • Thinning of the corpus callosum • Cystic encephalomalacia in the subcortical white matter, external capsules, and basal ganglia • Ventriculomegaly and diffuse cerebral atrophy, which may be consistent with ulegyria • Thinning of the corpus callosum • Cystic encephalomalacia in the subcortical white matter, external capsules, and basal ganglia • Ventriculomegaly and diffuse cerebral atrophy, which may be consistent with ulegyria • Thinning of the corpus callosum ## Laboratory Findings Note: (1) Urinary sulfite is very unstable and disappears rapidly from urine either at room temperature or even when urine is stored at 40° C; therefore, testing immediately after voiding is recommended [ Drugs containing free aliphatic sulfhydryl group such as N-acetyl cysteine, mercaptamine, dimercaprol, and mucolite drug 2-mercaptoethane sulfonate; Certain antibiotics such as cefotaxime, cefuroxime, ampicillin, and benzylpenicillin [ Bacterial degradation of urine samples as reflected by increased levels of compounds such as succinic acid, benzoic acid, 2-hydroxyglutaric acid, and uracil [ • • Note: (1) Urinary sulfite is very unstable and disappears rapidly from urine either at room temperature or even when urine is stored at 40° C; therefore, testing immediately after voiding is recommended [ • Drugs containing free aliphatic sulfhydryl group such as N-acetyl cysteine, mercaptamine, dimercaprol, and mucolite drug 2-mercaptoethane sulfonate; • Certain antibiotics such as cefotaxime, cefuroxime, ampicillin, and benzylpenicillin [ • Bacterial degradation of urine samples as reflected by increased levels of compounds such as succinic acid, benzoic acid, 2-hydroxyglutaric acid, and uracil [ • Drugs containing free aliphatic sulfhydryl group such as N-acetyl cysteine, mercaptamine, dimercaprol, and mucolite drug 2-mercaptoethane sulfonate; • Certain antibiotics such as cefotaxime, cefuroxime, ampicillin, and benzylpenicillin [ • Bacterial degradation of urine samples as reflected by increased levels of compounds such as succinic acid, benzoic acid, 2-hydroxyglutaric acid, and uracil [ • Drugs containing free aliphatic sulfhydryl group such as N-acetyl cysteine, mercaptamine, dimercaprol, and mucolite drug 2-mercaptoethane sulfonate; • Certain antibiotics such as cefotaxime, cefuroxime, ampicillin, and benzylpenicillin [ • Bacterial degradation of urine samples as reflected by increased levels of compounds such as succinic acid, benzoic acid, 2-hydroxyglutaric acid, and uracil [ ## Establishing the Diagnosis The diagnosis of ISOD 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 isolated sulfite oxidase deficiency is broad, children with the distinctive findings of classic ISOD described in When the phenotypic and laboratory findings suggest the diagnosis of ISOD, molecular genetic testing approaches can include For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited neonatal seizures, molecular genetic testing approaches can include For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Isolated Sulfite Oxidase Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 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 ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of ISOD, 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 neonatal seizures, molecular genetic testing approaches can include For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Isolated Sulfite Oxidase Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. • For an introduction to comprehensive genomic testing click ## Clinical Characteristics Isolated sulfite oxidase deficiency (ISOD), a rare inborn error of metabolism of sulfur-containing amino acids, comprises a spectrum ranging from classic early-onset (severe) disease to late-onset (mild) disease [ Classic ISOD typically manifests within few hours to days of life with intractable seizures, feeding difficulties, and rapidly progressive encephalopathy [ Almost all affected infants are born after uncomplicated pregnancy. Of note, sustained abdominal trembling resembling vibration of mobile phones (interpreted as fetal seizures) has been reported in the third trimester in one instance [ Multiple types of seizures including tonic-clonic and multifocal myoclonic seizures not responding to treatment are the main feature [ Neurologic examination reveals abnormalities in tone including opisthotonus, spastic quadriplegia, and pyramidal signs. All affected children develop profound psychomotor retardation: neurologic development is halted at the level of brain stem reflexes and children lack any response to environmental stimulation except for exaggerated startle and intermittent seizures [ Although head circumference is normal at birth, severe progressive postnatal microcephaly develops [ Systemic manifestations are rare and can include such findings as severe asthma and pyloric stenosis [ Prognosis is poor and children usually die during the first few months of life. A significant proportion of infants who survive the newborn period develop ectopia lentis (lens dislocation or subluxation) [ Late-onset ISOD differs from the classic form in that onset is between ages six and 18 months and some suggestive findings (e.g., intractable seizures, ectopia lentis) may be absent. The main clinical features are developmental delay/regression, movement disorder characterized by dystonia and choreoathetosis, ataxia, and (rarely) acute hemiplegia as a result of metabolic stroke. The clinical course may be progressive or episodic. In the episodic form encephalopathy, dystonia, choreoathetosis, and/or ataxia are intermittent [ Ectopia lentis (lens dislocation or subluxation) may or may not be present at the time of presentation. The number of individuals with confirmed pathogenic variants in Prevalence of ISOD is unknown. Approximately 50 affected individuals have been reported to date. The disorder is probably underdiagnosed. The incidence may be higher in populations with a high rate of consanguinity. ## Clinical Description Isolated sulfite oxidase deficiency (ISOD), a rare inborn error of metabolism of sulfur-containing amino acids, comprises a spectrum ranging from classic early-onset (severe) disease to late-onset (mild) disease [ Classic ISOD typically manifests within few hours to days of life with intractable seizures, feeding difficulties, and rapidly progressive encephalopathy [ Almost all affected infants are born after uncomplicated pregnancy. Of note, sustained abdominal trembling resembling vibration of mobile phones (interpreted as fetal seizures) has been reported in the third trimester in one instance [ Multiple types of seizures including tonic-clonic and multifocal myoclonic seizures not responding to treatment are the main feature [ Neurologic examination reveals abnormalities in tone including opisthotonus, spastic quadriplegia, and pyramidal signs. All affected children develop profound psychomotor retardation: neurologic development is halted at the level of brain stem reflexes and children lack any response to environmental stimulation except for exaggerated startle and intermittent seizures [ Although head circumference is normal at birth, severe progressive postnatal microcephaly develops [ Systemic manifestations are rare and can include such findings as severe asthma and pyloric stenosis [ Prognosis is poor and children usually die during the first few months of life. A significant proportion of infants who survive the newborn period develop ectopia lentis (lens dislocation or subluxation) [ Late-onset ISOD differs from the classic form in that onset is between ages six and 18 months and some suggestive findings (e.g., intractable seizures, ectopia lentis) may be absent. The main clinical features are developmental delay/regression, movement disorder characterized by dystonia and choreoathetosis, ataxia, and (rarely) acute hemiplegia as a result of metabolic stroke. The clinical course may be progressive or episodic. In the episodic form encephalopathy, dystonia, choreoathetosis, and/or ataxia are intermittent [ Ectopia lentis (lens dislocation or subluxation) may or may not be present at the time of presentation. ## Classic ISOD Classic ISOD typically manifests within few hours to days of life with intractable seizures, feeding difficulties, and rapidly progressive encephalopathy [ Almost all affected infants are born after uncomplicated pregnancy. Of note, sustained abdominal trembling resembling vibration of mobile phones (interpreted as fetal seizures) has been reported in the third trimester in one instance [ Multiple types of seizures including tonic-clonic and multifocal myoclonic seizures not responding to treatment are the main feature [ Neurologic examination reveals abnormalities in tone including opisthotonus, spastic quadriplegia, and pyramidal signs. All affected children develop profound psychomotor retardation: neurologic development is halted at the level of brain stem reflexes and children lack any response to environmental stimulation except for exaggerated startle and intermittent seizures [ Although head circumference is normal at birth, severe progressive postnatal microcephaly develops [ Systemic manifestations are rare and can include such findings as severe asthma and pyloric stenosis [ Prognosis is poor and children usually die during the first few months of life. A significant proportion of infants who survive the newborn period develop ectopia lentis (lens dislocation or subluxation) [ ## Late-Onset ISOD Late-onset ISOD differs from the classic form in that onset is between ages six and 18 months and some suggestive findings (e.g., intractable seizures, ectopia lentis) may be absent. The main clinical features are developmental delay/regression, movement disorder characterized by dystonia and choreoathetosis, ataxia, and (rarely) acute hemiplegia as a result of metabolic stroke. The clinical course may be progressive or episodic. In the episodic form encephalopathy, dystonia, choreoathetosis, and/or ataxia are intermittent [ Ectopia lentis (lens dislocation or subluxation) may or may not be present at the time of presentation. ## Genotype-Phenotype Correlations The number of individuals with confirmed pathogenic variants in ## Prevalence Prevalence of ISOD is unknown. Approximately 50 affected individuals have been reported to date. The disorder is probably underdiagnosed. The incidence may be higher in populations with a high rate of consanguinity. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Disorders to Consider in the Differential Diagnosis of Isolated Sulfite Oxidase Deficiency (ISOD) ASM = anti-seizure medication; AR = autosomal recessive; DiffDx = differential diagnosis; ID = intellectual disability; MOI = mode of inheritance ## Management To establish the extent of disease and/or needs in an individual with a diagnosis of isolated sulfite oxidase deficiency (ISOD), the following evaluations are recommended: Complete neurologic assessment by a pediatric neurologist Formal developmental assessment Ophthalmologic evaluation EEG/video EEG to monitor seizures Assessment of feeding and nutrition and appropriate intervention Consultation with a clinical geneticist and/or genetic counselor To date, no definitive treatment for ISOD has been identified. Symptomatic management by a multidisciplinary team consisting of specialists in neurology, nutrition, gastroenterology, pulmonary medicine, physiotherapy, and orthopedics is recommended. Management includes the following: Appropriate medications for management of seizures and spasticity Early consideration of gastrostomy tube placement to manage difficulties with swallowing to assure adequate caloric intake and reduce the risk of aspiration. Appropriate management of vomiting, gastroesophageal reflux disease, and aspiration pneumonia Chest physiotherapy to prevent respiratory complications Sleep studies to assess nocturnal hypoventilation and institute appropriate interventions Assessment for scoliosis The following treatment modalities have been tried with minimal success: Betaine has been used to increase the remethylation of homocysteine back to methionine, which reduces cysteine and leads to reduction in sulfite levels. Thiamine replacement has been attempted (given that the accumulation of sulfite leads to depletion of thiamine). Use of cysteamine and penicillamine (chelating agents used to chelate sulfite) resulted in no beneficial clinical effects. Periodic assessment by the multidisciplinary team with particular attention to the following: Nutritional status Neurologic status including evaluation of dosages of anti-seizure medication and their side effects Degree of spasticity and related complications, including scoliosis Periodic sleep studies See Search • Complete neurologic assessment by a pediatric neurologist • Formal developmental assessment • Ophthalmologic evaluation • EEG/video EEG to monitor seizures • Assessment of feeding and nutrition and appropriate intervention • Consultation with a clinical geneticist and/or genetic counselor • Appropriate medications for management of seizures and spasticity • Early consideration of gastrostomy tube placement to manage difficulties with swallowing to assure adequate caloric intake and reduce the risk of aspiration. • Appropriate management of vomiting, gastroesophageal reflux disease, and aspiration pneumonia • Chest physiotherapy to prevent respiratory complications • Sleep studies to assess nocturnal hypoventilation and institute appropriate interventions • Assessment for scoliosis • Betaine has been used to increase the remethylation of homocysteine back to methionine, which reduces cysteine and leads to reduction in sulfite levels. • Thiamine replacement has been attempted (given that the accumulation of sulfite leads to depletion of thiamine). • Use of cysteamine and penicillamine (chelating agents used to chelate sulfite) resulted in no beneficial clinical effects. • Betaine has been used to increase the remethylation of homocysteine back to methionine, which reduces cysteine and leads to reduction in sulfite levels. • Thiamine replacement has been attempted (given that the accumulation of sulfite leads to depletion of thiamine). • Use of cysteamine and penicillamine (chelating agents used to chelate sulfite) resulted in no beneficial clinical effects. • Betaine has been used to increase the remethylation of homocysteine back to methionine, which reduces cysteine and leads to reduction in sulfite levels. • Thiamine replacement has been attempted (given that the accumulation of sulfite leads to depletion of thiamine). • Use of cysteamine and penicillamine (chelating agents used to chelate sulfite) resulted in no beneficial clinical effects. • Nutritional status • Neurologic status including evaluation of dosages of anti-seizure medication and their side effects • Degree of spasticity and related complications, including scoliosis • Periodic sleep studies ## Evaluations Following Initial Diagnosis To establish the extent of disease and/or needs in an individual with a diagnosis of isolated sulfite oxidase deficiency (ISOD), the following evaluations are recommended: Complete neurologic assessment by a pediatric neurologist Formal developmental assessment Ophthalmologic evaluation EEG/video EEG to monitor seizures Assessment of feeding and nutrition and appropriate intervention Consultation with a clinical geneticist and/or genetic counselor • Complete neurologic assessment by a pediatric neurologist • Formal developmental assessment • Ophthalmologic evaluation • EEG/video EEG to monitor seizures • Assessment of feeding and nutrition and appropriate intervention • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations To date, no definitive treatment for ISOD has been identified. Symptomatic management by a multidisciplinary team consisting of specialists in neurology, nutrition, gastroenterology, pulmonary medicine, physiotherapy, and orthopedics is recommended. Management includes the following: Appropriate medications for management of seizures and spasticity Early consideration of gastrostomy tube placement to manage difficulties with swallowing to assure adequate caloric intake and reduce the risk of aspiration. Appropriate management of vomiting, gastroesophageal reflux disease, and aspiration pneumonia Chest physiotherapy to prevent respiratory complications Sleep studies to assess nocturnal hypoventilation and institute appropriate interventions Assessment for scoliosis The following treatment modalities have been tried with minimal success: Betaine has been used to increase the remethylation of homocysteine back to methionine, which reduces cysteine and leads to reduction in sulfite levels. Thiamine replacement has been attempted (given that the accumulation of sulfite leads to depletion of thiamine). Use of cysteamine and penicillamine (chelating agents used to chelate sulfite) resulted in no beneficial clinical effects. • Appropriate medications for management of seizures and spasticity • Early consideration of gastrostomy tube placement to manage difficulties with swallowing to assure adequate caloric intake and reduce the risk of aspiration. • Appropriate management of vomiting, gastroesophageal reflux disease, and aspiration pneumonia • Chest physiotherapy to prevent respiratory complications • Sleep studies to assess nocturnal hypoventilation and institute appropriate interventions • Assessment for scoliosis • Betaine has been used to increase the remethylation of homocysteine back to methionine, which reduces cysteine and leads to reduction in sulfite levels. • Thiamine replacement has been attempted (given that the accumulation of sulfite leads to depletion of thiamine). • Use of cysteamine and penicillamine (chelating agents used to chelate sulfite) resulted in no beneficial clinical effects. • Betaine has been used to increase the remethylation of homocysteine back to methionine, which reduces cysteine and leads to reduction in sulfite levels. • Thiamine replacement has been attempted (given that the accumulation of sulfite leads to depletion of thiamine). • Use of cysteamine and penicillamine (chelating agents used to chelate sulfite) resulted in no beneficial clinical effects. • Betaine has been used to increase the remethylation of homocysteine back to methionine, which reduces cysteine and leads to reduction in sulfite levels. • Thiamine replacement has been attempted (given that the accumulation of sulfite leads to depletion of thiamine). • Use of cysteamine and penicillamine (chelating agents used to chelate sulfite) resulted in no beneficial clinical effects. ## Surveillance Periodic assessment by the multidisciplinary team with particular attention to the following: Nutritional status Neurologic status including evaluation of dosages of anti-seizure medication and their side effects Degree of spasticity and related complications, including scoliosis Periodic sleep studies • Nutritional status • Neurologic status including evaluation of dosages of anti-seizure medication and their side effects • Degree of spasticity and related complications, including scoliosis • Periodic sleep studies ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Isolated sulfite oxidase deficiency (ISOD) 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 Isolated sulfite oxidase deficiency (ISOD) 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 • • United Kingdom • ## Molecular Genetics Isolated Sulfite Oxidase Deficiency: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Isolated Sulfite Oxidase Deficiency ( See An individual with uniparental disomy 12 (UPD12) with a paternal p.Tyr400Ter reduced to homozygosity has been reported [ Selected Variants listed in the table have been provided by the authors. The original publication does not use current naming conventions and the c. nomenclature could not be determined [ The original publication does not use current naming conventions and names this variant c.1244delG [ ## Chapter Notes The authors wish to thank all patients and their families for their collaboration. 21 September 2017 (bp) Review posted live 27 March 2017 (psb) Original submission • 21 September 2017 (bp) Review posted live • 27 March 2017 (psb) Original submission ## Acknowledgments The authors wish to thank all patients and their families for their collaboration. ## Revision History 21 September 2017 (bp) Review posted live 27 March 2017 (psb) Original submission • 21 September 2017 (bp) Review posted live • 27 March 2017 (psb) Original submission ## References ## Literature Cited Two males of Indian origin with classic isolated sulfite oxidase deficiency a. Male child age 14 months (head circumference 43 cm; <5th centile for age); note long philtrum and thick lips. b. Male child age eight years with severe microcephaly (head circumference 45 cm; <5th centile for age); note puffy cheeks, narrow bifrontal diameter, elongated palpebral fissures, and long philtrum. Brain MRI in a child with classic isolated sulfite oxidase deficiency a. T b. Follow-up MRI at age eight months shows ventricular dilatation and diffuse ulegyria. c. T	[ "SN Basheer, PJ Waters, CW Lam, C Acquaviva-Bourdain, G Hendson, K Poskitt, J Hukin. Isolated sulfite oxidase deficiency in the newborn: lactic acidaemia and leukoencephalopathy.. Neuropediatrics. 2007;38:38-41", "PS Bindu, R Christopher, A Mahadevan, RD Bharath. Clinical and imaging observations in isolated sulfite oxidase deficiency.. J Child Neurol. 2011;26:1036-40", "TM Bosley, IA Alorainy, DT Oystreck, AM Hellani, MZ Seidahmed, F Osman Mel, MA Sabry, MS Rashed, EA Al-Yamani, KK Abu-Amero, MA Salih. Neurologic injury in isolated sulfite oxidase deficiency.. Can J Neurol Sci. 2014;41:42-8", "LW Chen, YS Tsai, CC Huang. Prenatal multicystic encephalopathy in isolated sulfite oxidase deficiency with a novel mutation.. Pediatr Neurol. 2014;51:181-2", "SY Cho, DL Goh, KC Lau, HT Ong, CW Lam. Microarray analysis unmasked paternal uniparental disomy of chromosome 12 in a patient with isolated sulfite oxidase deficiency.. Clin Chim Acta. 2013;426:13-7", "M Del Rizzo, AP Burlina, JO Sass, F Beermann, C Zanco, C Cazzorla, A Bordugo, L Giordano, R Manara, AB Burlina. Metabolic stroke in a late-onset form of isolated sulfite oxidase deficiency.. Mol Genet Metab. 2013;108:263-6", "MC Edwards, JL Johnson, B Marriage, TN Graf, KE Coyne, KV Rajagopalan, IM MacDonald. Isolated sulfite oxidase deficiency: review of two cases in one family.. Ophthalmology. 1999;106:1957-61", "F Eichler, WH Tan, VE Shih, PE Grant, K Krishnamoorthy. Proton magnetic resonance spectroscopy and diffusion-weighted imaging in isolated sulfite oxidase deficiency.. J Child Neurol. 2006;21:801-5", "C Hoffmann, B Ben-Zeev, Y Anikster, A Nissenkorn, N Brand, J Kuint, T Kushnir. Magnetic resonance imaging and magnetic resonance spectroscopy in isolated sulfite oxidase deficiency.. J Child Neurol. 2007;22:1214-21", "YL Huang, DS Lin, JK Huang, NC Chiu, CS Ho. [99]mTc-ethyl cysteinate dimer cranial single-photon emission computed tomography and serial cranial magnetic resonance imaging in a girl with isolated sulfite oxidase deficiency.. Pediatr Neurol. 2012;47:44-6", "JL Holder, S Agadi, W Reese, C Rehder, MM Quach. Infantile spasms and hyperekplexia associated with isolated sulfite oxidase deficiency.. JAMA Neurol. 2014;71:782-4", "SJ Huang, LM Amendola, DL Sternen. Variation among DNA banking consent forms: points for clinicians to bank on.. J Community Genet. 2022;13:389-97", "E Karakas, C Kisker. Structural analysis of missense mutations causing isolated sulfite oxidase deficiency.. Dalton Trans. 2005;21:3459-63", "GT Lueder, RD Steiner. Ophthalmic abnormalities in molybdenum cofactor deficiency and isolated sulfite oxidase deficiency.. J Pediatr Ophthalmol Strabismus. 1995;32:334-7", "MS Rashed, AA Saadallah, Z Rahbeeni, W Eyaid, MZ Seidahmed, S Al-Shahwan, MA Salih, ME Osman, M Al-Amoudi, L Al-Ahaidib, M Jacob. Determination of urinary S-sulphocysteine, xanthine and hypoxanthine by liquid chromatography-electrospray tandem mass spectrometry.. Biomed Chromatogr. 2005;19:223-30", "B Relinque, L Bardallo, M Granero, PJ Jiménez, S Luna. Isolated sulfite oxidase deficiency.. J Neonatal Perinatal Med. 2015;8:53-5", "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 Rocha, AC Ferreira, AI Dias, JP Vieira, S Sequeira. Sulfite oxidase deficiency--an unusual late and mild presentation.. Brain Dev. 2014;36:176-9", "CA Rupar, J Gillett, BA Gordon, DA Ramsay, JL Johnson, RM Garrett, KV Rajagopalan, JH Jung, GS Bacheyie, AR Sellers. Isolated sulfite oxidase deficiency.. Neuropediatrics. 1996;27:299-304", "MA Salih, TM Bosley, IA Alorainy, MA Sabry, MS Rashed, EA Al-Yamani, S El-Akoum, SH Mohamed, KK Abu-Amero, AM Hellani. Preimplantation genetic diagnosis in isolated sulfite oxidase deficiency.. Can J Neurol Sci. 2013;40:109-12", "JO Sass, A Gunduz, C Araujo Rodrigues Funayama, B Korkmaz, KG Dantas Pinto, B Tuysuz, L Yanasse Dos Santos, E Taskiran, M de Fátima Turcato, CW Lam, J Reiss, M Walter, C Yalcinkaya, JS Camelo. Functional deficiencies of sulfite oxidase: differential diagnoses in neonates presenting with intractable seizures and cystic encephalomalacia.. Brain Dev. 2010;32:544-9", "MZ Seidahmed, EA Alyamani, MS Rashed, AA Saadallah, OB Abdelbasit, MM Shaheed, A Rasheed, FA Hamid, MA Sabry. Total truncation of the molybdopterin/dimerization domains of SUOX protein in an Arab family with isolated sulfite oxidase deficiency.. Am J Med Genet A. 2005;136:205-9", "WH Tan, FS Eichler, S Hoda, MS Lee, H Baris, CA Hanley, PE Grant, KS Krishnamoorthy, VE Shih. Isolated sulfite oxidase deficiency: a case report with a novel mutation and review of the literature.. Pediatrics. 2005;116:757-66", "MS Zaki, L Selim, HT El-Bassyouni, MY Issa, I Mahmoud, S Ismail, M Girgis, AA Sadek, JG Gleeson, MS Abdel Hamid. Molybdenum cofactor and isolated sulphite oxidase deficiencies: clinical and molecular spectrum among Egyptian patients.. Eur J Paediatr Neurol. 2016;20:714-22" ]	21/9/2017			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
isovaleric-a	isovaleric-a	[ "Classic Isovaleric Aciduria", "Isovaleryl-Coenzyme A Dehydrogenase Deficiency", "Classic Isovaleric Aciduria", "Isovaleryl-Coenzyme A Dehydrogenase Deficiency", "Isovaleryl-CoA dehydrogenase, mitochondrial", "IVD", "Classic Isovaleric Acidemia" ]	Classic Isovaleric Acidemia	Ulrike Mütze, Anna Reischl-Hajiabadi, Stefan Kölker	Summary Individuals with clinical manifestations of isovaleric acidemia (IVA) have either classic IVA identified on newborn screening or classic IVA with a later diagnosis due to a missed diagnosis or later onset of clinical manifestations. Classic IVA is characterized by acute metabolic decompensations (vomiting, poor feeding, lethargy, hypotonia, seizures, and a distinct odor of sweaty feet). Acute metabolic decompensations are typically triggered by fasting, (febrile) illness (especially gastroenteritis), or increased protein intake. Clinical deterioration often occurs within hours to days after birth. Additional manifestations of classic IVA include developmental delay, intellectual disability and/or impaired cognition, epilepsy, and movement disorder (tremor, dysmetria, extrapyramidal movements). Early treatment in those identified by newborn screening can significantly reduce morbidity and mortality in individuals with classic IVA. The diagnosis of classic IVA is established in a proband by identification of C5-carnitine metabolites by tandem mass spectrometry and isovalerylglycine (IVG) and 3-hydroxyisovaleric acid (3-HIVA) on analysis of urinary organic acids by gas chromatography-mass spectrometry, or identification of biallelic pathogenic variants in Emergency outpatient treatment includes carbohydrate supplementation orally or via tube feeding, transient reduction of natural protein intake, elevation of carnitine supplementation, and glycine; antipyretics for fever; antiemetics for vomiting. Acute inpatient treatment includes stopping protein intake, intravenous glucose, and hydration with normal saline; adjusting treatments for new or evolving neurologic manifestations; consider buffers as needed for life-threatening metabolic acidosis; nitrogen scavengers for hyperammonemia. Classic IVA is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an	## Diagnosis NBS for classic isovaleric acidemia (IVA) is based on the quantification of the first-tier analyte isovalerylcarnitine (as C5-carnitine) in dried blood spots. C5-carnitine (C5) values above the cutoff reported by the screening laboratory are considered positive and suggest a diagnosis of classic IVA; additional testing of urinary organic acids is required to Additional testing to decrease false positives includes C5 isobar analysis (when available), which can distinguish isovalerylcarnitine from other isobaric carnitines (pivaloylcarnitine, 2-methylbutyrylcarnitine, and N-valerylcarnitine) that cannot be distinguished by tandem mass spectrometry [ The majority of individuals with classic IVA present acutely with life-threatening metabolic decompensation during the first two weeks of life. Therefore, infants with C5 >4 µmol/L on the first NBS sample that do not have access to C5 isobar analysis should begin the following medical interventions while urine organic acids are performed to establish the diagnosis of classic IVA [ Promotion of catabolism and avoidance of fasting Clinical assessment by a pediatrician or at a pediatric metabolic center including measurement of ammonia and blood gases Consideration of carnitine supplementation (50-100 mg/kg/day orally or intravenously) A symptomatic individual can have delayed diagnosis of classic IVA or untreated classic IVA due to any of the following: NBS not performed, false negative NBS result, or caregivers not adherent to recommended treatment following a positive NBS result. Supportive – but nonspecific – can include the following clinical, preliminary laboratory, brain MRI, and family history findings. Acute metabolic decompensation (vomiting, altered mental status, reduced consciousness or coma, lethargy). An odor of sweaty feet can be present during these episodes. Feeding difficulties and episodic vomiting Hypotonia Developmental delay / intellectual disability Movement disorder (tremor, dysmetria, extrapyramidal movements) Ataxia Seizures Metabolic acidosis with elevated anion gap Ketonuria Hyperammonemia Hematologic abnormalities (e.g., bone marrow suppression resulting in leukopenia, thrombocytopenia, and/or anemia) The diagnosis of classic IVA in a proband with C5-carnitine (C5) metabolites, isovalerylglycine (IVG), and 3-hydroxyisovaleric acid (3-HIVA) on analysis of urinary organic acids by gas chromatography-mass spectrometry [ Biallelic pathogenic (or likely pathogenic) variants in Note: (1) Some Molecular Genetic Testing Used in Classic Isovaleric Acidemia See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small 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. • Promotion of catabolism and avoidance of fasting • Clinical assessment by a pediatrician or at a pediatric metabolic center including measurement of ammonia and blood gases • Consideration of carnitine supplementation (50-100 mg/kg/day orally or intravenously) • Acute metabolic decompensation (vomiting, altered mental status, reduced consciousness or coma, lethargy). An odor of sweaty feet can be present during these episodes. • Feeding difficulties and episodic vomiting • Hypotonia • Developmental delay / intellectual disability • Movement disorder (tremor, dysmetria, extrapyramidal movements) • Ataxia • Seizures • Metabolic acidosis with elevated anion gap • Ketonuria • Hyperammonemia • Hematologic abnormalities (e.g., bone marrow suppression resulting in leukopenia, thrombocytopenia, and/or anemia) • C5-carnitine (C5) metabolites, isovalerylglycine (IVG), and 3-hydroxyisovaleric acid (3-HIVA) on analysis of urinary organic acids by gas chromatography-mass spectrometry [ • • Biallelic pathogenic (or likely pathogenic) variants in • Note: (1) Some ## Suggestive Findings NBS for classic isovaleric acidemia (IVA) is based on the quantification of the first-tier analyte isovalerylcarnitine (as C5-carnitine) in dried blood spots. C5-carnitine (C5) values above the cutoff reported by the screening laboratory are considered positive and suggest a diagnosis of classic IVA; additional testing of urinary organic acids is required to Additional testing to decrease false positives includes C5 isobar analysis (when available), which can distinguish isovalerylcarnitine from other isobaric carnitines (pivaloylcarnitine, 2-methylbutyrylcarnitine, and N-valerylcarnitine) that cannot be distinguished by tandem mass spectrometry [ The majority of individuals with classic IVA present acutely with life-threatening metabolic decompensation during the first two weeks of life. Therefore, infants with C5 >4 µmol/L on the first NBS sample that do not have access to C5 isobar analysis should begin the following medical interventions while urine organic acids are performed to establish the diagnosis of classic IVA [ Promotion of catabolism and avoidance of fasting Clinical assessment by a pediatrician or at a pediatric metabolic center including measurement of ammonia and blood gases Consideration of carnitine supplementation (50-100 mg/kg/day orally or intravenously) A symptomatic individual can have delayed diagnosis of classic IVA or untreated classic IVA due to any of the following: NBS not performed, false negative NBS result, or caregivers not adherent to recommended treatment following a positive NBS result. Supportive – but nonspecific – can include the following clinical, preliminary laboratory, brain MRI, and family history findings. Acute metabolic decompensation (vomiting, altered mental status, reduced consciousness or coma, lethargy). An odor of sweaty feet can be present during these episodes. Feeding difficulties and episodic vomiting Hypotonia Developmental delay / intellectual disability Movement disorder (tremor, dysmetria, extrapyramidal movements) Ataxia Seizures Metabolic acidosis with elevated anion gap Ketonuria Hyperammonemia Hematologic abnormalities (e.g., bone marrow suppression resulting in leukopenia, thrombocytopenia, and/or anemia) • Promotion of catabolism and avoidance of fasting • Clinical assessment by a pediatrician or at a pediatric metabolic center including measurement of ammonia and blood gases • Consideration of carnitine supplementation (50-100 mg/kg/day orally or intravenously) • Acute metabolic decompensation (vomiting, altered mental status, reduced consciousness or coma, lethargy). An odor of sweaty feet can be present during these episodes. • Feeding difficulties and episodic vomiting • Hypotonia • Developmental delay / intellectual disability • Movement disorder (tremor, dysmetria, extrapyramidal movements) • Ataxia • Seizures • Metabolic acidosis with elevated anion gap • Ketonuria • Hyperammonemia • Hematologic abnormalities (e.g., bone marrow suppression resulting in leukopenia, thrombocytopenia, and/or anemia) ## Scenario 1: Abnormal Newborn Screening (NBS) Result NBS for classic isovaleric acidemia (IVA) is based on the quantification of the first-tier analyte isovalerylcarnitine (as C5-carnitine) in dried blood spots. C5-carnitine (C5) values above the cutoff reported by the screening laboratory are considered positive and suggest a diagnosis of classic IVA; additional testing of urinary organic acids is required to Additional testing to decrease false positives includes C5 isobar analysis (when available), which can distinguish isovalerylcarnitine from other isobaric carnitines (pivaloylcarnitine, 2-methylbutyrylcarnitine, and N-valerylcarnitine) that cannot be distinguished by tandem mass spectrometry [ The majority of individuals with classic IVA present acutely with life-threatening metabolic decompensation during the first two weeks of life. Therefore, infants with C5 >4 µmol/L on the first NBS sample that do not have access to C5 isobar analysis should begin the following medical interventions while urine organic acids are performed to establish the diagnosis of classic IVA [ Promotion of catabolism and avoidance of fasting Clinical assessment by a pediatrician or at a pediatric metabolic center including measurement of ammonia and blood gases Consideration of carnitine supplementation (50-100 mg/kg/day orally or intravenously) • Promotion of catabolism and avoidance of fasting • Clinical assessment by a pediatrician or at a pediatric metabolic center including measurement of ammonia and blood gases • Consideration of carnitine supplementation (50-100 mg/kg/day orally or intravenously) ## Scenario 2: Symptomatic Individual A symptomatic individual can have delayed diagnosis of classic IVA or untreated classic IVA due to any of the following: NBS not performed, false negative NBS result, or caregivers not adherent to recommended treatment following a positive NBS result. Supportive – but nonspecific – can include the following clinical, preliminary laboratory, brain MRI, and family history findings. Acute metabolic decompensation (vomiting, altered mental status, reduced consciousness or coma, lethargy). An odor of sweaty feet can be present during these episodes. Feeding difficulties and episodic vomiting Hypotonia Developmental delay / intellectual disability Movement disorder (tremor, dysmetria, extrapyramidal movements) Ataxia Seizures Metabolic acidosis with elevated anion gap Ketonuria Hyperammonemia Hematologic abnormalities (e.g., bone marrow suppression resulting in leukopenia, thrombocytopenia, and/or anemia) • Acute metabolic decompensation (vomiting, altered mental status, reduced consciousness or coma, lethargy). An odor of sweaty feet can be present during these episodes. • Feeding difficulties and episodic vomiting • Hypotonia • Developmental delay / intellectual disability • Movement disorder (tremor, dysmetria, extrapyramidal movements) • Ataxia • Seizures • Metabolic acidosis with elevated anion gap • Ketonuria • Hyperammonemia • Hematologic abnormalities (e.g., bone marrow suppression resulting in leukopenia, thrombocytopenia, and/or anemia) ## Establishing the Diagnosis The diagnosis of classic IVA in a proband with C5-carnitine (C5) metabolites, isovalerylglycine (IVG), and 3-hydroxyisovaleric acid (3-HIVA) on analysis of urinary organic acids by gas chromatography-mass spectrometry [ Biallelic pathogenic (or likely pathogenic) variants in Note: (1) Some Molecular Genetic Testing Used in Classic Isovaleric Acidemia See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small 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. • C5-carnitine (C5) metabolites, isovalerylglycine (IVG), and 3-hydroxyisovaleric acid (3-HIVA) on analysis of urinary organic acids by gas chromatography-mass spectrometry [ • • Biallelic pathogenic (or likely pathogenic) variants in • Note: (1) Some ## Molecular Genetic Testing Molecular Genetic Testing Used in Classic Isovaleric Acidemia See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Clinical Characteristics The clinical spectrum of classic isovaleric acidemia (IVA) is broad and differs according to age of onset and severity of disease. Classic IVA is characterized by early onset of acute metabolic decompensations (vomiting, poor feeding, lethargy, hypotonia, seizures, and a distinct odor of sweaty feet), epilepsy, developmental delay, intellectual disability and/or impaired cognition, and movement disorder. Individuals with classic IVA (not identified on newborn screening) may have delayed diagnosis if acute metabolic decompensations occur later in childhood and/or they have nonspecific poor weight gain, growth deficiency, and developmental delay. Select Features of Classic Isovaleric Acidemia NBS = newborn screening In those with classic IVA identified on newborn screening, 50% of decompensations occur in the neonatal period [ In those with classic IVA not identified on newborn screening, most present with metabolic decompensation [ This frequency is quite likely to be underestimated, as a relevant number of infants and children might have died without correct diagnosis. Individuals with Metabolic decompensations can occur any time throughout childhood in individuals with classic IVA (regardless of age of diagnosis). Metabolic decompensations did not occur after early adolescence in 21 children with classic IVA [ Among individuals with a later diagnosis, approximately 60% were reported to have normal neurocognitive outcomes. Learning disabilities were observed in approximately one quarter of affected individuals. Severe cognitive dysfunction was reported in 5% of individuals. Early diagnosis and treatment in those who survive the initial metabolic decompensation tends to result in better neurocognitive outcomes [ Fanconi syndrome (1 individual) [ Cardiac arrhythmias during general and local anesthesia (1 individual) [ Abnormalities of the globus pallidus (1 individual) [ Optic nerve atrophy (1 individual) [ Untreated individuals with classic IVA can develop metabolic decompensation resulting in cerebral edema and hemorrhage, coma, and death [ Metabolic decompensations rarely occur in individuals with classic IVA after adolescence, with only a few reports of metabolic decompensation in adulthood [ Limited information is available regarding genotype-phenotype correlations [ The pathogenic variant p.Ala311Val is particularly common in individuals identified through NBS and is associated with attenuated IVA in individuals who are homozygous or compound heterozygous for this variant (see Prevalence of classic IVA is 1:100,000 newborns [ • Individuals with • Metabolic decompensations can occur any time throughout childhood in individuals with classic IVA (regardless of age of diagnosis). Metabolic decompensations did not occur after early adolescence in 21 children with classic IVA [ • Fanconi syndrome (1 individual) [ • Cardiac arrhythmias during general and local anesthesia (1 individual) [ • Abnormalities of the globus pallidus (1 individual) [ • Optic nerve atrophy (1 individual) [ ## Clinical Description The clinical spectrum of classic isovaleric acidemia (IVA) is broad and differs according to age of onset and severity of disease. Classic IVA is characterized by early onset of acute metabolic decompensations (vomiting, poor feeding, lethargy, hypotonia, seizures, and a distinct odor of sweaty feet), epilepsy, developmental delay, intellectual disability and/or impaired cognition, and movement disorder. Individuals with classic IVA (not identified on newborn screening) may have delayed diagnosis if acute metabolic decompensations occur later in childhood and/or they have nonspecific poor weight gain, growth deficiency, and developmental delay. Select Features of Classic Isovaleric Acidemia NBS = newborn screening In those with classic IVA identified on newborn screening, 50% of decompensations occur in the neonatal period [ In those with classic IVA not identified on newborn screening, most present with metabolic decompensation [ This frequency is quite likely to be underestimated, as a relevant number of infants and children might have died without correct diagnosis. Individuals with Metabolic decompensations can occur any time throughout childhood in individuals with classic IVA (regardless of age of diagnosis). Metabolic decompensations did not occur after early adolescence in 21 children with classic IVA [ Among individuals with a later diagnosis, approximately 60% were reported to have normal neurocognitive outcomes. Learning disabilities were observed in approximately one quarter of affected individuals. Severe cognitive dysfunction was reported in 5% of individuals. Early diagnosis and treatment in those who survive the initial metabolic decompensation tends to result in better neurocognitive outcomes [ Fanconi syndrome (1 individual) [ Cardiac arrhythmias during general and local anesthesia (1 individual) [ Abnormalities of the globus pallidus (1 individual) [ Optic nerve atrophy (1 individual) [ Untreated individuals with classic IVA can develop metabolic decompensation resulting in cerebral edema and hemorrhage, coma, and death [ Metabolic decompensations rarely occur in individuals with classic IVA after adolescence, with only a few reports of metabolic decompensation in adulthood [ • Individuals with • Metabolic decompensations can occur any time throughout childhood in individuals with classic IVA (regardless of age of diagnosis). Metabolic decompensations did not occur after early adolescence in 21 children with classic IVA [ • Fanconi syndrome (1 individual) [ • Cardiac arrhythmias during general and local anesthesia (1 individual) [ • Abnormalities of the globus pallidus (1 individual) [ • Optic nerve atrophy (1 individual) [ ## Genotype-Phenotype Correlations Limited information is available regarding genotype-phenotype correlations [ The pathogenic variant p.Ala311Val is particularly common in individuals identified through NBS and is associated with attenuated IVA in individuals who are homozygous or compound heterozygous for this variant (see ## Nomenclature ## Prevalence Prevalence of classic IVA is 1:100,000 newborns [ ## Genetically Related (Allelic) Disorders ## Differential Diagnosis Genes of Interest in the Differential Diagnosis of an Infant with NBS Results and/or Other Laboratory Findings Suggestive of Classic Isovaleric Acidemia DD Seizures Autism Majority of persons remain asymptomatic ↑ C5 Metabolic acidosis Hypoglycemia Muscular hypotonia & weakness Liver dysfunction Cardiomyopathy C5 = C5-carnitine; AR = autosomal recessive; CoA = coenzyme A; DD = developmental delay; MOI = mode of inheritance Of note, pivaloylcarnitine, a derivate of pivalic acid-containing antibiotics (taken by mother and child) and pivalic acid-containing skin cream, can cause a false positive newborn screening (NBS) for isovaleric acidemia (IVA), as pivaloylcarnitine is isobaric for isovalerylcarnitine and can also cause elevated C5-carnitine values on tandem mass spectrometry of dried blood spots [ Genes of Interest in the Differential Diagnosis of a Symptomatic Individual with Findings Suggestive of Late-Onset or Untreated Infantile-Onset Classic Isovaleric Acidemia Acute encephalopathic crises Macrocephaly Seizures Metabolic acidosis Hyperammonemia Methylmalonic acid in urine Propionylcarnitine on acylcarnitine analysis Metabolic decompensations Cardiomyopathy Kidney failure Pancreatitis Metabolic acidosis Hyperammonemia 3-hydroxy-propionic acid & 2-methylcitrate in urine Propionylcarnitine on acylcarnitine analysis Hyperammonemia ↑ arginine in plasma ↑ liver enzymes Altered level of consciousness Encephalopathy Seizures Vomiting Cognitive impairment Hepatomegaly Hyperammonemia Argininosuccinic acid in plasma or urine ↑ liver enzymes Hyperammonemia ↑ citrulline in plasma ↑ liver enzymes Hyperammonemia Low citrulline in plasma Normal/low orotic acid in urine ↑ liver enzymes Hyperammonemia Low citrulline in plasma ↑ orotic acid in urine ↑ liver enzymes Hyperammonemia Low citrulline in plasma Normal/low orotic acid in urine ↑ liver enzymes Hyperammonemia ↑ citrulline, arginine, methionine, threonine, tyrosine, & lysine in plasma ↑ liver enzymes Hyperammonemia ↑ homocitrulline in urine ↑ liver enzymes AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked • DD • Seizures • Autism • Majority of persons remain asymptomatic • ↑ C5 • Metabolic acidosis • Hypoglycemia • Muscular hypotonia & weakness • Liver dysfunction • Cardiomyopathy • Acute encephalopathic crises • Macrocephaly • Seizures • Metabolic acidosis • Hyperammonemia • Methylmalonic acid in urine • Propionylcarnitine on acylcarnitine analysis • Metabolic decompensations • Cardiomyopathy • Kidney failure • Pancreatitis • Metabolic acidosis • Hyperammonemia • 3-hydroxy-propionic acid & 2-methylcitrate in urine • Propionylcarnitine on acylcarnitine analysis • Hyperammonemia • ↑ arginine in plasma • ↑ liver enzymes • Altered level of consciousness • Encephalopathy • Seizures • Vomiting • Cognitive impairment • Hepatomegaly • Hyperammonemia • Argininosuccinic acid in plasma or urine • ↑ liver enzymes • Hyperammonemia • ↑ citrulline in plasma • ↑ liver enzymes • Hyperammonemia • Low citrulline in plasma • Normal/low orotic acid in urine • ↑ liver enzymes • Hyperammonemia • Low citrulline in plasma • ↑ orotic acid in urine • ↑ liver enzymes • Hyperammonemia • Low citrulline in plasma • Normal/low orotic acid in urine • ↑ liver enzymes • Hyperammonemia • ↑ citrulline, arginine, methionine, threonine, tyrosine, & lysine in plasma • ↑ liver enzymes • Hyperammonemia • ↑ homocitrulline in urine • ↑ liver enzymes ## Scenario 1: Abnormal Newborn Screening (NBS) Result Genes of Interest in the Differential Diagnosis of an Infant with NBS Results and/or Other Laboratory Findings Suggestive of Classic Isovaleric Acidemia DD Seizures Autism Majority of persons remain asymptomatic ↑ C5 Metabolic acidosis Hypoglycemia Muscular hypotonia & weakness Liver dysfunction Cardiomyopathy C5 = C5-carnitine; AR = autosomal recessive; CoA = coenzyme A; DD = developmental delay; MOI = mode of inheritance Of note, pivaloylcarnitine, a derivate of pivalic acid-containing antibiotics (taken by mother and child) and pivalic acid-containing skin cream, can cause a false positive newborn screening (NBS) for isovaleric acidemia (IVA), as pivaloylcarnitine is isobaric for isovalerylcarnitine and can also cause elevated C5-carnitine values on tandem mass spectrometry of dried blood spots [ • DD • Seizures • Autism • Majority of persons remain asymptomatic • ↑ C5 • Metabolic acidosis • Hypoglycemia • Muscular hypotonia & weakness • Liver dysfunction • Cardiomyopathy ## Scenario 2: Symptomatic Individual Genes of Interest in the Differential Diagnosis of a Symptomatic Individual with Findings Suggestive of Late-Onset or Untreated Infantile-Onset Classic Isovaleric Acidemia Acute encephalopathic crises Macrocephaly Seizures Metabolic acidosis Hyperammonemia Methylmalonic acid in urine Propionylcarnitine on acylcarnitine analysis Metabolic decompensations Cardiomyopathy Kidney failure Pancreatitis Metabolic acidosis Hyperammonemia 3-hydroxy-propionic acid & 2-methylcitrate in urine Propionylcarnitine on acylcarnitine analysis Hyperammonemia ↑ arginine in plasma ↑ liver enzymes Altered level of consciousness Encephalopathy Seizures Vomiting Cognitive impairment Hepatomegaly Hyperammonemia Argininosuccinic acid in plasma or urine ↑ liver enzymes Hyperammonemia ↑ citrulline in plasma ↑ liver enzymes Hyperammonemia Low citrulline in plasma Normal/low orotic acid in urine ↑ liver enzymes Hyperammonemia Low citrulline in plasma ↑ orotic acid in urine ↑ liver enzymes Hyperammonemia Low citrulline in plasma Normal/low orotic acid in urine ↑ liver enzymes Hyperammonemia ↑ citrulline, arginine, methionine, threonine, tyrosine, & lysine in plasma ↑ liver enzymes Hyperammonemia ↑ homocitrulline in urine ↑ liver enzymes AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked • Acute encephalopathic crises • Macrocephaly • Seizures • Metabolic acidosis • Hyperammonemia • Methylmalonic acid in urine • Propionylcarnitine on acylcarnitine analysis • Metabolic decompensations • Cardiomyopathy • Kidney failure • Pancreatitis • Metabolic acidosis • Hyperammonemia • 3-hydroxy-propionic acid & 2-methylcitrate in urine • Propionylcarnitine on acylcarnitine analysis • Hyperammonemia • ↑ arginine in plasma • ↑ liver enzymes • Altered level of consciousness • Encephalopathy • Seizures • Vomiting • Cognitive impairment • Hepatomegaly • Hyperammonemia • Argininosuccinic acid in plasma or urine • ↑ liver enzymes • Hyperammonemia • ↑ citrulline in plasma • ↑ liver enzymes • Hyperammonemia • Low citrulline in plasma • Normal/low orotic acid in urine • ↑ liver enzymes • Hyperammonemia • Low citrulline in plasma • ↑ orotic acid in urine • ↑ liver enzymes • Hyperammonemia • Low citrulline in plasma • Normal/low orotic acid in urine • ↑ liver enzymes • Hyperammonemia • ↑ citrulline, arginine, methionine, threonine, tyrosine, & lysine in plasma • ↑ liver enzymes • Hyperammonemia • ↑ homocitrulline in urine • ↑ liver enzymes ## Management When classic isovaleric acidemia (IVA) is suspected during the diagnostic evaluation, that is, because of increased C5-carnitine concentrations in dried blood spots (acylcarnitine profile) or isovalerylglycine in urine (urine organic acids), 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 classic IVA, the evaluations summarized in Classic Isovaleric Acidemia: Recommended Evaluations Following Initial Diagnosis Transfer to specialist center w/experience in mgmt of inherited metabolic diseases (strongly recommended) Consideration of 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) IVA = isovaleric acidemia; MOI = mode of inheritance After a new diagnosis of classic IVA in a child, the closest hospital and local pediatrician should also be informed. Medical geneticist, certified genetic counselor, certified advanced genetic nurse All children with classic IVA require supervision of a specialist metabolic dietitian with experience in managing the diet recommended for those with classic IVA. The main principles of treatment are aimed at reducing leucine and enhancing physiologic detoxification of isovaleryl-coenzyme A, which is considered the main endogenous toxin of individuals with classic IVA. Reduction of total natural protein (leucine) intake via breast milk or conventional formula Leucine-free formulas to provide adequate supply of essential amino acids with minerals, trace elements, and vitamins Diet must balance reduced leucine intake while maintaining sufficient intake of essential nutrients. Total protein prescription is according to safe levels of protein recommended by the World Health Organization / Food and Agriculture Organization of the United Nations / United Nations University (WHO/FAO/UNU) Natural protein intake for individuals with classic IVA is adjusted to the individual leucine tolerance. For the first year of life this accounts for a natural protein intake of about 0.8-1 g/kg/day plus protein from leucine-free formulas (1-1.5 g/kg/day). Conjugation of isovaleryl-coenzyme A using carnitine or combined carnitine and glycine Carnitine supplementation dose: 50-100 mg/kg/day Glycine supplementation dose: 150 mg/kg/day Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This involves multidisciplinary care by specialists in relevant fields for routine daily treatment (see Classic Isovaleric Acidemia: Routine Daily Treatment Breastfeeding should be encouraged. Leucine content in breast milk is 130 mg per 100 mL. Daily leucine intake can be calculated when breast milk is the only natural protein source & breast milk intake is calculated & stable. Protein-controlled diet Adequate supplies of specialized dietary products should always be maintained at home. Treatment protocols & provision of emergency letters or cards to include guidance for care in the event of illness while on holiday/vacation MedicAlert Written protocols for maintenance & emergency treatment should be provided to parents, primary care providers / pediatricians, teachers, & school staff. Emergency letters/cards should be provided summarizing key information & principles of emergency treatment for classic IVA & containing contact information for primary treating metabolic center. For any planned travel or vacations, consider contacting a center of expertise near the destination prior to travel dates. Physical therapy Aggressive rehab therapy 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). Based on IVA = isovaleric acidemia; WHO/FAO/UNU = World Health Organization / Food and Agriculture Organization of the United Nations / United Nations University Essential information including written treatment protocols should be provided before inpatient emergency treatment might be necessary. 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 manifestations occur. Classic Isovaleric Acidemia: Emergency Outpatient Treatment Carbohydrate supplementation orally or via tube feeding Transient reduction of natural protein intake Increase carnitine supplementation (up to 200 mg/kg/day) Glycine supplementation (up to 300 mg/kg/day) Trial of outpatient treatment at home for up to 12 hours Reassessment (~every 2 hours) for clinical changes Based on Fever <38.5 °C (101 °F); enteral or gastrostomy tube feeding is 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. 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 the hospital. Classic Isovaleric Acidemia: Acute Inpatient Treatment Transient stop of protein intake Intravenous glucose to restore anabolism Normal saline for rehydration Do not stop protein for >24 hours to avoid protein catabolism. Glucose should be administered according to age, aiming to cover the gluconeogenesis rate of the liver (e.g., 12-15 g/kg/day in newborns). Fluid intake is adjusted to age-dependent demands & should consider additional losses (e.g., vomiting, diarrhea). In addition to regular evaluations by a metabolic specialist and metabolic dietician, the evaluations summarized in Classic Isovaleric Acidemia: Recommended Surveillance At least every 3 months until age 1 year Every 6 months from ages 1-6 years Annually age ≥6 years Neuropsychological testing using age-appropriate standardized assessments Standardized quality-of-life assessment tools for affected persons & parents/caregivers Avoid the following: Excess of dietary protein or protein malnutrition inducing catabolic state Prolonged fasting Catabolism during illness (intercurrent infection; brief febrile illness post vaccination) IVA biochemical or molecular genetic testing of all at-risk sibs of any age is warranted to allow for early diagnosis and treatment of classic IVA. See Search • Transfer to specialist center w/experience in mgmt of inherited metabolic diseases (strongly recommended) • Consideration of 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) • Reduction of total natural protein (leucine) intake via breast milk or conventional formula • Leucine-free formulas to provide adequate supply of essential amino acids with minerals, trace elements, and vitamins • Diet must balance reduced leucine intake while maintaining sufficient intake of essential nutrients. • Total protein prescription is according to safe levels of protein recommended by the World Health Organization / Food and Agriculture Organization of the United Nations / United Nations University (WHO/FAO/UNU) • Natural protein intake for individuals with classic IVA is adjusted to the individual leucine tolerance. For the first year of life this accounts for a natural protein intake of about 0.8-1 g/kg/day plus protein from leucine-free formulas (1-1.5 g/kg/day). • Conjugation of isovaleryl-coenzyme A using carnitine or combined carnitine and glycine • Carnitine supplementation dose: 50-100 mg/kg/day • Glycine supplementation dose: 150 mg/kg/day • Breastfeeding should be encouraged. • Leucine content in breast milk is 130 mg per 100 mL. • Daily leucine intake can be calculated when breast milk is the only natural protein source & breast milk intake is calculated & stable. • Protein-controlled diet • Adequate supplies of specialized dietary products should always be maintained at home. • Treatment protocols & provision of emergency letters or cards to include guidance for care in the event of illness while on holiday/vacation • MedicAlert • Written protocols for maintenance & emergency treatment should be provided to parents, primary care providers / pediatricians, teachers, & school staff. • Emergency letters/cards should be provided summarizing key information & principles of emergency treatment for classic IVA & containing contact information for primary treating metabolic center. • For any planned travel or vacations, consider contacting a center of expertise near the destination prior to travel dates. • Physical therapy • Aggressive rehab therapy • 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). • Carbohydrate supplementation orally or via tube feeding • Transient reduction of natural protein intake • Increase carnitine supplementation (up to 200 mg/kg/day) • Glycine supplementation (up to 300 mg/kg/day) • Trial of outpatient treatment at home for up to 12 hours • Reassessment (~every 2 hours) for clinical changes • Transient stop of protein intake • Intravenous glucose to restore anabolism • Normal saline for rehydration • Do not stop protein for >24 hours to avoid protein catabolism. • Glucose should be administered according to age, aiming to cover the gluconeogenesis rate of the liver (e.g., 12-15 g/kg/day in newborns). • Fluid intake is adjusted to age-dependent demands & should consider additional losses (e.g., vomiting, diarrhea). • At least every 3 months until age 1 year • Every 6 months from ages 1-6 years • Annually age ≥6 years • Neuropsychological testing using age-appropriate standardized assessments • Standardized quality-of-life assessment tools for affected persons & parents/caregivers • Excess of dietary protein or protein malnutrition inducing catabolic state • Prolonged fasting • Catabolism during illness (intercurrent infection; brief febrile illness post vaccination) ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with classic IVA, the evaluations summarized in Classic Isovaleric Acidemia: Recommended Evaluations Following Initial Diagnosis Transfer to specialist center w/experience in mgmt of inherited metabolic diseases (strongly recommended) Consideration of 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) IVA = isovaleric acidemia; MOI = mode of inheritance After a new diagnosis of classic IVA 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) • Consideration of 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) ## Treatment of Manifestations All children with classic IVA require supervision of a specialist metabolic dietitian with experience in managing the diet recommended for those with classic IVA. The main principles of treatment are aimed at reducing leucine and enhancing physiologic detoxification of isovaleryl-coenzyme A, which is considered the main endogenous toxin of individuals with classic IVA. Reduction of total natural protein (leucine) intake via breast milk or conventional formula Leucine-free formulas to provide adequate supply of essential amino acids with minerals, trace elements, and vitamins Diet must balance reduced leucine intake while maintaining sufficient intake of essential nutrients. Total protein prescription is according to safe levels of protein recommended by the World Health Organization / Food and Agriculture Organization of the United Nations / United Nations University (WHO/FAO/UNU) Natural protein intake for individuals with classic IVA is adjusted to the individual leucine tolerance. For the first year of life this accounts for a natural protein intake of about 0.8-1 g/kg/day plus protein from leucine-free formulas (1-1.5 g/kg/day). Conjugation of isovaleryl-coenzyme A using carnitine or combined carnitine and glycine Carnitine supplementation dose: 50-100 mg/kg/day Glycine supplementation dose: 150 mg/kg/day Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This involves multidisciplinary care by specialists in relevant fields for routine daily treatment (see Classic Isovaleric Acidemia: Routine Daily Treatment Breastfeeding should be encouraged. Leucine content in breast milk is 130 mg per 100 mL. Daily leucine intake can be calculated when breast milk is the only natural protein source & breast milk intake is calculated & stable. Protein-controlled diet Adequate supplies of specialized dietary products should always be maintained at home. Treatment protocols & provision of emergency letters or cards to include guidance for care in the event of illness while on holiday/vacation MedicAlert Written protocols for maintenance & emergency treatment should be provided to parents, primary care providers / pediatricians, teachers, & school staff. Emergency letters/cards should be provided summarizing key information & principles of emergency treatment for classic IVA & containing contact information for primary treating metabolic center. For any planned travel or vacations, consider contacting a center of expertise near the destination prior to travel dates. Physical therapy Aggressive rehab therapy 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). Based on IVA = isovaleric acidemia; WHO/FAO/UNU = World Health Organization / Food and Agriculture Organization of the United Nations / United Nations University Essential information including written treatment protocols should be provided before inpatient emergency treatment might be necessary. 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 manifestations occur. Classic Isovaleric Acidemia: Emergency Outpatient Treatment Carbohydrate supplementation orally or via tube feeding Transient reduction of natural protein intake Increase carnitine supplementation (up to 200 mg/kg/day) Glycine supplementation (up to 300 mg/kg/day) Trial of outpatient treatment at home for up to 12 hours Reassessment (~every 2 hours) for clinical changes Based on Fever <38.5 °C (101 °F); enteral or gastrostomy tube feeding is 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. 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 the hospital. Classic Isovaleric Acidemia: Acute Inpatient Treatment Transient stop of protein intake Intravenous glucose to restore anabolism Normal saline for rehydration Do not stop protein for >24 hours to avoid protein catabolism. Glucose should be administered according to age, aiming to cover the gluconeogenesis rate of the liver (e.g., 12-15 g/kg/day in newborns). Fluid intake is adjusted to age-dependent demands & should consider additional losses (e.g., vomiting, diarrhea). • Reduction of total natural protein (leucine) intake via breast milk or conventional formula • Leucine-free formulas to provide adequate supply of essential amino acids with minerals, trace elements, and vitamins • Diet must balance reduced leucine intake while maintaining sufficient intake of essential nutrients. • Total protein prescription is according to safe levels of protein recommended by the World Health Organization / Food and Agriculture Organization of the United Nations / United Nations University (WHO/FAO/UNU) • Natural protein intake for individuals with classic IVA is adjusted to the individual leucine tolerance. For the first year of life this accounts for a natural protein intake of about 0.8-1 g/kg/day plus protein from leucine-free formulas (1-1.5 g/kg/day). • Conjugation of isovaleryl-coenzyme A using carnitine or combined carnitine and glycine • Carnitine supplementation dose: 50-100 mg/kg/day • Glycine supplementation dose: 150 mg/kg/day • Breastfeeding should be encouraged. • Leucine content in breast milk is 130 mg per 100 mL. • Daily leucine intake can be calculated when breast milk is the only natural protein source & breast milk intake is calculated & stable. • Protein-controlled diet • Adequate supplies of specialized dietary products should always be maintained at home. • Treatment protocols & provision of emergency letters or cards to include guidance for care in the event of illness while on holiday/vacation • MedicAlert • Written protocols for maintenance & emergency treatment should be provided to parents, primary care providers / pediatricians, teachers, & school staff. • Emergency letters/cards should be provided summarizing key information & principles of emergency treatment for classic IVA & containing contact information for primary treating metabolic center. • For any planned travel or vacations, consider contacting a center of expertise near the destination prior to travel dates. • Physical therapy • Aggressive rehab therapy • 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). • Carbohydrate supplementation orally or via tube feeding • Transient reduction of natural protein intake • Increase carnitine supplementation (up to 200 mg/kg/day) • Glycine supplementation (up to 300 mg/kg/day) • Trial of outpatient treatment at home for up to 12 hours • Reassessment (~every 2 hours) for clinical changes • Transient stop of protein intake • Intravenous glucose to restore anabolism • Normal saline for rehydration • Do not stop protein for >24 hours to avoid protein catabolism. • Glucose should be administered according to age, aiming to cover the gluconeogenesis rate of the liver (e.g., 12-15 g/kg/day in newborns). • Fluid intake is adjusted to age-dependent demands & should consider additional losses (e.g., vomiting, diarrhea). ## Targeted Therapy Reduction of total natural protein (leucine) intake via breast milk or conventional formula Leucine-free formulas to provide adequate supply of essential amino acids with minerals, trace elements, and vitamins Diet must balance reduced leucine intake while maintaining sufficient intake of essential nutrients. Total protein prescription is according to safe levels of protein recommended by the World Health Organization / Food and Agriculture Organization of the United Nations / United Nations University (WHO/FAO/UNU) Natural protein intake for individuals with classic IVA is adjusted to the individual leucine tolerance. For the first year of life this accounts for a natural protein intake of about 0.8-1 g/kg/day plus protein from leucine-free formulas (1-1.5 g/kg/day). Conjugation of isovaleryl-coenzyme A using carnitine or combined carnitine and glycine Carnitine supplementation dose: 50-100 mg/kg/day Glycine supplementation dose: 150 mg/kg/day • Reduction of total natural protein (leucine) intake via breast milk or conventional formula • Leucine-free formulas to provide adequate supply of essential amino acids with minerals, trace elements, and vitamins • Diet must balance reduced leucine intake while maintaining sufficient intake of essential nutrients. • Total protein prescription is according to safe levels of protein recommended by the World Health Organization / Food and Agriculture Organization of the United Nations / United Nations University (WHO/FAO/UNU) • Natural protein intake for individuals with classic IVA is adjusted to the individual leucine tolerance. For the first year of life this accounts for a natural protein intake of about 0.8-1 g/kg/day plus protein from leucine-free formulas (1-1.5 g/kg/day). • Conjugation of isovaleryl-coenzyme A using carnitine or combined carnitine and glycine • Carnitine supplementation dose: 50-100 mg/kg/day • Glycine supplementation dose: 150 mg/kg/day ## Supportive Care Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This involves multidisciplinary care by specialists in relevant fields for routine daily treatment (see Classic Isovaleric Acidemia: Routine Daily Treatment Breastfeeding should be encouraged. Leucine content in breast milk is 130 mg per 100 mL. Daily leucine intake can be calculated when breast milk is the only natural protein source & breast milk intake is calculated & stable. Protein-controlled diet Adequate supplies of specialized dietary products should always be maintained at home. Treatment protocols & provision of emergency letters or cards to include guidance for care in the event of illness while on holiday/vacation MedicAlert Written protocols for maintenance & emergency treatment should be provided to parents, primary care providers / pediatricians, teachers, & school staff. Emergency letters/cards should be provided summarizing key information & principles of emergency treatment for classic IVA & containing contact information for primary treating metabolic center. For any planned travel or vacations, consider contacting a center of expertise near the destination prior to travel dates. Physical therapy Aggressive rehab therapy 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). Based on IVA = isovaleric acidemia; WHO/FAO/UNU = World Health Organization / Food and Agriculture Organization of the United Nations / United Nations University Essential information including written treatment protocols should be provided before inpatient emergency treatment might be necessary. 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 manifestations occur. Classic Isovaleric Acidemia: Emergency Outpatient Treatment Carbohydrate supplementation orally or via tube feeding Transient reduction of natural protein intake Increase carnitine supplementation (up to 200 mg/kg/day) Glycine supplementation (up to 300 mg/kg/day) Trial of outpatient treatment at home for up to 12 hours Reassessment (~every 2 hours) for clinical changes Based on Fever <38.5 °C (101 °F); enteral or gastrostomy tube feeding is 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. 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 the hospital. Classic Isovaleric Acidemia: Acute Inpatient Treatment Transient stop of protein intake Intravenous glucose to restore anabolism Normal saline for rehydration Do not stop protein for >24 hours to avoid protein catabolism. Glucose should be administered according to age, aiming to cover the gluconeogenesis rate of the liver (e.g., 12-15 g/kg/day in newborns). Fluid intake is adjusted to age-dependent demands & should consider additional losses (e.g., vomiting, diarrhea). • Breastfeeding should be encouraged. • Leucine content in breast milk is 130 mg per 100 mL. • Daily leucine intake can be calculated when breast milk is the only natural protein source & breast milk intake is calculated & stable. • Protein-controlled diet • Adequate supplies of specialized dietary products should always be maintained at home. • Treatment protocols & provision of emergency letters or cards to include guidance for care in the event of illness while on holiday/vacation • MedicAlert • Written protocols for maintenance & emergency treatment should be provided to parents, primary care providers / pediatricians, teachers, & school staff. • Emergency letters/cards should be provided summarizing key information & principles of emergency treatment for classic IVA & containing contact information for primary treating metabolic center. • For any planned travel or vacations, consider contacting a center of expertise near the destination prior to travel dates. • Physical therapy • Aggressive rehab therapy • 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). • Carbohydrate supplementation orally or via tube feeding • Transient reduction of natural protein intake • Increase carnitine supplementation (up to 200 mg/kg/day) • Glycine supplementation (up to 300 mg/kg/day) • Trial of outpatient treatment at home for up to 12 hours • Reassessment (~every 2 hours) for clinical changes • Transient stop of protein intake • Intravenous glucose to restore anabolism • Normal saline for rehydration • Do not stop protein for >24 hours to avoid protein catabolism. • Glucose should be administered according to age, aiming to cover the gluconeogenesis rate of the liver (e.g., 12-15 g/kg/day in newborns). • Fluid intake is adjusted to age-dependent demands & should consider additional losses (e.g., vomiting, diarrhea). ## Surveillance In addition to regular evaluations by a metabolic specialist and metabolic dietician, the evaluations summarized in Classic Isovaleric Acidemia: Recommended Surveillance At least every 3 months until age 1 year Every 6 months from ages 1-6 years Annually age ≥6 years Neuropsychological testing using age-appropriate standardized assessments Standardized quality-of-life assessment tools for affected persons & parents/caregivers • At least every 3 months until age 1 year • Every 6 months from ages 1-6 years • Annually age ≥6 years • Neuropsychological testing using age-appropriate standardized assessments • Standardized quality-of-life assessment tools for affected persons & parents/caregivers ## Agents/Circumstances to Avoid Avoid the following: Excess of dietary protein or protein malnutrition inducing catabolic state Prolonged fasting Catabolism during illness (intercurrent infection; brief febrile illness post vaccination) • Excess of dietary protein or protein malnutrition inducing catabolic state • Prolonged fasting • Catabolism during illness (intercurrent infection; brief febrile illness post vaccination) ## Evaluation of Relatives at Risk IVA biochemical or molecular genetic testing of all at-risk sibs of any age is warranted to allow for early diagnosis and treatment of classic IVA. See ## Therapies Under Investigation Search ## Genetic Counseling Classic isovaleric acidemia (IVA) is inherited in an autosomal recessive manner. The parents of an affected child are presumed to be heterozygous for an Once a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual 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 The neurologic phenotype of classic IVA and the frequency of acute metabolic crisis can vary widely among untreated individuals and family members with the same 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 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 • Once a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual 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 • The neurologic phenotype of classic IVA and the frequency of acute metabolic crisis can vary widely among untreated individuals and family members with the same biallelic • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance Classic isovaleric acidemia (IVA) is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected child are presumed to be heterozygous for an Once a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual 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 The neurologic phenotype of classic IVA and the frequency of acute metabolic crisis can vary widely among untreated individuals and family members with the same biallelic 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 • Once a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual 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 • The neurologic phenotype of classic IVA and the frequency of acute metabolic crisis can vary widely among untreated individuals and family members with the same biallelic • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues 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 TEMPLE (Tools Enabling Metabolic Parents LEarning) United Kingdom Health Resources & Services Administration • • TEMPLE (Tools Enabling Metabolic Parents LEarning) • United Kingdom • • • • • • • Health Resources & Services Administration • • • • • ## Molecular Genetics Classic Isovaleric Acidemia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Classic Isovaleric Acidemia ( Biallelic ## Molecular Pathogenesis Biallelic ## Chapter Notes Long-term observational registries for individuals with inherited metabolic diseases that also includes individuals with IVA: Long-term outcome of individuals with inherited metabolic diseases after diagnosis by expanded newborn screening (NGS2020/NGS2025) – German Clinical Trials registration Drs Ulrike Mütze and Stefan Kölker are actively involved in clinical research regarding individuals with IVA. They would be happy to communicate with persons who have any questions regarding diagnosis of IVA or other considerations. 14 March 2024 (sw) Review posted live 26 June 2023 (sk) Original submission • • • 14 March 2024 (sw) Review posted live • 26 June 2023 (sk) Original submission ## Author Notes Long-term observational registries for individuals with inherited metabolic diseases that also includes individuals with IVA: Long-term outcome of individuals with inherited metabolic diseases after diagnosis by expanded newborn screening (NGS2020/NGS2025) – German Clinical Trials registration Drs Ulrike Mütze and Stefan Kölker are actively involved in clinical research regarding individuals with IVA. They would be happy to communicate with persons who have any questions regarding diagnosis of IVA or other considerations. • • ## Revision History 14 March 2024 (sw) Review posted live 26 June 2023 (sk) Original submission • 14 March 2024 (sw) Review posted live • 26 June 2023 (sk) Original submission ## Key Sections in this ## References ## Literature Cited Proposed algorithm following newborn screening (NBS) result suggestive of isovaleric acidemia (IVA) C0 = free carnitine; C5 = C5-carnitine; DBS = dried blood spot; IVA = isovaleric acidemia; IVG = isovalerylglycine; NBS = newborn screening; NH * Cutoff values are provided from the Heidelberg University Hospital laboratory to assist the reader in comparing the data of their own laboratories. Due to differences between NBS programs worldwide, this algorithm should be adapted to the respective national NBS organization structures and cutoffs prior to use. Statistically derived absolute cutoffs should be used with caution. 1. False positive results on tandem mass spectrometry can be caused by exposure to pivaloylcarnitine, a derivative of pivalic acid-containing antibiotics (taken by mother and child) and pivalic acid-containing skin cream. If available without time loss, a second-tier using ultra-performance liquid chromatography-tandem mass spectrometry to analyze C5 isobars significantly reduces such false positives [ 2. Confirmatory diagnostics consist of a second NBS dried blood sample and the analysis of urine organic acids to confirm or exclude classic IVA. Republished with permission from Age at first metabolic decompensation Kaplan-Meier analysis of age at onset of first metabolic decompensation. Individuals with attenuated IVA (red; n = 67) experienced no metabolic decompensations (see Republished with permission from	[]	14/3/2024			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
issd	issd	[ "Severe FSASD (Infantile Free Sialic Acid Storage Disease; ISSD)", "Less Severe FSASD (Salla Disease)", "Intermediate Severe FSASD", "Sialin", "SLC17A5", "Free Sialic Acid Storage Disorder" ]	Free Sialic Acid Storage Disorder	David Adams, Marjan Huizing, Melissa Wasserstein	Summary Free sialic acid storage disorder (FSASD) is a spectrum of neurodegenerative phenotypes resulting from increased lysosomal storage of free sialic acid. Less severe FSASD (historically called Salla disease) is characterized by normal appearance and absence of neurologic findings at birth, followed by slowly progressive neurologic deterioration resulting in mild-to-moderate psychomotor delays, spasticity, athetosis, and epileptic seizures. Severe FSASD (historically referred to as infantile free sialic acid storage disease, or ISSD) is characterized by severe developmental delay, coarse facial features, hepatosplenomegaly, and cardiomegaly; death usually occurs in early childhood. The diagnosis of FSASD is established in a proband by identification of biallelic pathogenic variants in FSASD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an	Less severe FSASD (historically referred to as Salla disease) Intermediate severe FSASD Severe FSASD (historically referred to as infantile free sialic acid storage disease; ISSD) For synonyms and outdated names see • Less severe FSASD (historically referred to as Salla disease) • Intermediate severe FSASD • Severe FSASD (historically referred to as infantile free sialic acid storage disease; ISSD) ## Diagnosis There are no consensus clinical diagnostic criteria for free sialic acid storage disorder (FSASD). FSASD Truncal ataxia and hypotonia apparent at approximately age one year Developmental delay Growth deficiency (short stature) Intellectual disability Spasticity Facial coarsening (variable and not always present) Hypomyelination of the basal ganglia Hypoplasia of the corpus callosum Nonimmune hydrops fetalis (24%) Hepatosplenomegaly Poor weight gain / growth deficiency Severe developmental delay Cardiomegaly Clubfeet Increasingly coarse facial features Neurologic deterioration Early death Urinary excretion of free sialic acid, measured by fluorimetric thiobarbituric acid assay, thin-layer chromatography, or mass spectrometry, is elevated about tenfold in individuals with less severe FSASD and about 100-fold in individuals with ISSD. High-performance liquid chromatography / tandem mass spectrometry is also able to detect free sialic acid in urine [ Note: (1) In the thiobarbituric acid assay, interfering substances may lower the measurement and chromophores may contribute to absorbance, creating a false measurement. (2) In thin-layer chromatography, an elevation of free sialic acid may be overlooked. The diagnosis of FSASD 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 FSASD, molecular genetic testing approaches can include Note: Targeted analysis for founder pathogenic variants can be performed first in individuals of certain ancestries. The Finnish founder variant For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by neurodegeneration, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Free Sialic Acid Storage Disorder See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small 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 Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • Truncal ataxia and hypotonia apparent at approximately age one year • Developmental delay • Growth deficiency (short stature) • Intellectual disability • Spasticity • Facial coarsening (variable and not always present) • Hypomyelination of the basal ganglia • Hypoplasia of the corpus callosum • Nonimmune hydrops fetalis (24%) • Hepatosplenomegaly • Poor weight gain / growth deficiency • Severe developmental delay • Cardiomegaly • Clubfeet • Increasingly coarse facial features • Neurologic deterioration • Early death • Note: Targeted analysis for founder pathogenic variants can be performed first in individuals of certain ancestries. The Finnish founder variant • For an introduction to multigene panels click ## Suggestive Findings FSASD Truncal ataxia and hypotonia apparent at approximately age one year Developmental delay Growth deficiency (short stature) Intellectual disability Spasticity Facial coarsening (variable and not always present) Hypomyelination of the basal ganglia Hypoplasia of the corpus callosum Nonimmune hydrops fetalis (24%) Hepatosplenomegaly Poor weight gain / growth deficiency Severe developmental delay Cardiomegaly Clubfeet Increasingly coarse facial features Neurologic deterioration Early death Urinary excretion of free sialic acid, measured by fluorimetric thiobarbituric acid assay, thin-layer chromatography, or mass spectrometry, is elevated about tenfold in individuals with less severe FSASD and about 100-fold in individuals with ISSD. High-performance liquid chromatography / tandem mass spectrometry is also able to detect free sialic acid in urine [ Note: (1) In the thiobarbituric acid assay, interfering substances may lower the measurement and chromophores may contribute to absorbance, creating a false measurement. (2) In thin-layer chromatography, an elevation of free sialic acid may be overlooked. • Truncal ataxia and hypotonia apparent at approximately age one year • Developmental delay • Growth deficiency (short stature) • Intellectual disability • Spasticity • Facial coarsening (variable and not always present) • Hypomyelination of the basal ganglia • Hypoplasia of the corpus callosum • Nonimmune hydrops fetalis (24%) • Hepatosplenomegaly • Poor weight gain / growth deficiency • Severe developmental delay • Cardiomegaly • Clubfeet • Increasingly coarse facial features • Neurologic deterioration • Early death ## Less Severe FSASD (including Salla disease) Truncal ataxia and hypotonia apparent at approximately age one year Developmental delay Growth deficiency (short stature) Intellectual disability Spasticity Facial coarsening (variable and not always present) Hypomyelination of the basal ganglia Hypoplasia of the corpus callosum • Truncal ataxia and hypotonia apparent at approximately age one year • Developmental delay • Growth deficiency (short stature) • Intellectual disability • Spasticity • Facial coarsening (variable and not always present) • Hypomyelination of the basal ganglia • Hypoplasia of the corpus callosum ## Severe FSASD (including infantile free sialic acid storage disease [ISSD]) Nonimmune hydrops fetalis (24%) Hepatosplenomegaly Poor weight gain / growth deficiency Severe developmental delay Cardiomegaly Clubfeet Increasingly coarse facial features Neurologic deterioration Early death • Nonimmune hydrops fetalis (24%) • Hepatosplenomegaly • Poor weight gain / growth deficiency • Severe developmental delay • Cardiomegaly • Clubfeet • Increasingly coarse facial features • Neurologic deterioration • Early death ## Laboratory Findings (both less severe and severe forms) Urinary excretion of free sialic acid, measured by fluorimetric thiobarbituric acid assay, thin-layer chromatography, or mass spectrometry, is elevated about tenfold in individuals with less severe FSASD and about 100-fold in individuals with ISSD. High-performance liquid chromatography / tandem mass spectrometry is also able to detect free sialic acid in urine [ Note: (1) In the thiobarbituric acid assay, interfering substances may lower the measurement and chromophores may contribute to absorbance, creating a false measurement. (2) In thin-layer chromatography, an elevation of free sialic acid may be overlooked. ## Establishing the Diagnosis The diagnosis of FSASD 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 FSASD, molecular genetic testing approaches can include Note: Targeted analysis for founder pathogenic variants can be performed first in individuals of certain ancestries. The Finnish founder variant For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by neurodegeneration, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Free Sialic Acid Storage Disorder See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small 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 Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 founder pathogenic variants can be performed first in individuals of certain ancestries. The Finnish founder variant • For an introduction to multigene panels click ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of FSASD, molecular genetic testing approaches can include Note: Targeted analysis for founder pathogenic variants can be performed first in individuals of certain ancestries. The Finnish founder variant For an introduction to multigene panels click • Note: Targeted analysis for founder pathogenic variants can be performed first in individuals of certain ancestries. The Finnish founder variant • For an introduction to multigene panels click ## Option 2 When the phenotype is indistinguishable from many other inherited disorders characterized by neurodegeneration, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Free Sialic Acid Storage Disorder See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small 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 Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 Free sialic acid storage disorder (FSASD) comprises a spectrum of neurodegenerative phenotypes resulting from increased lysosomal storage of free sialic acid [ Free Sialic Acid Storage Disorder: Frequency of Select Features Adapted from Includes features reported in entire spectrum of phenotypes (less severe to severe FSASD) Coarse facies are more frequent in severe FSASD. This was likely underascertained in this cohort. Severe hypomyelination and delayed brain myelination is a consistent hallmark of FSASD [D Adams, M Huizing, & M Wasserstein, unpublished data] Salla disease, which serves as a model for less severe FSASD, has the mildest phenotype [ Some individuals with Salla disease present later in life with spasticity, athetosis, and epileptic seizures, becoming nonambulatory and nonverbal. Affected individuals are characterized as good-humored and sociable [ T Life expectancy appears to be shortened, although affected individuals up to age 72 years have been observed. Since the advent of molecular studies, phenotypes with a severity between those of Salla disease and ISSD [ Two sisters described as having intermediate severe Salla disease with ISSD, the most severe phenotype, is characterized by severe developmental delay, coarse facial features, hepatosplenomegaly, and cardiomegaly. Additional reported features include early truncal hypotonia with later spasticity and ataxia, skeletal abnormalities, and seizures (see ISSD can present prenatally and in the neonatal period with nonimmune hydrops fetalis (24% of individuals) [ Skeletal abnormalities can include irregular metaphyses, diffuse hypomineralization, clubfeet, short femurs, enlarged metaphyses, fractures, hip dysplasia, anterior beaking of the dorsal vertebrae, and hypoplasia of the distal phalanges [ Dysmorphic facial features are nonspecific and generally fall into the spectrum of "coarsened" features (e.g., epicanthal folds, ptosis, anteverted nose, gum hypertrophy). Reported ocular findings include nystagmus, exotropia, optic atrophy, and albinoid fundi. Corneal clouding has been rarely reported. Additional reported features include nephropathy and/or nephrotic syndrome and hernias [ Death usually occurs in early childhood, typically from recurrent respiratory infections. Correlations between the type of Homozygosity for the Finnish founder pathogenic variant Compound heterozygosity for the p.Arg39Cys pathogenic variant and another Variable phenotypic expression has been observed among affected family members [ FSASD appears to be fully penetrant. However, two individuals homozygous for Reference to FSASD by historically defined terms such as Salla disease, intermediate severe Salla disease, and ISSD has resulted in confusion for clinicians, affected individuals, researchers, diagnostic laboratories, disease databases, and the pharmaceutical rare disease industry. The designation "free sialic acid storage disorder" (FSASD) was proposed as an encompassing term for the entire spectrum of disease severity in order to improve worldwide disease awareness and to facilitate diagnosis, estimation of disease prevalence, and therapeutic research [ The prevalence of FSASD was estimated to be 1-3 in 1,000,000 individuals worldwide using population databases of genetic variants [ To date, there are about 260 individuals reported worldwide with biallelic pathogenic variants in • Homozygosity for the Finnish founder pathogenic variant • Compound heterozygosity for the p.Arg39Cys pathogenic variant and another ## Clinical Description Free sialic acid storage disorder (FSASD) comprises a spectrum of neurodegenerative phenotypes resulting from increased lysosomal storage of free sialic acid [ Free Sialic Acid Storage Disorder: Frequency of Select Features Adapted from Includes features reported in entire spectrum of phenotypes (less severe to severe FSASD) Coarse facies are more frequent in severe FSASD. This was likely underascertained in this cohort. Severe hypomyelination and delayed brain myelination is a consistent hallmark of FSASD [D Adams, M Huizing, & M Wasserstein, unpublished data] Salla disease, which serves as a model for less severe FSASD, has the mildest phenotype [ Some individuals with Salla disease present later in life with spasticity, athetosis, and epileptic seizures, becoming nonambulatory and nonverbal. Affected individuals are characterized as good-humored and sociable [ T Life expectancy appears to be shortened, although affected individuals up to age 72 years have been observed. Since the advent of molecular studies, phenotypes with a severity between those of Salla disease and ISSD [ Two sisters described as having intermediate severe Salla disease with ISSD, the most severe phenotype, is characterized by severe developmental delay, coarse facial features, hepatosplenomegaly, and cardiomegaly. Additional reported features include early truncal hypotonia with later spasticity and ataxia, skeletal abnormalities, and seizures (see ISSD can present prenatally and in the neonatal period with nonimmune hydrops fetalis (24% of individuals) [ Skeletal abnormalities can include irregular metaphyses, diffuse hypomineralization, clubfeet, short femurs, enlarged metaphyses, fractures, hip dysplasia, anterior beaking of the dorsal vertebrae, and hypoplasia of the distal phalanges [ Dysmorphic facial features are nonspecific and generally fall into the spectrum of "coarsened" features (e.g., epicanthal folds, ptosis, anteverted nose, gum hypertrophy). Reported ocular findings include nystagmus, exotropia, optic atrophy, and albinoid fundi. Corneal clouding has been rarely reported. Additional reported features include nephropathy and/or nephrotic syndrome and hernias [ Death usually occurs in early childhood, typically from recurrent respiratory infections. ## Less Severe FSASD (including Salla disease) Salla disease, which serves as a model for less severe FSASD, has the mildest phenotype [ Some individuals with Salla disease present later in life with spasticity, athetosis, and epileptic seizures, becoming nonambulatory and nonverbal. Affected individuals are characterized as good-humored and sociable [ T Life expectancy appears to be shortened, although affected individuals up to age 72 years have been observed. ## Intermediate Severe FSASD Since the advent of molecular studies, phenotypes with a severity between those of Salla disease and ISSD [ Two sisters described as having intermediate severe Salla disease with ## Severe FSASD (including infantile free sialic acid storage disease [ISSD]) ISSD, the most severe phenotype, is characterized by severe developmental delay, coarse facial features, hepatosplenomegaly, and cardiomegaly. Additional reported features include early truncal hypotonia with later spasticity and ataxia, skeletal abnormalities, and seizures (see ISSD can present prenatally and in the neonatal period with nonimmune hydrops fetalis (24% of individuals) [ Skeletal abnormalities can include irregular metaphyses, diffuse hypomineralization, clubfeet, short femurs, enlarged metaphyses, fractures, hip dysplasia, anterior beaking of the dorsal vertebrae, and hypoplasia of the distal phalanges [ Dysmorphic facial features are nonspecific and generally fall into the spectrum of "coarsened" features (e.g., epicanthal folds, ptosis, anteverted nose, gum hypertrophy). Reported ocular findings include nystagmus, exotropia, optic atrophy, and albinoid fundi. Corneal clouding has been rarely reported. Additional reported features include nephropathy and/or nephrotic syndrome and hernias [ Death usually occurs in early childhood, typically from recurrent respiratory infections. ## Genotype-Phenotype Correlations Correlations between the type of Homozygosity for the Finnish founder pathogenic variant Compound heterozygosity for the p.Arg39Cys pathogenic variant and another Variable phenotypic expression has been observed among affected family members [ • Homozygosity for the Finnish founder pathogenic variant • Compound heterozygosity for the p.Arg39Cys pathogenic variant and another ## Penetrance FSASD appears to be fully penetrant. However, two individuals homozygous for ## Nomenclature Reference to FSASD by historically defined terms such as Salla disease, intermediate severe Salla disease, and ISSD has resulted in confusion for clinicians, affected individuals, researchers, diagnostic laboratories, disease databases, and the pharmaceutical rare disease industry. The designation "free sialic acid storage disorder" (FSASD) was proposed as an encompassing term for the entire spectrum of disease severity in order to improve worldwide disease awareness and to facilitate diagnosis, estimation of disease prevalence, and therapeutic research [ ## Prevalence The prevalence of FSASD was estimated to be 1-3 in 1,000,000 individuals worldwide using population databases of genetic variants [ To date, there are about 260 individuals reported worldwide with biallelic pathogenic variants in ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Based on clinical suspicion and the finding of elevated free sialic acid in urine, one of two steps is taken to distinguish these conditions: The cellular (cytoplasmic versus lysosomal) localization of free sialic acid can be documented; a predominantly lysosomal localization indicates FSASD. Molecular genetic testing of Note: Other causes of mild elevation in urinary free sialic acid may exist. See Other Genes of Interest in the Differential Diagnosis of Free Sialic Acid Storage Disorder From Saudubray & Charpentier, Chapter 86, Table 42, AR = autosomal recessive; FSASD = free sialic acid storage disorder; MOI = mode of inheritance; MPS = mucopolysaccharidosis; XL = X-linked • The cellular (cytoplasmic versus lysosomal) localization of free sialic acid can be documented; a predominantly lysosomal localization indicates FSASD. • Molecular genetic testing of ## Biochemical Findings Based on clinical suspicion and the finding of elevated free sialic acid in urine, one of two steps is taken to distinguish these conditions: The cellular (cytoplasmic versus lysosomal) localization of free sialic acid can be documented; a predominantly lysosomal localization indicates FSASD. Molecular genetic testing of Note: Other causes of mild elevation in urinary free sialic acid may exist. • The cellular (cytoplasmic versus lysosomal) localization of free sialic acid can be documented; a predominantly lysosomal localization indicates FSASD. • Molecular genetic testing of ## Clinical Findings See Other Genes of Interest in the Differential Diagnosis of Free Sialic Acid Storage Disorder From Saudubray & Charpentier, Chapter 86, Table 42, AR = autosomal recessive; FSASD = free sialic acid storage disorder; MOI = mode of inheritance; MPS = mucopolysaccharidosis; XL = X-linked ## Management No clinical practice guidelines for free sialic acid storage disorder (FSASD) 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 FSASD, the evaluations summarized in Free Sialic Acid Storage Disorder: Recommended Evaluations Following Initial Diagnosis To incl brain MRI Consider EEG if seizures are a concern. To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Gross motor & fine motor skills Mobility, activities of daily living, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Gastroenterology / nutrition / feeding team eval Assess for hernia in those w/intermediate severe or severe FSASD. To incl eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk. Community or Social work involvement for parental support Home nursing referral FSASD = free sialic acid storage disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) The medical and psychosocial management of individuals with FSASD is symptomatic and supportive. Free Sialic Acid Storage Disorder: Treatment of Manifestations Many ASMs may be effective; none has been demonstrated effective specifically for FSASD Education of parents/caregivers Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Treatment per ophthalmologist Low vision services as needed 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; FSASD = free sialic acid storage disorder; OT = occupational therapy; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision consultants should be a part of the child’s IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child’s access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Free Sialic Acid Storage Disorder: Recommended Surveillance Monitor those w/seizures as clinically indicated. Assess for new manifestations (e.g., seizures, changes in tone, movement disorders). Physical medicine &/or rehab medicine & OT/PT assessment of mobility & self-help skills Assess bone health incl vitamin D intake. Measurement of growth parameters Eval of nutritional status & safety of oral intake FSASD = free sialic acid storage disorder; OT = occupational therapy; PT = physical therapy No routine testing of apparently asymptomatic at-risk family members is recommended because adult presentations are unusual, and no early interventions are available. See Search • To incl brain MRI • Consider EEG if seizures are a concern. • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • 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) • Gastroenterology / nutrition / feeding team eval • Assess for hernia in those w/intermediate severe or severe FSASD. • To incl eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk. • Community or • Social work involvement for parental support • Home nursing referral • Many ASMs may be effective; none has been demonstrated effective specifically for FSASD • Education of parents/caregivers • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Treatment per ophthalmologist • Low vision services as needed • 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 baclofen, tizanidine, Botox • Monitor those w/seizures as clinically indicated. • Assess for new manifestations (e.g., seizures, changes in tone, movement disorders). • Physical medicine &/or rehab medicine & OT/PT assessment of mobility & self-help skills • Assess bone health incl vitamin D intake. • 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 FSASD, the evaluations summarized in Free Sialic Acid Storage Disorder: Recommended Evaluations Following Initial Diagnosis To incl brain MRI Consider EEG if seizures are a concern. To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Gross motor & fine motor skills Mobility, activities of daily living, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Gastroenterology / nutrition / feeding team eval Assess for hernia in those w/intermediate severe or severe FSASD. To incl eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk. Community or Social work involvement for parental support Home nursing referral FSASD = free sialic acid storage disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • To incl brain MRI • Consider EEG if seizures are a concern. • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Gross motor & fine motor skills • Mobility, activities of daily living, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Gastroenterology / nutrition / feeding team eval • Assess for hernia in those w/intermediate severe or severe FSASD. • To incl eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk. • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations The medical and psychosocial management of individuals with FSASD is symptomatic and supportive. Free Sialic Acid Storage Disorder: Treatment of Manifestations Many ASMs may be effective; none has been demonstrated effective specifically for FSASD Education of parents/caregivers Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Treatment per ophthalmologist Low vision services as needed 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; FSASD = free sialic acid storage disorder; OT = occupational therapy; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision consultants should be a part of the child’s IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child’s access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic 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 • Many ASMs may be effective; none has been demonstrated effective specifically for FSASD • Education of parents/caregivers • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Treatment per ophthalmologist • Low vision services as needed • 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 baclofen, tizanidine, Botox ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision consultants should be a part of the child’s IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child’s access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child’s IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child’s access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child’s IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child’s access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child’s IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child’s access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Motor Dysfunction Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Free Sialic Acid Storage Disorder: Recommended Surveillance Monitor those w/seizures as clinically indicated. Assess for new manifestations (e.g., seizures, changes in tone, movement disorders). Physical medicine &/or rehab medicine & OT/PT assessment of mobility & self-help skills Assess bone health incl vitamin D intake. Measurement of growth parameters Eval of nutritional status & safety of oral intake FSASD = free sialic acid storage disorder; OT = occupational therapy; PT = physical therapy • Monitor those w/seizures as clinically indicated. • Assess for new manifestations (e.g., seizures, changes in tone, movement disorders). • Physical medicine &/or rehab medicine & OT/PT assessment of mobility & self-help skills • Assess bone health incl vitamin D intake. • Measurement of growth parameters • Eval of nutritional status & safety of oral intake ## Evaluation of Relatives at Risk No routine testing of apparently asymptomatic at-risk family members is recommended because adult presentations are unusual, and no early interventions are available. See ## Therapies Under Investigation Search ## Genetic Counseling Free sialic acid storage disorder (FSASD) is inherited in an autosomal recessive manner. The parents of an affected child are presumed to be heterozygous for an Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an Variable expression has been observed among affected sibs [ Heterozygotes are asymptomatic and are not at risk of developing the disorder. Molecular genetic carrier testing for at-risk relatives requires prior identification of the Biochemically based carrier testing is not feasible. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. Carrier testing should be considered for the reproductive partners of known carriers, particularly if both partners are of the same ancestry. The carrier frequency of 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 • Variable expression has been observed among affected sibs [ • Heterozygotes are asymptomatic and are not at risk of developing the disorder. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. • Carrier testing should be considered for the reproductive partners of known carriers, particularly if both partners are of the same ancestry. The carrier frequency of the ## Mode of Inheritance Free sialic acid storage disorder (FSASD) is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected child are presumed to be heterozygous for an Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an Variable expression has been observed among affected sibs [ Heterozygotes 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 • Variable expression has been observed among affected sibs [ • Heterozygotes are asymptomatic and are not at risk of developing the disorder. ## Carrier Detection Molecular genetic carrier testing for at-risk relatives requires prior identification of the Biochemically based carrier testing is not feasible. ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. Carrier testing should be considered for the reproductive partners of known carriers, particularly if both partners are of the same ancestry. The carrier frequency of the • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. • Carrier testing should be considered for the reproductive partners of known carriers, particularly if both partners are of the same ancestry. The carrier frequency of the ## Prenatal Testing and Preimplantation Genetic Testing Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom • • • • United Kingdom • • • • • ## Molecular Genetics Free Sialic Acid Storage Disorder: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Free Sialic Acid Storage Disorder ( The gene product of Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis The gene product of Variants listed in the table have been provided by the authors. ## Chapter Notes David Adams, MD, PhD (2008-present)William A Gahl, MD, PhD; National Human Genome Research Institute (2003-2020)Marjan Huizing, PhD (2025-present)Robert Kleta, MD, PhD; National Human Genome Research Institute (2003-2008)Melissa Wasserstein, MD (2020-present) 26 June 2025 (sw) Comprehensive update posted live 23 January 2020 (sw) Comprehensive update posted live 6 June 2013 (me) Comprehensive update posted live 3 July 2008 (me) Comprehensive update posted live 4 October 2005 (me) Comprehensive update posted live 13 June 2003 (ca) Review posted live 28 February 2003 (wg) Original submission • 26 June 2025 (sw) Comprehensive update posted live • 23 January 2020 (sw) Comprehensive update posted live • 6 June 2013 (me) Comprehensive update posted live • 3 July 2008 (me) Comprehensive update posted live • 4 October 2005 (me) Comprehensive update posted live • 13 June 2003 (ca) Review posted live • 28 February 2003 (wg) Original submission ## Author Notes ## Author History David Adams, MD, PhD (2008-present)William A Gahl, MD, PhD; National Human Genome Research Institute (2003-2020)Marjan Huizing, PhD (2025-present)Robert Kleta, MD, PhD; National Human Genome Research Institute (2003-2008)Melissa Wasserstein, MD (2020-present) ## Revision History 26 June 2025 (sw) Comprehensive update posted live 23 January 2020 (sw) Comprehensive update posted live 6 June 2013 (me) Comprehensive update posted live 3 July 2008 (me) Comprehensive update posted live 4 October 2005 (me) Comprehensive update posted live 13 June 2003 (ca) Review posted live 28 February 2003 (wg) Original submission • 26 June 2025 (sw) Comprehensive update posted live • 23 January 2020 (sw) Comprehensive update posted live • 6 June 2013 (me) Comprehensive update posted live • 3 July 2008 (me) Comprehensive update posted live • 4 October 2005 (me) Comprehensive update posted live • 13 June 2003 (ca) Review posted live • 28 February 2003 (wg) Original submission ## References ## Literature Cited	[]	13/6/2003	26/6/2025		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
jh	jh	[ "Hemochromatosis Type 2", "Juvenile Hereditary Hemochromatosis", "Juvenile Hereditary Hemochromatosis", "Hemochromatosis Type 2", "Hemojuvelin", "Hepcidin", "HAMP", "HJV", "Juvenile Hemochromatosis" ]	Juvenile Hemochromatosis	Alberto Piperno, Francesca Bertola, Angela Bentivegna	Summary Juvenile hemochromatosis is characterized by onset of severe iron overload occurring typically in the first to third decades of life. Males and females are equally affected. Prominent clinical features include hypogonadotropic hypogonadism, cardiomyopathy, glucose intolerance and diabetes, arthropathy, and liver fibrosis or cirrhosis. Hepatocellular cancer has been reported occasionally. The main cause of death is cardiac disease. If juvenile hemochromatosis is detected early enough and if blood is removed regularly through the process of phlebotomy to achieve iron depletion, morbidity and mortality are greatly reduced. The diagnosis of juvenile hemochromatosis is established in a proband with clinical and laboratory features of iron overload by identification of biallelic pathogenic variants in Juvenile hemochromatosis is inherited in an autosomal recessive manner. If each parent is known to be heterozygous for a	## Diagnosis Juvenile hemochromatosis Less specific symptoms in the first decade (e.g., fatigue, arthralgia, lack of appetite), which are often erroneously attributed to iron deficiency anemia Decreased libido, impotence (males), and amenorrhea (females) in adolescents and/or young adults suggesting hypogonadotropic hypogonadism Hepatomegaly, slight alterations of serum transaminases suggesting liver disease or severe fibrosis/cirrhosis Fasting hyperglycemia, glucose intolerance, or frank diabetes Arrhythmias, dyspnea on exertion, heart failure suggesting cardiomyopathy Arthropathy and osteoporosis Hyperpigmentation Note: Many of these features are evident before age 30 years, although they may appear at a later age in some individuals [ Upper normal value in male and female children and young adolescents: 100-125 ng/mL Upper normal value in premenopausal adult women: 150 ng/mL, and in postmenopausal women: 250 ng/mL [ Upper normal value in healthy adult men: 400 ng/mL [ In the earlier stages of juvenile hemochromatosis, serum ferritin can be slightly increased, but can rapidly increase over 1000 ng/mL and even much higher. The diagnosis of juvenile hemochromatosis Molecular genetic testing approaches can include use of a For an introduction to multigene panels click Molecular Genetic Testing Used in Juvenile Hemochromatosis Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Data derived from the subscription-based professional view of Human Gene Mutation Database [ Includes identification of the most common Relaxometry is the quantitative evaluation of the MRI signal loss due to the predominant shortening of the T The signal intensity ratio (SIR) method ( Liver biopsy is currently limited to prognostic purposes (assessment of liver damage) in individuals with serum ferritin higher than 1000 ng/mL or high amount of iron at quantitative MRI, whereas its use for diagnostic purposes is limited to selected situations [ • Less specific symptoms in the first decade (e.g., fatigue, arthralgia, lack of appetite), which are often erroneously attributed to iron deficiency anemia • Decreased libido, impotence (males), and amenorrhea (females) in adolescents and/or young adults suggesting hypogonadotropic hypogonadism • Hepatomegaly, slight alterations of serum transaminases suggesting liver disease or severe fibrosis/cirrhosis • Fasting hyperglycemia, glucose intolerance, or frank diabetes • Arrhythmias, dyspnea on exertion, heart failure suggesting cardiomyopathy • Arthropathy and osteoporosis • Hyperpigmentation • Upper normal value in male and female children and young adolescents: 100-125 ng/mL • Upper normal value in premenopausal adult women: 150 ng/mL, and in postmenopausal women: 250 ng/mL [ • Upper normal value in healthy adult men: 400 ng/mL [ • In the earlier stages of juvenile hemochromatosis, serum ferritin can be slightly increased, but can rapidly increase over 1000 ng/mL and even much higher. • Upper normal value in male and female children and young adolescents: 100-125 ng/mL • Upper normal value in premenopausal adult women: 150 ng/mL, and in postmenopausal women: 250 ng/mL [ • Upper normal value in healthy adult men: 400 ng/mL [ • In the earlier stages of juvenile hemochromatosis, serum ferritin can be slightly increased, but can rapidly increase over 1000 ng/mL and even much higher. • Upper normal value in male and female children and young adolescents: 100-125 ng/mL • Upper normal value in premenopausal adult women: 150 ng/mL, and in postmenopausal women: 250 ng/mL [ • Upper normal value in healthy adult men: 400 ng/mL [ • In the earlier stages of juvenile hemochromatosis, serum ferritin can be slightly increased, but can rapidly increase over 1000 ng/mL and even much higher. • For an introduction to multigene panels click • Relaxometry is the quantitative evaluation of the MRI signal loss due to the predominant shortening of the T • The signal intensity ratio (SIR) method ( ## Suggestive Findings Juvenile hemochromatosis Less specific symptoms in the first decade (e.g., fatigue, arthralgia, lack of appetite), which are often erroneously attributed to iron deficiency anemia Decreased libido, impotence (males), and amenorrhea (females) in adolescents and/or young adults suggesting hypogonadotropic hypogonadism Hepatomegaly, slight alterations of serum transaminases suggesting liver disease or severe fibrosis/cirrhosis Fasting hyperglycemia, glucose intolerance, or frank diabetes Arrhythmias, dyspnea on exertion, heart failure suggesting cardiomyopathy Arthropathy and osteoporosis Hyperpigmentation Note: Many of these features are evident before age 30 years, although they may appear at a later age in some individuals [ Upper normal value in male and female children and young adolescents: 100-125 ng/mL Upper normal value in premenopausal adult women: 150 ng/mL, and in postmenopausal women: 250 ng/mL [ Upper normal value in healthy adult men: 400 ng/mL [ In the earlier stages of juvenile hemochromatosis, serum ferritin can be slightly increased, but can rapidly increase over 1000 ng/mL and even much higher. • Less specific symptoms in the first decade (e.g., fatigue, arthralgia, lack of appetite), which are often erroneously attributed to iron deficiency anemia • Decreased libido, impotence (males), and amenorrhea (females) in adolescents and/or young adults suggesting hypogonadotropic hypogonadism • Hepatomegaly, slight alterations of serum transaminases suggesting liver disease or severe fibrosis/cirrhosis • Fasting hyperglycemia, glucose intolerance, or frank diabetes • Arrhythmias, dyspnea on exertion, heart failure suggesting cardiomyopathy • Arthropathy and osteoporosis • Hyperpigmentation • Upper normal value in male and female children and young adolescents: 100-125 ng/mL • Upper normal value in premenopausal adult women: 150 ng/mL, and in postmenopausal women: 250 ng/mL [ • Upper normal value in healthy adult men: 400 ng/mL [ • In the earlier stages of juvenile hemochromatosis, serum ferritin can be slightly increased, but can rapidly increase over 1000 ng/mL and even much higher. • Upper normal value in male and female children and young adolescents: 100-125 ng/mL • Upper normal value in premenopausal adult women: 150 ng/mL, and in postmenopausal women: 250 ng/mL [ • Upper normal value in healthy adult men: 400 ng/mL [ • In the earlier stages of juvenile hemochromatosis, serum ferritin can be slightly increased, but can rapidly increase over 1000 ng/mL and even much higher. • Upper normal value in male and female children and young adolescents: 100-125 ng/mL • Upper normal value in premenopausal adult women: 150 ng/mL, and in postmenopausal women: 250 ng/mL [ • Upper normal value in healthy adult men: 400 ng/mL [ • In the earlier stages of juvenile hemochromatosis, serum ferritin can be slightly increased, but can rapidly increase over 1000 ng/mL and even much higher. ## Establishing the Diagnosis The diagnosis of juvenile hemochromatosis Molecular genetic testing approaches can include use of a For an introduction to multigene panels click Molecular Genetic Testing Used in Juvenile Hemochromatosis Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Data derived from the subscription-based professional view of Human Gene Mutation Database [ Includes identification of the most common Relaxometry is the quantitative evaluation of the MRI signal loss due to the predominant shortening of the T The signal intensity ratio (SIR) method ( Liver biopsy is currently limited to prognostic purposes (assessment of liver damage) in individuals with serum ferritin higher than 1000 ng/mL or high amount of iron at quantitative MRI, whereas its use for diagnostic purposes is limited to selected situations [ • For an introduction to multigene panels click • Relaxometry is the quantitative evaluation of the MRI signal loss due to the predominant shortening of the T • The signal intensity ratio (SIR) method ( ## Imaging Relaxometry is the quantitative evaluation of the MRI signal loss due to the predominant shortening of the T The signal intensity ratio (SIR) method ( • Relaxometry is the quantitative evaluation of the MRI signal loss due to the predominant shortening of the T • The signal intensity ratio (SIR) method ( ## Liver Biopsy Liver biopsy is currently limited to prognostic purposes (assessment of liver damage) in individuals with serum ferritin higher than 1000 ng/mL or high amount of iron at quantitative MRI, whereas its use for diagnostic purposes is limited to selected situations [ ## Clinical Characteristics To date, approximately 120 individuals have been identified with juvenile hemochromatosis [ Features of Juvenile Hemochromatosis In Not enough information is available to determine the proportion of individuals with this feature. Not all individuals in reported studies underwent liver biopsy. Proportion of persons with Juvenile hemochromatosis is characterized by early-onset severe iron overload. Individuals with juvenile hemochromatosis typically present in the first to third decade of life; however, adult presentation has been described in individuals with Individuals with juvenile hemochromatosis are rarely diagnosed before significant iron overload occurs. Prominent clinical features include hypogonadotropic hypogonadism, cardiomyopathy, diabetes and glucose intolerance, arthropathy, and liver fibrosis or cirrhosis. If juvenile hemochromatosis is detected early and treated with phlebotomy to achieve iron depletion, morbidity and mortality are greatly reduced. No genotype-phenotype correlations can be provided for Despite use of the locus names HFE2A and HFE2B for the two juvenile hemochromatosis genes ( Juvenile hemochromatosis is rare; global ## Clinical Description To date, approximately 120 individuals have been identified with juvenile hemochromatosis [ Features of Juvenile Hemochromatosis In Not enough information is available to determine the proportion of individuals with this feature. Not all individuals in reported studies underwent liver biopsy. Proportion of persons with Juvenile hemochromatosis is characterized by early-onset severe iron overload. Individuals with juvenile hemochromatosis typically present in the first to third decade of life; however, adult presentation has been described in individuals with Individuals with juvenile hemochromatosis are rarely diagnosed before significant iron overload occurs. Prominent clinical features include hypogonadotropic hypogonadism, cardiomyopathy, diabetes and glucose intolerance, arthropathy, and liver fibrosis or cirrhosis. If juvenile hemochromatosis is detected early and treated with phlebotomy to achieve iron depletion, morbidity and mortality are greatly reduced. ## Genotype-Phenotype Correlations No genotype-phenotype correlations can be provided for ## Nomenclature Despite use of the locus names HFE2A and HFE2B for the two juvenile hemochromatosis genes ( ## Prevalence Juvenile hemochromatosis is rare; global ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Iron overload phenotypes can be primary or secondary. Note: Iron overload disorders presenting with hyperferritinemia with normal or reduced transferrin saturation (e.g., Primary Iron Overload-Related Disorders with High Transferrin Saturation and Serum Ferritin to Consider in the Differential Diagnosis of Juvenile Hemochromatosis Iron overload distribution mainly involving parenchymal cell; sparing reticuloendothelial macrophages Hepatic fibrosis/cirrhosis Diabetes mellitus Skin hyperpigmentation Cardiomyopathy Hypogonadotropic hypogonadism Transferrin saturation less ↑ (variably ranges >45%) Low penetrance w/variable expression Later onset (40s-50s) Hepatic fibrosis/cirrhosis more common Hepatocellular carcinoma most frequent cause of death Cardiomyopathy & hypogonadism less common Transferrin saturation in Iron overload distribution mainly involving parenchymal cells; sparing reticuloendothelial macrophages Hepatic fibrosis/cirrhosis Diabetes mellitus Skin hyperpigmentation Cardiomyopathy Hypogonadotropic hypogonadism Cardiomyopathy & hypogonadism less common Phenotype (age of onset & complications) intermediate between Iron overload distribution mainly involving parenchymal cells; sparing reticuloendothelial macrophages Hepatic fibrosis/cirrhosis Diabetes mellitus Skin hyperpigmentation Cardiomyopathy (less than in JH) Hypogonadotropic hypogonadism (less than in JH) Typically presents in 40s & 50s (vs <30 yrs in JH) Because of lower rate of iron accumulation, clinical findings (esp hypogonadism & cardiomyopathy) less common than in JH Note: It is generally assumed that type 4 HHC is similar to Ultra-rare; <15 individuals Age of presentation: 1-2 yrs Severe microcytic anemia that may require blood transfusion Undetectable serum transferrin & very ↓ serum iron levels If untreated, growth deficiency, severe iron-related complications & death may occur. Ultra-rare, <10 individuals Age of presentation: postnatal to young adult Severe microcytic anemia that may require blood transfusion If untreated, growth deficiency may occur. AD = autosomal dominant; AR = autosomal recessive; DMT1 = divalent metal transporter; HHC = hemochromatosis; JH = juvenile hemochromatosis; MOI = mode of inheritance Some Mutation of Because of the rarity of type 4 hemochromatosis, data should be interpreted with caution. In atransferrinemia, the lack of serum transferrin causes the loss of its iron scavenger and transport functions leading to severe iron deficiency anemia, non-transferrin-bound iron formation and severe iron overload in non-hematopoietic tissues. DMT1 deficiency is also referred to as hypochromic microcytic anemia with iron overload-1. DMT1 transmembrane protein is involved in dietary non-heme iron uptake and plays a crucial role in iron utilization at the endosomal membrane of the erythroid precursors. In humans, DMT1 has a prevalent role in erythroid cells, and the reduction of DMT1 causes a more complex phenotype characterized by congenital microcytic anemia (due to defective iron transport and utilization in erythroid precursors) and biochemical and histologic features of iron overload [ • Iron overload distribution mainly involving parenchymal cell; sparing reticuloendothelial macrophages • Hepatic fibrosis/cirrhosis • Diabetes mellitus • Skin hyperpigmentation • Cardiomyopathy • Hypogonadotropic hypogonadism • Transferrin saturation less ↑ (variably ranges >45%) • Low penetrance w/variable expression • Later onset (40s-50s) • Hepatic fibrosis/cirrhosis more common • Hepatocellular carcinoma most frequent cause of death • Cardiomyopathy & hypogonadism less common • Transferrin saturation in • Iron overload distribution mainly involving parenchymal cells; sparing reticuloendothelial macrophages • Hepatic fibrosis/cirrhosis • Diabetes mellitus • Skin hyperpigmentation • Cardiomyopathy • Hypogonadotropic hypogonadism • Cardiomyopathy & hypogonadism less common • Phenotype (age of onset & complications) intermediate between • Iron overload distribution mainly involving parenchymal cells; sparing reticuloendothelial macrophages • Hepatic fibrosis/cirrhosis • Diabetes mellitus • Skin hyperpigmentation • Cardiomyopathy (less than in JH) • Hypogonadotropic hypogonadism (less than in JH) • Typically presents in 40s & 50s (vs <30 yrs in JH) • Because of lower rate of iron accumulation, clinical findings (esp hypogonadism & cardiomyopathy) less common than in JH • Note: It is generally assumed that type 4 HHC is similar to • Ultra-rare; <15 individuals • Age of presentation: 1-2 yrs • Severe microcytic anemia that may require blood transfusion • Undetectable serum transferrin & very ↓ serum iron levels • If untreated, growth deficiency, severe iron-related complications & death may occur. • Ultra-rare, <10 individuals • Age of presentation: postnatal to young adult • Severe microcytic anemia that may require blood transfusion • If untreated, growth deficiency may occur. ## Primary Iron Overload Disorders Primary Iron Overload-Related Disorders with High Transferrin Saturation and Serum Ferritin to Consider in the Differential Diagnosis of Juvenile Hemochromatosis Iron overload distribution mainly involving parenchymal cell; sparing reticuloendothelial macrophages Hepatic fibrosis/cirrhosis Diabetes mellitus Skin hyperpigmentation Cardiomyopathy Hypogonadotropic hypogonadism Transferrin saturation less ↑ (variably ranges >45%) Low penetrance w/variable expression Later onset (40s-50s) Hepatic fibrosis/cirrhosis more common Hepatocellular carcinoma most frequent cause of death Cardiomyopathy & hypogonadism less common Transferrin saturation in Iron overload distribution mainly involving parenchymal cells; sparing reticuloendothelial macrophages Hepatic fibrosis/cirrhosis Diabetes mellitus Skin hyperpigmentation Cardiomyopathy Hypogonadotropic hypogonadism Cardiomyopathy & hypogonadism less common Phenotype (age of onset & complications) intermediate between Iron overload distribution mainly involving parenchymal cells; sparing reticuloendothelial macrophages Hepatic fibrosis/cirrhosis Diabetes mellitus Skin hyperpigmentation Cardiomyopathy (less than in JH) Hypogonadotropic hypogonadism (less than in JH) Typically presents in 40s & 50s (vs <30 yrs in JH) Because of lower rate of iron accumulation, clinical findings (esp hypogonadism & cardiomyopathy) less common than in JH Note: It is generally assumed that type 4 HHC is similar to Ultra-rare; <15 individuals Age of presentation: 1-2 yrs Severe microcytic anemia that may require blood transfusion Undetectable serum transferrin & very ↓ serum iron levels If untreated, growth deficiency, severe iron-related complications & death may occur. Ultra-rare, <10 individuals Age of presentation: postnatal to young adult Severe microcytic anemia that may require blood transfusion If untreated, growth deficiency may occur. AD = autosomal dominant; AR = autosomal recessive; DMT1 = divalent metal transporter; HHC = hemochromatosis; JH = juvenile hemochromatosis; MOI = mode of inheritance Some Mutation of Because of the rarity of type 4 hemochromatosis, data should be interpreted with caution. In atransferrinemia, the lack of serum transferrin causes the loss of its iron scavenger and transport functions leading to severe iron deficiency anemia, non-transferrin-bound iron formation and severe iron overload in non-hematopoietic tissues. DMT1 deficiency is also referred to as hypochromic microcytic anemia with iron overload-1. DMT1 transmembrane protein is involved in dietary non-heme iron uptake and plays a crucial role in iron utilization at the endosomal membrane of the erythroid precursors. In humans, DMT1 has a prevalent role in erythroid cells, and the reduction of DMT1 causes a more complex phenotype characterized by congenital microcytic anemia (due to defective iron transport and utilization in erythroid precursors) and biochemical and histologic features of iron overload [ • Iron overload distribution mainly involving parenchymal cell; sparing reticuloendothelial macrophages • Hepatic fibrosis/cirrhosis • Diabetes mellitus • Skin hyperpigmentation • Cardiomyopathy • Hypogonadotropic hypogonadism • Transferrin saturation less ↑ (variably ranges >45%) • Low penetrance w/variable expression • Later onset (40s-50s) • Hepatic fibrosis/cirrhosis more common • Hepatocellular carcinoma most frequent cause of death • Cardiomyopathy & hypogonadism less common • Transferrin saturation in • Iron overload distribution mainly involving parenchymal cells; sparing reticuloendothelial macrophages • Hepatic fibrosis/cirrhosis • Diabetes mellitus • Skin hyperpigmentation • Cardiomyopathy • Hypogonadotropic hypogonadism • Cardiomyopathy & hypogonadism less common • Phenotype (age of onset & complications) intermediate between • Iron overload distribution mainly involving parenchymal cells; sparing reticuloendothelial macrophages • Hepatic fibrosis/cirrhosis • Diabetes mellitus • Skin hyperpigmentation • Cardiomyopathy (less than in JH) • Hypogonadotropic hypogonadism (less than in JH) • Typically presents in 40s & 50s (vs <30 yrs in JH) • Because of lower rate of iron accumulation, clinical findings (esp hypogonadism & cardiomyopathy) less common than in JH • Note: It is generally assumed that type 4 HHC is similar to • Ultra-rare; <15 individuals • Age of presentation: 1-2 yrs • Severe microcytic anemia that may require blood transfusion • Undetectable serum transferrin & very ↓ serum iron levels • If untreated, growth deficiency, severe iron-related complications & death may occur. • Ultra-rare, <10 individuals • Age of presentation: postnatal to young adult • Severe microcytic anemia that may require blood transfusion • If untreated, growth deficiency may occur. ## Secondary Iron Overload Disorders ## Management To establish the extent of disease in an individual diagnosed with juvenile hemochromatosis, the evaluations summarized Recommended Evaluations Following Initial Diagnosis in Individuals with Juvenile Hemochromatosis Biochemical tests: serum transaminases, gammaglutamyl transferase, albumin, INR, bilirubin Instrumental tests: abdominal ultrasound, fibroelastography MR-based quantification of liver iron overload CT & MR as needed (e.g., if focal lesions on ultrasound) Liver biopsy for prognostic evaluation (severe fibrosis/cirrhosis) in those w/severe iron overload EKG & Holter EKG Transthoracic echocardiogram MR-based quantification of myocardial iron overload Myocardial iron accumulation often precedes cardiac dysfunction. Findings of left ventricular diastolic dysfunction (↓ left ventricular compliance) often precede ventricular dilatation & compromised ejection fraction in those w/out manifestations of cardiac failure or arrhythmias. Overnight fasting serum glucose & insulin measurement Oral glucose tolerance test w/baseline & 120-min serum glucose & insulin measurement Measurement of serum FSH & LH, & testosterone or estradiol GnRH stimulation test as needed Pituitary MRI as needed DXA = dual-energy x-ray absorptiometry; FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; INR = international normalized ratio; LH = luteinizing hormone Current recommendations for Management and treatment recommendations for juvenile hemochromatosis stated here are based on the established Hemoglobin should be monitored prior to phlebotomy; if the value is less than 11 g/dL, the treatment schedule is modified to every other week [ Serum ferritin concentration reflects body iron stores and is used to monitor the progress of therapy; it is expected to fall progressively, along with iron mobilization. Measuring serum ferritin concentration every 4-8 phlebotomies according to the amount of iron overload is reasonable; however, once serum ferritin concentration is below 100 ng/mL, it should be measured more often. Individuals are treated until the serum ferritin is approximately 50 ng/mL, a value in the lower reference range that signifies that there is little or no storage iron [ Transferrin saturation usually decreases much less rapidly in response to phlebotomy therapy than the serum ferritin level. It may remain increased when body iron stores and serum ferritin values have already reached target levels. Despite successful iron depletion, transferrin saturation often remains increased in individuals with juvenile hemochromatosis, and reducing transferrin saturation to low-normal values may result in iron deficiency. Thus, experts recommend that serum ferritin, not transferrin saturation, be used as the indicator for cessation of phlebotomy induction therapy [ Erythrocytoapheresis can be a rapid and safe alternative treatment, but it requires special apparatus and facilities and has limited availability. Although this treatment is excellent in selected individuals, erythropoietin stimulation may be required to maintain adequate hemoglobin level. This treatment may be preferred for individuals with severe iron overload and individuals whose clinical condition requires maintaining the isovolemic status or sparing of plasma proteins as in severe cardiomyopathy or advanced liver disease [ Hypogonadism is treated with testosterone replacement in males and cyclical estrogen and progesterone therapy in fertile females. Although iron-induced pituitary hypogonadism is generally considered irreversible, it has been shown that gonadotropin cell dysfunction can be reversed when specific treatment is introduced early in the progression of the disease [ Limited data regarding treatment of the joint involvement of hemochromatosis exist. Treatment relies on symptomatic measures with the use of analgesics and NSAIDs. Colchicine can be useful during flares most probably due to calcium pyrophosphate deposition. Intra-articular corticosteroid injections can be used but no relevant published data is available. Some data suggest the possible efficacy of phlebotomy but its effects, if any, are unpredictable. Joint prosthetic replacement (mainly hip and knee) is an option [ Cardiac failure and arrhythmias require treatment as per cardiologist. Iron removal is mandatory because of the evidence of its significant effect in improving cardiac function [ Based on data related to other liver disease and Glucose intolerance or diabetes may require oral agents or insulin administration. Phlebotomy has a variable impact on diabetes control. In general, it may prevent progression if started in the earlier stages of disease, although the majority of individuals with diabetes will experience no significant change or worsening in their glucose metabolism control [ Individuals with biochemical evidence of iron overload but without evidence of organ dysfunction or failure should be encouraged to undergo regular phlebotomies until excess iron stores are depleted to prevent the development of complications associated with excess iron stores. Treatment by phlebotomy in presymptomatic stages can prevent organ damage. Hormone replacement therapy may prevent the development of osteoporosis. If hepatic cirrhosis is identified, monitoring for hepatocellular cancer (HCC) is recommended. The imaging test most widely used for surveillance is ultrasonography (US), and a 6-month interval represents a reasonable choice. The performance of US in early detection of HCC is highly dependent on the expertise of the operator and the quality of the equipment. Thus, special training for ultrasonographers is recommended. AFP is the most widely tested biomarker in HCC, but it has a suboptimal performance as a serologic test for surveillance [ Recommended Surveillance for Individuals with Juvenile Hemochromatosis DXA = dual-energy x-ray absorptiometry; PTH = parathyroid hormone Avoid the following [ Alcohol consumption, which has a synergistic effect with iron-induced liver damage in individuals with liver damage Iron-containing preparations and supplemental vitamin C Handling or eating uncooked shellfish or marine fish, because of susceptibility to fatal septicemia from the marine bacterium Once a diagnosis of juvenile hemochromatosis has been made in a family, it is appropriate to clarify the clinical/genetic status of all at-risk family members (i.e., sibs) of an affected individual in order to identify as early as possible those who would benefit from early monitoring for the development of iron overload. If juvenile hemochromatosis is detected before evidence of organ damage, treatment via phlebotomy can reverse or prevent many of the secondary complications resulting from organ damage. Evaluation of at-risk family members can include: Serum iron indices (serum iron, transferrin saturation, and serum ferritin) and serum transaminases as first evaluation of coexistent liver damage and C-reactive protein to exclude inflammatory conditions that can influence serum iron indices; Molecular genetic testing (if the See All pregnant women with juvenile hemochromatosis should be under the care of a maternal-fetal medicine specialist, an endocrinologist, and a cardiologist. Preferably women with juvenile hemochromatosis should be seen by these specialists prior to becoming pregnant. Pregnancy in women with untreated juvenile hemochromatosis is high risk because the increased hemodynamic burden of pregnancy can precipitate cardiac failure in women with an underlying cardiomyopathy. Of note, it is critically important for specialists in endocrinology and infertility to be aware of juvenile hemochromatosis as a cause of infertility and to evaluate individuals for iron overload prior to correcting the underlying hormonal imbalance [ Search • Biochemical tests: serum transaminases, gammaglutamyl transferase, albumin, INR, bilirubin • Instrumental tests: abdominal ultrasound, fibroelastography • MR-based quantification of liver iron overload • CT & MR as needed (e.g., if focal lesions on ultrasound) • Liver biopsy for prognostic evaluation (severe fibrosis/cirrhosis) in those w/severe iron overload • EKG & Holter EKG • Transthoracic echocardiogram • MR-based quantification of myocardial iron overload • Myocardial iron accumulation often precedes cardiac dysfunction. • Findings of left ventricular diastolic dysfunction (↓ left ventricular compliance) often precede ventricular dilatation & compromised ejection fraction in those w/out manifestations of cardiac failure or arrhythmias. • Overnight fasting serum glucose & insulin measurement • Oral glucose tolerance test w/baseline & 120-min serum glucose & insulin measurement • Measurement of serum FSH & LH, & testosterone or estradiol • GnRH stimulation test as needed • Pituitary MRI as needed • Hypogonadism is treated with testosterone replacement in males and cyclical estrogen and progesterone therapy in fertile females. Although iron-induced pituitary hypogonadism is generally considered irreversible, it has been shown that gonadotropin cell dysfunction can be reversed when specific treatment is introduced early in the progression of the disease [ • Limited data regarding treatment of the joint involvement of hemochromatosis exist. Treatment relies on symptomatic measures with the use of analgesics and NSAIDs. Colchicine can be useful during flares most probably due to calcium pyrophosphate deposition. Intra-articular corticosteroid injections can be used but no relevant published data is available. Some data suggest the possible efficacy of phlebotomy but its effects, if any, are unpredictable. Joint prosthetic replacement (mainly hip and knee) is an option [ • Cardiac failure and arrhythmias require treatment as per cardiologist. Iron removal is mandatory because of the evidence of its significant effect in improving cardiac function [ • Based on data related to other liver disease and • Glucose intolerance or diabetes may require oral agents or insulin administration. Phlebotomy has a variable impact on diabetes control. In general, it may prevent progression if started in the earlier stages of disease, although the majority of individuals with diabetes will experience no significant change or worsening in their glucose metabolism control [ • Alcohol consumption, which has a synergistic effect with iron-induced liver damage in individuals with liver damage • Iron-containing preparations and supplemental vitamin C • Handling or eating uncooked shellfish or marine fish, because of susceptibility to fatal septicemia from the marine bacterium • Serum iron indices (serum iron, transferrin saturation, and serum ferritin) and serum transaminases as first evaluation of coexistent liver damage and C-reactive protein to exclude inflammatory conditions that can influence serum iron indices; • Molecular genetic testing (if the ## Evaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with juvenile hemochromatosis, the evaluations summarized Recommended Evaluations Following Initial Diagnosis in Individuals with Juvenile Hemochromatosis Biochemical tests: serum transaminases, gammaglutamyl transferase, albumin, INR, bilirubin Instrumental tests: abdominal ultrasound, fibroelastography MR-based quantification of liver iron overload CT & MR as needed (e.g., if focal lesions on ultrasound) Liver biopsy for prognostic evaluation (severe fibrosis/cirrhosis) in those w/severe iron overload EKG & Holter EKG Transthoracic echocardiogram MR-based quantification of myocardial iron overload Myocardial iron accumulation often precedes cardiac dysfunction. Findings of left ventricular diastolic dysfunction (↓ left ventricular compliance) often precede ventricular dilatation & compromised ejection fraction in those w/out manifestations of cardiac failure or arrhythmias. Overnight fasting serum glucose & insulin measurement Oral glucose tolerance test w/baseline & 120-min serum glucose & insulin measurement Measurement of serum FSH & LH, & testosterone or estradiol GnRH stimulation test as needed Pituitary MRI as needed DXA = dual-energy x-ray absorptiometry; FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; INR = international normalized ratio; LH = luteinizing hormone Current recommendations for • Biochemical tests: serum transaminases, gammaglutamyl transferase, albumin, INR, bilirubin • Instrumental tests: abdominal ultrasound, fibroelastography • MR-based quantification of liver iron overload • CT & MR as needed (e.g., if focal lesions on ultrasound) • Liver biopsy for prognostic evaluation (severe fibrosis/cirrhosis) in those w/severe iron overload • EKG & Holter EKG • Transthoracic echocardiogram • MR-based quantification of myocardial iron overload • Myocardial iron accumulation often precedes cardiac dysfunction. • Findings of left ventricular diastolic dysfunction (↓ left ventricular compliance) often precede ventricular dilatation & compromised ejection fraction in those w/out manifestations of cardiac failure or arrhythmias. • Overnight fasting serum glucose & insulin measurement • Oral glucose tolerance test w/baseline & 120-min serum glucose & insulin measurement • Measurement of serum FSH & LH, & testosterone or estradiol • GnRH stimulation test as needed • Pituitary MRI as needed ## Treatment of Manifestations Management and treatment recommendations for juvenile hemochromatosis stated here are based on the established Hemoglobin should be monitored prior to phlebotomy; if the value is less than 11 g/dL, the treatment schedule is modified to every other week [ Serum ferritin concentration reflects body iron stores and is used to monitor the progress of therapy; it is expected to fall progressively, along with iron mobilization. Measuring serum ferritin concentration every 4-8 phlebotomies according to the amount of iron overload is reasonable; however, once serum ferritin concentration is below 100 ng/mL, it should be measured more often. Individuals are treated until the serum ferritin is approximately 50 ng/mL, a value in the lower reference range that signifies that there is little or no storage iron [ Transferrin saturation usually decreases much less rapidly in response to phlebotomy therapy than the serum ferritin level. It may remain increased when body iron stores and serum ferritin values have already reached target levels. Despite successful iron depletion, transferrin saturation often remains increased in individuals with juvenile hemochromatosis, and reducing transferrin saturation to low-normal values may result in iron deficiency. Thus, experts recommend that serum ferritin, not transferrin saturation, be used as the indicator for cessation of phlebotomy induction therapy [ Erythrocytoapheresis can be a rapid and safe alternative treatment, but it requires special apparatus and facilities and has limited availability. Although this treatment is excellent in selected individuals, erythropoietin stimulation may be required to maintain adequate hemoglobin level. This treatment may be preferred for individuals with severe iron overload and individuals whose clinical condition requires maintaining the isovolemic status or sparing of plasma proteins as in severe cardiomyopathy or advanced liver disease [ Hypogonadism is treated with testosterone replacement in males and cyclical estrogen and progesterone therapy in fertile females. Although iron-induced pituitary hypogonadism is generally considered irreversible, it has been shown that gonadotropin cell dysfunction can be reversed when specific treatment is introduced early in the progression of the disease [ Limited data regarding treatment of the joint involvement of hemochromatosis exist. Treatment relies on symptomatic measures with the use of analgesics and NSAIDs. Colchicine can be useful during flares most probably due to calcium pyrophosphate deposition. Intra-articular corticosteroid injections can be used but no relevant published data is available. Some data suggest the possible efficacy of phlebotomy but its effects, if any, are unpredictable. Joint prosthetic replacement (mainly hip and knee) is an option [ Cardiac failure and arrhythmias require treatment as per cardiologist. Iron removal is mandatory because of the evidence of its significant effect in improving cardiac function [ Based on data related to other liver disease and Glucose intolerance or diabetes may require oral agents or insulin administration. Phlebotomy has a variable impact on diabetes control. In general, it may prevent progression if started in the earlier stages of disease, although the majority of individuals with diabetes will experience no significant change or worsening in their glucose metabolism control [ • Hypogonadism is treated with testosterone replacement in males and cyclical estrogen and progesterone therapy in fertile females. Although iron-induced pituitary hypogonadism is generally considered irreversible, it has been shown that gonadotropin cell dysfunction can be reversed when specific treatment is introduced early in the progression of the disease [ • Limited data regarding treatment of the joint involvement of hemochromatosis exist. Treatment relies on symptomatic measures with the use of analgesics and NSAIDs. Colchicine can be useful during flares most probably due to calcium pyrophosphate deposition. Intra-articular corticosteroid injections can be used but no relevant published data is available. Some data suggest the possible efficacy of phlebotomy but its effects, if any, are unpredictable. Joint prosthetic replacement (mainly hip and knee) is an option [ • Cardiac failure and arrhythmias require treatment as per cardiologist. Iron removal is mandatory because of the evidence of its significant effect in improving cardiac function [ • Based on data related to other liver disease and • Glucose intolerance or diabetes may require oral agents or insulin administration. Phlebotomy has a variable impact on diabetes control. In general, it may prevent progression if started in the earlier stages of disease, although the majority of individuals with diabetes will experience no significant change or worsening in their glucose metabolism control [ ## Prevention of Primary Manifestations Individuals with biochemical evidence of iron overload but without evidence of organ dysfunction or failure should be encouraged to undergo regular phlebotomies until excess iron stores are depleted to prevent the development of complications associated with excess iron stores. Treatment by phlebotomy in presymptomatic stages can prevent organ damage. ## Prevention of Secondary Complications Hormone replacement therapy may prevent the development of osteoporosis. ## Surveillance If hepatic cirrhosis is identified, monitoring for hepatocellular cancer (HCC) is recommended. The imaging test most widely used for surveillance is ultrasonography (US), and a 6-month interval represents a reasonable choice. The performance of US in early detection of HCC is highly dependent on the expertise of the operator and the quality of the equipment. Thus, special training for ultrasonographers is recommended. AFP is the most widely tested biomarker in HCC, but it has a suboptimal performance as a serologic test for surveillance [ Recommended Surveillance for Individuals with Juvenile Hemochromatosis DXA = dual-energy x-ray absorptiometry; PTH = parathyroid hormone ## Agents/Circumstances to Avoid Avoid the following [ Alcohol consumption, which has a synergistic effect with iron-induced liver damage in individuals with liver damage Iron-containing preparations and supplemental vitamin C Handling or eating uncooked shellfish or marine fish, because of susceptibility to fatal septicemia from the marine bacterium • Alcohol consumption, which has a synergistic effect with iron-induced liver damage in individuals with liver damage • Iron-containing preparations and supplemental vitamin C • Handling or eating uncooked shellfish or marine fish, because of susceptibility to fatal septicemia from the marine bacterium ## Evaluation of Relatives at Risk Once a diagnosis of juvenile hemochromatosis has been made in a family, it is appropriate to clarify the clinical/genetic status of all at-risk family members (i.e., sibs) of an affected individual in order to identify as early as possible those who would benefit from early monitoring for the development of iron overload. If juvenile hemochromatosis is detected before evidence of organ damage, treatment via phlebotomy can reverse or prevent many of the secondary complications resulting from organ damage. Evaluation of at-risk family members can include: Serum iron indices (serum iron, transferrin saturation, and serum ferritin) and serum transaminases as first evaluation of coexistent liver damage and C-reactive protein to exclude inflammatory conditions that can influence serum iron indices; Molecular genetic testing (if the See • Serum iron indices (serum iron, transferrin saturation, and serum ferritin) and serum transaminases as first evaluation of coexistent liver damage and C-reactive protein to exclude inflammatory conditions that can influence serum iron indices; • Molecular genetic testing (if the ## Pregnancy Management All pregnant women with juvenile hemochromatosis should be under the care of a maternal-fetal medicine specialist, an endocrinologist, and a cardiologist. Preferably women with juvenile hemochromatosis should be seen by these specialists prior to becoming pregnant. Pregnancy in women with untreated juvenile hemochromatosis is high risk because the increased hemodynamic burden of pregnancy can precipitate cardiac failure in women with an underlying cardiomyopathy. Of note, it is critically important for specialists in endocrinology and infertility to be aware of juvenile hemochromatosis as a cause of infertility and to evaluate individuals for iron overload prior to correcting the underlying hormonal imbalance [ ## Therapies Under Investigation Search ## Genetic Counseling Juvenile hemochromatosis is inherited in an autosomal recessive manner. The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is heterozygous for a pathogenic variant in either Heterozygotes (carriers) are not at risk of developing juvenile hemochromatosis. Middle-age-onset hemochromatosis has been reported in some If both parents are known to be heterozygous for a pathogenic variant in either Heterozygotes (carriers) are not at risk of developing juvenile hemochromatosis. Middle-age-onset hemochromatosis has been reported in some 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 juvenile hemochromatosis-causing pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for juvenile hemochromatosis 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 affected individual are obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is heterozygous for a pathogenic variant in either • Heterozygotes (carriers) are not at risk of developing juvenile hemochromatosis. Middle-age-onset hemochromatosis has been reported in some • If both parents are known to be heterozygous for a pathogenic variant in either • Heterozygotes (carriers) are not at risk of developing juvenile hemochromatosis. Middle-age-onset hemochromatosis has been reported in some • 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 Juvenile hemochromatosis is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is heterozygous for a pathogenic variant in either Heterozygotes (carriers) are not at risk of developing juvenile hemochromatosis. Middle-age-onset hemochromatosis has been reported in some If both parents are known to be heterozygous for a pathogenic variant in either Heterozygotes (carriers) are not at risk of developing juvenile hemochromatosis. Middle-age-onset hemochromatosis has been reported in some • The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is heterozygous for a pathogenic variant in either • Heterozygotes (carriers) are not at risk of developing juvenile hemochromatosis. Middle-age-onset hemochromatosis has been reported in some • If both parents are known to be heterozygous for a pathogenic variant in either • Heterozygotes (carriers) are not at risk of developing juvenile hemochromatosis. Middle-age-onset hemochromatosis has been reported in some ## Carrier (Heterozygote) Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the juvenile hemochromatosis-causing pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for juvenile hemochromatosis are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom Canada • • • • United Kingdom • • • Canada • • • • • ## Molecular Genetics Juvenile Hemochromatosis: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Juvenile Hemochromatosis ( Diferric transferrin (Tf-Fe2) provides iron to most cells of the body. The control of systemic iron levels occurs through the regulation of: Enterocytes. Absorption through duodenal and upper jejunum Macrophages. Senescent erythrocytes Hepatocytes. Tf-Fe2 Placental cells. Maternal transferrin There is no known regulated form of iron excretion; however, 1-2 mg iron are lost daily through cellular exfoliation. The iron saturation of serum transferrin is both a major indicator and a determinant of systemic iron homeostasis [ Juvenile Hemochromatosis: Gene-Specific Laboratory Technical Considerations Genes from Juvenile Hemochromatosis: 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 • • Enterocytes. Absorption through duodenal and upper jejunum • Macrophages. Senescent erythrocytes • Hepatocytes. Tf-Fe2 • Placental cells. Maternal transferrin • Enterocytes. Absorption through duodenal and upper jejunum • Macrophages. Senescent erythrocytes • Hepatocytes. Tf-Fe2 • Placental cells. Maternal transferrin • Enterocytes. Absorption through duodenal and upper jejunum • Macrophages. Senescent erythrocytes • Hepatocytes. Tf-Fe2 • Placental cells. Maternal transferrin ## Molecular Pathogenesis Diferric transferrin (Tf-Fe2) provides iron to most cells of the body. The control of systemic iron levels occurs through the regulation of: Enterocytes. Absorption through duodenal and upper jejunum Macrophages. Senescent erythrocytes Hepatocytes. Tf-Fe2 Placental cells. Maternal transferrin There is no known regulated form of iron excretion; however, 1-2 mg iron are lost daily through cellular exfoliation. The iron saturation of serum transferrin is both a major indicator and a determinant of systemic iron homeostasis [ Juvenile Hemochromatosis: Gene-Specific Laboratory Technical Considerations Genes from Juvenile Hemochromatosis: 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 • • Enterocytes. Absorption through duodenal and upper jejunum • Macrophages. Senescent erythrocytes • Hepatocytes. Tf-Fe2 • Placental cells. Maternal transferrin • Enterocytes. Absorption through duodenal and upper jejunum • Macrophages. Senescent erythrocytes • Hepatocytes. Tf-Fe2 • Placental cells. Maternal transferrin • Enterocytes. Absorption through duodenal and upper jejunum • Macrophages. Senescent erythrocytes • Hepatocytes. Tf-Fe2 • Placental cells. Maternal transferrin ## References ## Literature Cited ## Chapter Notes Xenon Pharmaceuticals IncWeb: International BioIron Society (IBIS)Two Woodfield Lake1100 E Woodfield RoadSuite 350Schaumburg, IL 60173Phone: 847-517-7225Text: 847-517-7229Email: Angela Bentivegna, PhD (2020-present)Francesca Bertola, PhD (2020-present)Y Paul Goldberg, MB ChB, PhD, FRCPC; Xenon Pharmaceuticals Inc (2005-2020)Julie MacFarlane, MS, CCGC; Xenon Pharmaceuticals Inc (2005-2011)George Papanikalaou, MD, PhD; National and Kapodistrian University of Athens (2005-2011)Alberto Piperno, MD (2020-present) 9 January 2020 (sw) Comprehensive update posted live 11 August 2011 (me) Comprehensive update posted live 17 February 2005 (me) Review posted live 12 July 2004 (pg) Original submission • 9 January 2020 (sw) Comprehensive update posted live • 11 August 2011 (me) Comprehensive update posted live • 17 February 2005 (me) Review posted live • 12 July 2004 (pg) Original submission ## Author Notes Xenon Pharmaceuticals IncWeb: International BioIron Society (IBIS)Two Woodfield Lake1100 E Woodfield RoadSuite 350Schaumburg, IL 60173Phone: 847-517-7225Text: 847-517-7229Email: ## Author History Angela Bentivegna, PhD (2020-present)Francesca Bertola, PhD (2020-present)Y Paul Goldberg, MB ChB, PhD, FRCPC; Xenon Pharmaceuticals Inc (2005-2020)Julie MacFarlane, MS, CCGC; Xenon Pharmaceuticals Inc (2005-2011)George Papanikalaou, MD, PhD; National and Kapodistrian University of Athens (2005-2011)Alberto Piperno, MD (2020-present) ## Revision History 9 January 2020 (sw) Comprehensive update posted live 11 August 2011 (me) Comprehensive update posted live 17 February 2005 (me) Review posted live 12 July 2004 (pg) Original submission • 9 January 2020 (sw) Comprehensive update posted live • 11 August 2011 (me) Comprehensive update posted live • 17 February 2005 (me) Review posted live • 12 July 2004 (pg) Original submission	[ "PC Adams, JC Barton. How I treat hemochromatosis.. Blood. 2010;116:317-25", "KJ Allen, NA Bertalli, NJ Osborne, CC Constantine, MB Delatycki, AE Nisselle, AJ Nicoll, DM Gertig, CE McLaren, GG Giles, JL Hopper, GJ Anderson, JK Olynyk, LW Powell, LC Gurrin. HealthIron Study Investigators. HFE Cys282Tyr homozygotes with serum ferritin concentrations below 1000 microg/L are at low risk of hemochromatosis.. Hepatology. 2010;52:925-33", "GJ Anderson, DM Frazer. Current understanding of iron homeostasis.. Am J Clin Nutr. 2017;106:1559S-1566S", "NG Angelopoulos, AK Goula, G Papanikolaou, G Tolis. Osteoporosis in HFE2 juvenile hemochromatosis. A case report and review of the literature.. Osteoporos Int. 2006;17:150-5", "N Angelopoulos, G Papanikolaou, M Noutsou, G Rombopoulos, A Goula, G Tolis. Glucose metabolism, insulin secretion and insulin sensitivity in juvenile hemochromatosis. A case report and review of the literature.. Exp Clin Endocrinol Diabetes. 2007;115:192-7", "S Aschemeyer, B Qiao, D Stefanova, EV Valore, AC Sek, TA Ruwe, KR Vieth, G Jung, C Casu, S Rivella, M Jormakka, B Mackenzie, T Ganz, E Nemeth. Structure-function analysis of ferroportin defines the binding site and an alternative mechanism of action of hepcidin.. Blood. 2018;131:899-910", "MB Backe, IW Moen, C Ellervik, JB Hansen, T Mandrup-Poulsen. Iron regulation of pancreatic beta-cell functions and oxidative stress.. Annu Rev Nutr. 2016;36:241-73", "S Badar, F Busti, A Ferrarini, L Xumerle, P Bozzini, P Capelli, R Pozzi-Mucelli, N Campostrini, G De Matteis, S Marin Vargas, A Giorgetti, M Delledonne, O Olivieri, D. Girelli. Identification of novel mutations in hemochromatosis genes by targeted next generation sequencing in Italian patients with unexplained iron overload.. Am J Hematol. 2016;91:420-5", "ML Bassett, PE Hickman, JE Dahlstrom. The changing role of liver biopsy in diagnosis and management of haemochromatosis.. Pathology. 2011;43:433-9", "C Borgna-Pignatti, S Rugolotto, P De Stefano, H Zhao, MD Cappellini, GC Del Vecchio, MA Romeo, GL Forni, MR Gamberini, R Ghilardi, A Piga, A Cnaan. Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine.. Haematologica. 2004;89:1187-93", "P Brissot, O Loréal. Iron metabolism and related genetic diseases: A cleared land, keeping mysteries.. J Hepatol. 2016;64:505-15", "P Brissot, A Pietrangelo, PC Adams, B de Graaff, CE McLaren, O Loréal. Haemochromatosis.. Nat Rev Dis Primers. 2018;4:18016", "AE Caines, J Kpodonu, MG Massad, R Chaer, A Evans, JC Lee, AS Geha. Cardiac transplantation in patients with iron overload cardiomyopathy.. J Heart Lung Transplant. 2005;24:486-8", "C Camaschella, E. Poggiali. Towards explaining \"unexplained hyperferritinemia\".. Haematologica. 2009;94:307-9", "A Castiella, JM Alústiza, JI Emparanza, EM Zapata, B Costero, MI Díez. Liver iron concentration quantification by MRI: are recommended protocols accurate enough for clinical practice?. Eur Radiol. 2011;21:137-41", "FS Dar, W Faraj, MB Zaman, A Bartlett, A Bomford, A O'Sullivan, J O'Grady, M Heneghan, M Rela, ND Heaton. Outcome of liver transplantation in hereditary hemochromatosis.. Transpl Int. 2009;22:717-24", "M De Gobbi, P Pasquero, F Brunello, P Paccotti, U Mazza, C Camaschella. Juvenile hemochromatosis associated with B-thalassemia treated by phlebotomy and recombinant human erythropoietin.. Haematologica. 2000;85:865-7", "M De Gobbi, A Roetto, A Piperno, R Mariani, F Alberti, G Papanikolaou, M Politou, G Lockitch, D Girelli, S Fargion, TM Cox, P Gasparini, M Cazzola, C Camaschella. Natural history of juvenile haemochromatosis.. Br J Haematol. 2002;117:973-9", "MB Delatycki, KJ Allen, P Gow, J MacFarlane, C Radomski, J Thompson, MR Hayden, YP Goldberg, ME Samuels. A homozygous HAMP mutation in a multiply consanguineous family with pseudo-dominant juvenile hemochromatosis.. Clin Genet. 2004;65:378-83", "BK Dhillon, G Chopra, M Jamwal, GR Chandak, A Duseja, P Malhotra, YK Chawla, G Garewal, R Das. Adult onset hereditary hemochromatosis is associated with a novel recurrent Hemojuvelin (HJV) gene mutation in north Indians.. Blood Cells Mol Dis. 2018;73:14-21", "Clinical practice guidelines: management of hepatocellular carcinoma.. J Hepatol. 2012;56:908-43", "L Falize, A Guillygomarc'h, M Perrin, F Laine, D Guyader, P Brissot, B Turlin, Y Deugnier. Reversibility of hepatic fibrosis in treated genetic hemochromatosis: a study of 36 cases.. Hepatology. 2006;44:472-7", "R Faria, B Silva, C Silva, P Loureiro, A Queiroz, S Fraga, J Esteves, D Mendes, R Fleming, L Vieira, J Gonçalves, P Faustino. Next-generation sequencing of hereditary hemochromatosis-related genes: Novel likely pathogenic variants found in the Portuguese population.. Blood Cells Mol Dis. 2016;61:10-5", "M Filali, C Le Jeunne, E Durand, JM Grinda, A Roetto, F Daraio, P Bruneval, X Jeunemaitre, AP Gimenez-Roqueplo. Juvenile hemochromatosis HJV-related revealed by cardiogenic shock.. Blood Cells Mol Dis. 2004;33:120-4", "F Fu, X Li, C Chen, Y Bai, Q Liu, D Shi, J Sang, K Wang, M Wang. Non-invasive assessment of hepatic fibrosis: comparison of MR elastography to transient elastography and intravoxel incoherent motion diffusion-weighted MRI.. Abdom Radiol (NY) 2020;45:73-82", "EB Fung, R Fischer, Z Pakbaz, RL Fagaly, E Vichinsky, TN Starr, T Ewing, DN Paulson, WV Hassenzahl, P Harmatz. The new SQUID biosusceptometer at Oakland: first year of experience.. Neurol Clin Neurophysiol. 2004;2004:5", "S Galimberti, P Trombini, DP Bernasconi, I Redaelli, S Pelucchi, G Bovo, F Di Gennaro, N Zucchini, N Paruccini, A Piperno. Simultaneous liver iron and fat measures by magnetic resonance imaging in patients with hyperferritinemia.. Scand J Gastroenterol. 2015;50:429-38", "Y Gandon, D Olivie, D Guyader, C Aube, F Oberti, V Sebille, Y Deugnier. Non-invasive assessment of hepatic iron stores by MRI.. Lancet. 2004;363:357-62", "VR Gordeuk, A Caleffi, E Corradini, F Ferrara, RA Jones, O Castro, O Onyekwere, R Kittles, E Pignatti, G Montosi, C Garuti, IT Gangaidzo, ZA Gomo, VM Moyo, TA Rouault, P MacPhail, A Pietrangelo. Iron overload in Africans and African-Americans and a common mutation in the SCL40A1 (ferroportin 1) gene.. Blood Cells Mol Dis. 2003;31:299-304", "P Guggenbuhl, P Brissot, O Loréal. Miscellaneous non-inflammatory musculoskeletal conditions. Haemochromatosis: the bone and the joint.. Best Pract Res Clin Rheumatol. 2011;25:649-64", "H Hamdi-Rozé, Z Ben Ali, M Ropert, L Detivaud, S Aggoune, D Simon, G Pelletier, Y Deugnier, V David, E. Bardou-Jacquet. Variable expressivity of HJV related hemochromatosis: \"juvenile\" hemochromatosis?. Blood Cells Mol Dis. 2019;74:30-33", "A Hattori, N Tomosugi, Y Tatsumi, A Suzuki, K Hayashi, Y Katano, Y Inagaki, T Ishikawa, H Hayashi, H Goto, S Wakusawa. Identification of a novel mutation in the HAMP gene that causes non-detectable hepcidin molecules in a Japanese male patient with juvenile hemochromatosis.. Blood Cells Mol Dis. 2012;48:179-82", "B Henninger, J Alustiza, M Garbowski, Y Gandon. Practical guide to quantification of hepatic iron with MRI.. Eur Radiol. 2020;30:383-93", "K Ikuta, M Hatayama, L Addo, Y Toki, K Sasaki, Y Tatsumi, A Hattori, A Kato, K Kato, H Hayashi, T Suzuki, M Kobune, M Tsutsui, A Gotoh, Y Aota, M Matsuura, Y Hamada, T Tokuda, N Komatsu, Y. Kohgo. Iron overload patients with unknown etiology from national survey in Japan.. Int J Hematol. 2017;105:353-60", "A Iolascon, L De Falco. Mutations in the gene encoding DMT1: clinical presentation and treatment.. Semin Hematol. 2009;46:358-70", "ML Island, AM Jouanolle, A Mosser, Y Deugnier, V David, P Brissot, O Loréal. A new mutation in the hepcidin promoter impairs its BMP response and contributes to a severe phenotype in HFE related hemochromatosis.. Haematologica. 2009;94:720-4", "S Jacolot, G Le Gac, V Scotet, I Quere, C Mura, C. Ferec. HAMP as a modifier gene that increases the phenotypic expression of the HFE pC282Y homozygous genotype.. Blood. 2004;103:2835-40", "H Jónsson, P Sulem, B Kehr, S Kristmundsdottir, F Zink, E Hjartarson, MT Hardarson, KE Hjorleifsson, HP Eggertsson, SA Gudjonsson, LD Ward, GA Arnadottir, EA Helgason, H Helgason, A Gylfason, A Jonasdottir, A Jonasdottir, T Rafnar, M Frigge, SN Stacey, O Th Magnusson, U Thorsteinsdottir, G Masson, A Kong, BV Halldorsson, A Helgason, DF Gudbjartsson, K Stefansson. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.. Nature. 2017;549:519-22", "P Kirk, T He, LJ Anderson, M Roughton, MA Tanner, WW Lam, WY Au, WC Chu, G Chan, R Galanello, G Matta, M Fogel, AR Cohen, RS Tan, K Chen, I Ng, A Lai, S Fucharoen, J Laothamata, S Chuncharunee, S Jongjirasiri, DN Firmin, GC Smith, DJ Pennell. International reproducibility of single breathhold T2* MR for cardiac and liver iron assessment among five thalassemia centers.. J Magn Reson Imaging. 2010;32:315-9", "X Kong, L Xie, H Zhu, L Song, X Xing, W Yang, X Chen. Genotypic and phenotypic spectra of hemojuvelin mutations in primary hemochromatosis patients: a systematic review.. Orphanet J Rare Dis. 2019;14:171", "C Koyama, H Hayashi, S Wakusawa, T Ueno, M Yano, Y Katano, H Goto, R Kidokoro. Three patients with middle-age-onset hemochromatosis caused by novel mutations in the hemojuvelin gene.. J Hepatol. 2005;43:740-2", "MB Lanktree, B Sadikovic, JS Waye, A Levstik, BB Lanktree, J Yudin, MA Crowther, G Pare, PC Adams. Clinical evaluation of a hemochromatosis next-generation sequencing gene panel.. Eur J Haematol. 2017;98:228-34", "C Lanzara, A Roetto, F Daraio, S Rivard, R Ficarella, H Simard, TM Cox, M Cazzola, A Piperno, AP Gimenez-Roqueplo, P Grammatico, S Volinia, P Gasparini, C Camaschella. Spectrum of hemojuvelin gene mutations in 1q-linked juvenile hemochromatosis.. Blood. 2004;103:4317-21", "PL Lee, JC Barton, D Brandhagen, E Beutler. Hemojuvelin (HJV) mutations in persons of European, African-American and Asian ancestry with adult onset haemochromatosis.. Br J Haematol. 2004;127:224-9", "G Le Gac, F Mons, S Jacolot, V Scotet, C Ferec, T Frebourg. Early onset hereditary hemochromatosis resulting from a novel TFR2 gene nonsense mutation (R105X) in two siblings of north French descent.. Br J Haematol. 2004;125:674-8", "CY Lok, AT Merryweather-Clarke, V Viprakasit, Y Chinthammitr, S Srichairatanakool, C Limwongse, D Oleesky, AJ Robins, J Hudson, P Wai, A Premawardhena, HJ de Silva, A Dassanayake, C McKeown, M Jackson, R Gama, N Khan, W Newman, G Banait, A Chilton, I Wilson-Morkeh, DJ Weatherall, KJ Robson. Iron overload in the Asian community.. Blood. 2009;114:20-5", "T Lv, W Zhang, A Xu, Y Li, D Zhou, B Zhang, X Li, X Zhao, Y Wang, X Wang, W Duan, Q Wang, H Xu, J Zheng, R Zhao, L Zhu, Y Dong, L Lu, Y Chen, J Long, S Zheng, W Wang, H You, J Jia, X Ou, J Huang. Non-HFE mutations in haemochromatosis in China: combination of heterozygous mutations involving HJV signal peptide variants.. J Med Genet. 2018;55:650-60", "SR Lynch, BS Skikne, JD Cook. Food iron absorption in idiopathic hemochromatosis.. Blood. 1989;74:2187-93", "T Maeda, T Nakamaki, B Saito, H Nakashima, H Ariizumi, K Yanagisawa, A Hattori, Y Tatsumi, H Hayashi, K Suzuki, S Tomoyasu. Hemojuvelin hemochromatosis receiving iron chelation therapy with deferasirox: improvement of liver disease activity, cardiac and hematological function.. Eur J Haematol. 2011;87:467-9", "S Majore, F Binni, A Pennese, A De Santis, A Crisi, P. Grammatico. HAMP gene mutation c.208T>C (p.C70R) identified in an Italian patient with severe hereditary hemochromatosis.. Hum Mutat. 2004;23:400", "N Masera, A Cattoni, V Decimi, V D'Apolito, C Arosio, R Mariani, A Piperno. Efficacy of deferasirox for the treatment of iron overload in a child affected by juvenile hemochromatosis.. Case Rep Clin Med. 2013;2:126-8", "T Matthes, P Aguilar-Martinez, L Pizzi-Bosman, R Darbellay, L Rubbia-Brandt, E Giostra, M Michel, T Ganz, P Beris. Severe hemochromatosis in a Portuguese family associated with a new mutation in the 5'UTR of the hepcidin gene.. Blood. 2004;104:2181-3", "L McNamara, VR Gordeuk, AP MacPhail. Ferroportin (Q248H) mutations in African families with dietary iron overload.. J Gastroenterol Hepatol. 2005;20:1855-8", "AT Merryweather-Clarke, E Cadet, A Bomford, D Capron, V Viprakasit, A Miller, PJ McHugh, RW Chapman, JJ Pointon, VL Wimhurst, KJ Livesey, V Tanphaichitr, J Rochette, KJ Robson. Digenic inheritance of mutations in HAMP and HFE results in different types of haemochromatosis.. Hum Mol Genet. 2003;12:2241-7", "N Milman, K-E Byg, L Ovesen, M Kirchhoff, K S-L Jurgensen. Iron status in Danish men 1984–94: a cohort comparison of changes in iron stores and the prevalence of iron deficiency and iron overload.. Eur J Haematol 2002;68:332-40", "N Milman, KE Byg, L Ovesen, M Kirchhoff, KS Jürgensen. Iron status in Danish women 1984–1994: a cohort comparison of changes in iron stores and the prevalence of iron deficiency and iron overload.. Eur J Haematol 2003;71:51-61", "MU Muckenthaler, S Rivella, MW Hentze, B Galy. A red carpet for iron metabolism.. Cell. 2017;168:344-61", "CJ Murphy, GY Oudit. Iron-overload cardiomyopathy: pathophysiology, diagnosis, and treatment.. J Card Fail. 2010;16:888-900", "C Pelusi, DI Gasparini, N Bianchi, R Pasquali. Endocrine dysfunction in hereditary hemochromatosis.. J Endocrinol Invest. 2016;39:837-47", "A Pietrangelo, A Caleffi, J Henrion, F Ferrara, E Corradini, H Kulaksiz, W Stremmel, P Andreone, C Garuti. Juvenile hemochromatosis associated with pathogenic mutations of adult hemochromatosis genes.. Gastroenterology. 2005;128:470-9", "A. Pietrangelo. Ferroportin disease: pathogenesis, diagnosis and treatment.. Haematologica. 2017;102:1972-84", "A Piperno, D Girelli, E Nemeth, P Trombini, C Bozzini, E Poggiali, Y Phung, T Ganz, C Camaschella. Blunted hepcidin response to oral iron challenge in HFE-related hemochromatosis.. Blood. 2007;110:4096-100", "A. Piperno. Molecular diagnosis of hemochromatosis.. Expert Opin Med Diagn. 2013;7:161-77", "JB Porter, PB Walter, LD Neumayr, P Evans, S Bansal, M Garbowski, MG Weyhmiller, PR Harmatz, JC Wood, JL Miller, C Byrnes, G Weiss, M Seifert, R Grosse, D Grabowski, A Schmidt, R Fischer, P Nielsen, C Niemeyer, E Vichinsky. Mechanisms of plasma non-transferrin bound iron generation: insights from comparing transfused diamond blackfan anaemia with sickle cell and thalassaemia patients.. Br J Haematol. 2014;167:692-6", "G Porto, P Brissot, DW Swinkels, H Zoller, O Kamarainen, S Patton, I Alonso, M Morris, S Keeney. EMQN best practice guidelines for the molecular genetic diagnosis of hereditary hemochromatosis (HH).. Eur J Hum Genet. 2016;24:479-95", "K Ramzan, F Imtiaz, HI Al-Ashgar, M AlSayed, RA Sulaiman. Juvenile hemochromatosis and hepatocellular carcinoma in a patient with a novel mutation in the HJV gene.. Eur J Med Genet. 2017;60:308-11", "G Ravasi, M Rausa, S Pelucchi, C Arosio, F Greni, R Mariani, I Pelloni, L Silvestri, P Pineda, C Camaschella, A. Piperno. Transferrin receptor 2 mutations in patients with juvenile hemochromatosis phenotype.. Am J Hematol. 2015;90:E226-7", "G Ravasi, S Pelucchi, R Mariani, L Silvestri, C Camaschella, A. Piperno. A severe hemojuvelin mutation leading to late onset of HFE2-hemochromatosis.. Dig Liver Dis. 2018;50:859-62", "A Roetto, G Papanikolaou, M Politou, F Alberti, D Girelli, J Christakis, D Loukopoulos, C Camaschella. Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis.. Nat Genet. 2003;33:21-2", "A Roetto, F Daraio, P Porporato, R Caruso, TM Cox, M Cazzola, P Gasparini, A Piperno, C Camaschella. Screening hepcidin for mutations in juvenile hemochromatosis: identification of a new mutation (C70R).. Blood. 2004;103:2407-9", "E Rombout-Sestrienkova, MG van Kraaij, GH Koek. How we manage patients with hereditary haemochromatosis.. Br J Haematol. 2016;175:759-70", "E Sahinbegovic, T Dallos, E Aigner, R Axmann, B Manger, M Englbrecht, M Schöniger-Hekele, T Karonitsch, T Stamm, M Farkas, T Karger, U Stölzel, G Keysser, C Datz, G Schett, J. Zwerina. Musculoskeletal disease burden of hereditary hemochromatosis.. Arthritis Rheum. 2010;62:3792-8", "PC Santos, RD Cançado, AC Pereira, IT Schettert, RA Soares, RA Pagliusi, RD Hirata, MH Hirata, AC Teixeira, MS Figueiredo, CS Chiattone, JE Krieger, EM Guerra-Shinohara. Hereditary hemochromatosis: mutations in genes involved in iron homeostasis in Brazilian patients.. Blood Cells Mol Dis. 2011;46:302-7", "Y Shizukuda, DR Rosing. Iron overload and arrhythmias: Influence of confounding factors.. J Arrhythm. 2019;35:575-83", "L Silvestri, A Nai, A Dulja, A. Pagani. Hepcidin and the BMP-SMAD pathway: An unexpected liaison.. Vitam Horm. 2019;110:71-99", "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", "G Vaiopoulos, G Papanikolaou, M Politou, I Jibreel, N Sakellaropoulos, D. Loukopoulos. Arthropathy in juvenile hemochromatosis.. Arthritis Rheum. 2003;48:227-30", "J Varkonyi, JP Kaltwasser, C Seidl, G Kollai, H Andrikovics, A Tordai. A case of non-HFE juvenile haemochromatosis presenting with adrenocortical insufficiency.. Br J Haematol. 2000;109:252-3", "A Viveiros, B Schaefer, H Tilg, H Zoller. Iron matryoshka-haemochromatosis nested in ferroportin disease?. Liver Int. 2019;39:1014-5", "DF Wallace, VN Subramaniam. The global prevalence of HFE and non-HFE hemochromatosis estimated from analysis of next-generation sequencing data.. Genet Med. 2016;18:618-26" ]	17/2/2005	9/1/2020		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
jln	jln	[ "JLNS", "JLNS", "Surdo Cardiac Syndrome", "Potassium voltage-gated channel subfamily E member 1", "Potassium voltage-gated channel subfamily KQT member 1", "KCNE1", "KCNQ1", "Jervell and Lange-Nielsen Syndrome" ]	Jervell and Lange-Nielsen Syndrome	Lisbeth Tranebjærg, Ricardo A Samson, Glenn Edward Green	Summary Jervell and Lange-Nielsen syndrome (JLNS) is characterized by congenital profound bilateral sensorineural hearing loss and long QTc, usually >500 msec. Prolongation of the QTc interval is associated with tachyarrhythmias, including ventricular tachycardia, episodes of The diagnosis of JLNS is established in a child with congenital sensorineural deafness, long QT interval, and presence of biallelic pathogenic variants in either JLNS is inherited in an autosomal recessive manner. Parents of a child with JLNS are usually heterozygotes; rarely, only one parent is heterozygous (i.e., the proband has one inherited and one	## Diagnosis Jervell and Lange-Nielsen syndrome (JLNS) Profound congenital sensorineural deafness Long QTc interval (>500 msec), often manifest as syncope, most often elicited by emotion or exercise. Note: Normal QTc interval in males is <440 msec and in post-pubertal females is <460 msec. The diagnosis of JLNS Note: (1) It is not currently known how many children with molecularly confirmed JLNS have a borderline QTc interval (440-500 msec) or a normal QTc interval. (2) Hearing loss commonly occurs in individuals with Molecular genetic testing approaches can include In countries with For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Jervell and Lange-Nielsen Syndrome Genes are listed alphabetically. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and 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. In a study of ten families, nine had pathogenic variants in Three variants in No deletions or duplications of Both deletion and duplication of one or more exons of • Profound congenital sensorineural deafness • Long QTc interval (>500 msec), often manifest as syncope, most often elicited by emotion or exercise. Note: Normal QTc interval in males is <440 msec and in post-pubertal females is <460 msec. • In countries with • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings Jervell and Lange-Nielsen syndrome (JLNS) Profound congenital sensorineural deafness Long QTc interval (>500 msec), often manifest as syncope, most often elicited by emotion or exercise. Note: Normal QTc interval in males is <440 msec and in post-pubertal females is <460 msec. • Profound congenital sensorineural deafness • Long QTc interval (>500 msec), often manifest as syncope, most often elicited by emotion or exercise. Note: Normal QTc interval in males is <440 msec and in post-pubertal females is <460 msec. ## Establishing the Diagnosis The diagnosis of JLNS Note: (1) It is not currently known how many children with molecularly confirmed JLNS have a borderline QTc interval (440-500 msec) or a normal QTc interval. (2) Hearing loss commonly occurs in individuals with Molecular genetic testing approaches can include In countries with For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Jervell and Lange-Nielsen Syndrome Genes are listed alphabetically. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and 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. In a study of ten families, nine had pathogenic variants in Three variants in No deletions or duplications of Both deletion and duplication of one or more exons of • In countries with • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics The classic presentation of JLNS is a deaf child who experiences syncopal episodes during periods of stress, exercise, or fright. QTc prolongation in JLNS, particularly when severe, appears to be associated with increased risk for death in infancy (SIDS). In the Physical examination is unremarkable except for deafness. Among six asymptomatic individuals reported by Among 63 individuals who were genotyped, 33% were compound heterozygotes [ Lange-Nielsen syndrome has also been called cardioauditory syndrome of Jervell and Lange-Nielsen and surdo-cardiac syndrome. JLNS is now appreciated to be a true syndrome, in which the cardiac and cochlear pathologies are attributable to a common molecular etiology. Although there are several case reports in the older literature of individuals with long QT syndrome and non-profound hearing loss, in many of these reports it is likely that the hearing loss and prolonged QT interval have different etiologies (see Prevalence varies depending on the population studied: Norway has an unusually high prevalence of at least one in 200,000 [ Sweden also has a prevalence of one in 200,000 based on a study of preadolescent children, identifying 19 affected individuals from 13 families. Eight In a study of 350 children with congenital deafness in Turkey, one in 175 had JLNS [ A particular missense An overview of worldwide occurrence was published by These data are the best available; however, diagnostic criteria using a QTc >440 msec in children are likely to include some false positives, perhaps as many as 15%-20% [ • Norway has an unusually high prevalence of at least one in 200,000 [ • Sweden also has a prevalence of one in 200,000 based on a study of preadolescent children, identifying 19 affected individuals from 13 families. Eight • In a study of 350 children with congenital deafness in Turkey, one in 175 had JLNS [ • A particular missense • An overview of worldwide occurrence was published by ## Clinical Description The classic presentation of JLNS is a deaf child who experiences syncopal episodes during periods of stress, exercise, or fright. QTc prolongation in JLNS, particularly when severe, appears to be associated with increased risk for death in infancy (SIDS). In the Physical examination is unremarkable except for deafness. ## Phenotype Correlations by Gene Among six asymptomatic individuals reported by ## Genotype-Phenotype Correlations Among 63 individuals who were genotyped, 33% were compound heterozygotes [ ## Nomenclature Lange-Nielsen syndrome has also been called cardioauditory syndrome of Jervell and Lange-Nielsen and surdo-cardiac syndrome. JLNS is now appreciated to be a true syndrome, in which the cardiac and cochlear pathologies are attributable to a common molecular etiology. Although there are several case reports in the older literature of individuals with long QT syndrome and non-profound hearing loss, in many of these reports it is likely that the hearing loss and prolonged QT interval have different etiologies (see ## Prevalence Prevalence varies depending on the population studied: Norway has an unusually high prevalence of at least one in 200,000 [ Sweden also has a prevalence of one in 200,000 based on a study of preadolescent children, identifying 19 affected individuals from 13 families. Eight In a study of 350 children with congenital deafness in Turkey, one in 175 had JLNS [ A particular missense An overview of worldwide occurrence was published by These data are the best available; however, diagnostic criteria using a QTc >440 msec in children are likely to include some false positives, perhaps as many as 15%-20% [ • Norway has an unusually high prevalence of at least one in 200,000 [ • Sweden also has a prevalence of one in 200,000 based on a study of preadolescent children, identifying 19 affected individuals from 13 families. Eight • In a study of 350 children with congenital deafness in Turkey, one in 175 had JLNS [ • A particular missense • An overview of worldwide occurrence was published by ## Genetically Related (Allelic) Disorders Heterozygosity for pathogenic variants in ## Differential Diagnosis Prior to the availability of molecular genetic testing, the diagnosis of Jervell and Lange-Nielsen syndrome (JLNS) was based on clinical criteria alone. (Romano-Ward syndrome was commonly diagnosed in persons with LQTS and normal hearing.) Some children with JLNS may be misdiagnosed with epilepsy and incorrectly treated with anti-seizure medication before the correct diagnosis of JLNS is established [ Acquired causes of QTc interval prolongation include the following: Electrolyte abnormalities: hypokalemia, hypomagnesemia, hypocalcemia Malnutrition or liquid protein diet Drugs: vasodilators, tricyclic antidepressants, organophosphates, antihistamines, phenothiazines, procainamide, disopyramide, quinidine, and many others. For a complete, updated list see Primary myocardial problems: cardiomyopathy, myocarditis, ischemia Central nervous or autonomic system injury; subarachnoid hemorrhage; stellate ganglion blockade One disorder that should be noted specifically is • Prior to the availability of molecular genetic testing, the diagnosis of Jervell and Lange-Nielsen syndrome (JLNS) was based on clinical criteria alone. (Romano-Ward syndrome was commonly diagnosed in persons with LQTS and normal hearing.) • Some children with JLNS may be misdiagnosed with epilepsy and incorrectly treated with anti-seizure medication before the correct diagnosis of JLNS is established [ • Electrolyte abnormalities: hypokalemia, hypomagnesemia, hypocalcemia • Malnutrition or liquid protein diet • Drugs: vasodilators, tricyclic antidepressants, organophosphates, antihistamines, phenothiazines, procainamide, disopyramide, quinidine, and many others. For a complete, updated list see • Primary myocardial problems: cardiomyopathy, myocarditis, ischemia • Central nervous or autonomic system injury; subarachnoid hemorrhage; stellate ganglion blockade ## Management To establish the extent of disease and needs in an individual diagnosed with Jervell and Lange-Nielsen syndrome (JLNS), the following evaluations are recommended if they have not already been completed: Formal audiology evaluation for extent of hearing loss Cardiac examination including calculation of QTc A three-generation family history that focuses on cardiac disease, syncope, and hearing ability Complete blood count to screen for anemia. If anemia is present, screening for iron deficiency is recommended. Consultation with a clinical geneticist Note: Although cochlear implantation appears to be safe, special precautions are necessary during anesthesia because of the increased risk for cardiac arrhythmia [ Administration of beta-adrenergic blockers has been the traditional first-line medical therapy for cardiac events, but more aggressive, immediate treatment may be appropriate. Cardiac events in JLNS frequently occur despite beta blockade [ Implantable cardioverter defibrillators (ICDs) should be considered in individuals with a history of cardiac arrest or failure to respond to other treatments [ QTc interval >550 msec Syncope before age five years Male sex, age >20 years with The risk for sudden cardiac death appears to be low in individuals younger than age five years, but medical therapy should be administered early in these high-risk individuals and ICD placement considered after age five years [ In certain cases, the availability of automated external defibrillators in the home, workplace, or school may be applicable, as is appropriate CPR training of family members and those who have regular contact with individuals with JLNS. Left cardiac sympathetic denervation has been effective for some individuals. See Special precautions during anesthesia are necessary because of the increased risk for cardiac arrhythmia [ Beta-blocker dose should be regularly assessed for efficacy and adverse effects, and doses altered as needed. Because dose adjustment is especially important in growing children, evaluation is appropriate every three to six months during rapid growth phases. Regular, periodic evaluation of implantable cardioverter defibrillators (ICDs) for inappropriate shocks and pocket or lead complications is indicated. The following should be avoided: Drugs that cause further prolongation of the QT interval or provoke Triggers for intense or sudden emotion; activities that are known to precipitate syncopal events in individuals with long QT syndrome, including: Competitive sports Amusement park rides Frightening movies Jumping into cold water A cardiologist should make recommendations for activity restrictions based on the effectiveness of medical intervention. It is appropriate to evaluate sibs and parents of a proband in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures. If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk family members. If the pathogenic variants in the family are not known, EKG testing should be undertaken to evaluate for QT prolongation. Standard newborn screening programs are sufficient to identify hearing loss in children with JLNS. Because of the relationship between JLNS and long QT syndrome, EKG should be considered for relatives at risk for JLNS even if they have normal hearing. If the JLNS-causing pathogenic variants in an affected family member are known, molecular genetic testing of a relative with congenital profound sensorineural hearing loss is recommended to confirm the diagnosis of JLNS. See Consideration should be given as to whether a mother who has a fetus affected with JLNS herself has long QT syndrome [ Search Family members of individuals with JLNS should be trained in cardiopulmonary resuscitation (CPR) as up to 95% of individuals with JLNS have a cardiac event before adulthood [ Affected individuals should wear an ID bracelet explaining their diagnosis. It is appropriate to notify local emergency medical services (EMS) of high-risk persons, including those with JLNS [ • Formal audiology evaluation for extent of hearing loss • Cardiac examination including calculation of QTc • A three-generation family history that focuses on cardiac disease, syncope, and hearing ability • Complete blood count to screen for anemia. If anemia is present, screening for iron deficiency is recommended. • Consultation with a clinical geneticist • Administration of beta-adrenergic blockers has been the traditional first-line medical therapy for cardiac events, but more aggressive, immediate treatment may be appropriate. Cardiac events in JLNS frequently occur despite beta blockade [ • Implantable cardioverter defibrillators (ICDs) should be considered in individuals with a history of cardiac arrest or failure to respond to other treatments [ • QTc interval >550 msec • Syncope before age five years • Male sex, age >20 years with • QTc interval >550 msec • Syncope before age five years • Male sex, age >20 years with • The risk for sudden cardiac death appears to be low in individuals younger than age five years, but medical therapy should be administered early in these high-risk individuals and ICD placement considered after age five years [ • In certain cases, the availability of automated external defibrillators in the home, workplace, or school may be applicable, as is appropriate CPR training of family members and those who have regular contact with individuals with JLNS. • Left cardiac sympathetic denervation has been effective for some individuals. • QTc interval >550 msec • Syncope before age five years • Male sex, age >20 years with • Drugs that cause further prolongation of the QT interval or provoke • Triggers for intense or sudden emotion; activities that are known to precipitate syncopal events in individuals with long QT syndrome, including: • Competitive sports • Amusement park rides • Frightening movies • Jumping into cold water • Competitive sports • Amusement park rides • Frightening movies • Jumping into cold water • Competitive sports • Amusement park rides • Frightening movies • Jumping into cold water • If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk family members. • If the pathogenic variants in the family are not known, EKG testing should be undertaken to evaluate for QT prolongation. • Standard newborn screening programs are sufficient to identify hearing loss in children with JLNS. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Jervell and Lange-Nielsen syndrome (JLNS), the following evaluations are recommended if they have not already been completed: Formal audiology evaluation for extent of hearing loss Cardiac examination including calculation of QTc A three-generation family history that focuses on cardiac disease, syncope, and hearing ability Complete blood count to screen for anemia. If anemia is present, screening for iron deficiency is recommended. Consultation with a clinical geneticist • Formal audiology evaluation for extent of hearing loss • Cardiac examination including calculation of QTc • A three-generation family history that focuses on cardiac disease, syncope, and hearing ability • Complete blood count to screen for anemia. If anemia is present, screening for iron deficiency is recommended. • Consultation with a clinical geneticist ## Treatment of Manifestations Note: Although cochlear implantation appears to be safe, special precautions are necessary during anesthesia because of the increased risk for cardiac arrhythmia [ Administration of beta-adrenergic blockers has been the traditional first-line medical therapy for cardiac events, but more aggressive, immediate treatment may be appropriate. Cardiac events in JLNS frequently occur despite beta blockade [ Implantable cardioverter defibrillators (ICDs) should be considered in individuals with a history of cardiac arrest or failure to respond to other treatments [ QTc interval >550 msec Syncope before age five years Male sex, age >20 years with The risk for sudden cardiac death appears to be low in individuals younger than age five years, but medical therapy should be administered early in these high-risk individuals and ICD placement considered after age five years [ In certain cases, the availability of automated external defibrillators in the home, workplace, or school may be applicable, as is appropriate CPR training of family members and those who have regular contact with individuals with JLNS. Left cardiac sympathetic denervation has been effective for some individuals. • Administration of beta-adrenergic blockers has been the traditional first-line medical therapy for cardiac events, but more aggressive, immediate treatment may be appropriate. Cardiac events in JLNS frequently occur despite beta blockade [ • Implantable cardioverter defibrillators (ICDs) should be considered in individuals with a history of cardiac arrest or failure to respond to other treatments [ • QTc interval >550 msec • Syncope before age five years • Male sex, age >20 years with • QTc interval >550 msec • Syncope before age five years • Male sex, age >20 years with • The risk for sudden cardiac death appears to be low in individuals younger than age five years, but medical therapy should be administered early in these high-risk individuals and ICD placement considered after age five years [ • In certain cases, the availability of automated external defibrillators in the home, workplace, or school may be applicable, as is appropriate CPR training of family members and those who have regular contact with individuals with JLNS. • Left cardiac sympathetic denervation has been effective for some individuals. • QTc interval >550 msec • Syncope before age five years • Male sex, age >20 years with ## Prevention of Primary Manifestations See ## Prevention of Secondary Complications Special precautions during anesthesia are necessary because of the increased risk for cardiac arrhythmia [ ## Surveillance Beta-blocker dose should be regularly assessed for efficacy and adverse effects, and doses altered as needed. Because dose adjustment is especially important in growing children, evaluation is appropriate every three to six months during rapid growth phases. Regular, periodic evaluation of implantable cardioverter defibrillators (ICDs) for inappropriate shocks and pocket or lead complications is indicated. ## Agents/Circumstances to Avoid The following should be avoided: Drugs that cause further prolongation of the QT interval or provoke Triggers for intense or sudden emotion; activities that are known to precipitate syncopal events in individuals with long QT syndrome, including: Competitive sports Amusement park rides Frightening movies Jumping into cold water A cardiologist should make recommendations for activity restrictions based on the effectiveness of medical intervention. • Drugs that cause further prolongation of the QT interval or provoke • Triggers for intense or sudden emotion; activities that are known to precipitate syncopal events in individuals with long QT syndrome, including: • Competitive sports • Amusement park rides • Frightening movies • Jumping into cold water • Competitive sports • Amusement park rides • Frightening movies • Jumping into cold water • Competitive sports • Amusement park rides • Frightening movies • Jumping into cold water ## Evaluation of Relatives at Risk It is appropriate to evaluate sibs and parents of a proband in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures. If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk family members. If the pathogenic variants in the family are not known, EKG testing should be undertaken to evaluate for QT prolongation. Standard newborn screening programs are sufficient to identify hearing loss in children with JLNS. Because of the relationship between JLNS and long QT syndrome, EKG should be considered for relatives at risk for JLNS even if they have normal hearing. If the JLNS-causing pathogenic variants in an affected family member are known, molecular genetic testing of a relative with congenital profound sensorineural hearing loss is recommended to confirm the diagnosis of JLNS. See • If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk family members. • If the pathogenic variants in the family are not known, EKG testing should be undertaken to evaluate for QT prolongation. • Standard newborn screening programs are sufficient to identify hearing loss in children with JLNS. ## Pregnancy Management Consideration should be given as to whether a mother who has a fetus affected with JLNS herself has long QT syndrome [ ## Therapies Under Investigation Search ## Other Family members of individuals with JLNS should be trained in cardiopulmonary resuscitation (CPR) as up to 95% of individuals with JLNS have a cardiac event before adulthood [ Affected individuals should wear an ID bracelet explaining their diagnosis. It is appropriate to notify local emergency medical services (EMS) of high-risk persons, including those with JLNS [ ## Genetic Counseling Jervell and Lange-Nielsen syndrome (JLNS) is inherited in an autosomal recessive manner. Parents of a child with JLNS are usually obligate heterozygotes (i.e., carriers of one Parents may or may not have the long QT syndrome (LQTS) phenotype. Studies have documented autosomal dominant inheritance of moderately prolonged QTc intervals in some, but not all, families in which one or more sibs have JLNS [ Recommendations for evaluation of the parents of a child with JLNS include: Molecular genetic testing if the pathogenic variants have been identified; Comprehensive electrocardiographic testing for evidence of QTc prolongation by a physician familiar with LQTS. If both parents of the proband are heterozygous for a JLNS-related pathogenic variant (i.e., both of the variants identified in the proband are inherited), the typical risks at conception to each sib are: A 25% chance of inheriting two pathogenic variants and being affected with JLNS; A 50% chance of inheriting one pathogenic variant. A sib who inherits one pathogenic variant would not be expected to have JLNS but is at risk for LQTS if the inherited pathogenic variant is associated with the LQTS phenotype (approximately 67% of JLNS-associated pathogenic variants are also known to also be associated with autosomal dominant LQTS) [ A 25% chance of inheriting neither of the pathogenic variants identified in the proband. A sib who inherits neither of the JLNS-related pathogenic variants is not at increased risk for JLNS or, potentially, LQTS. If only one parent of the proband is heterozygous for a JLNS-related pathogenic variant (i.e., the proband has one inherited and one Recommendations for evaluation of sibs of a proband with JLNS include: Audiology evaluation; Electrophysiologic evaluation for evidence of LQTS; Molecular genetic testing if the pathogenic variants in the proband are known; Comprehensive electrocardiographic testing for evidence of QTc prolongation by a physician familiar with LQTS. The offspring of an individual with JLNS inherit one pathogenic variant; thus, 100% of the proband's offspring are potentially at risk for LQTS. In the event that the reproductive partner of the proband is also heterozygous for a pathogenic variant in the same gene in which two pathogenic variants have been identified in the proband, the risk to offspring of having JLNS is 50%. Recommendations for evaluation of the offspring of an individual with JLNS include comprehensive electrocardiographic testing for evidence of QTc prolongation by a physician familiar with LQTS. Carrier testing for at-risk relatives requires prior identification of the See Management, Because prolonged QTc interval in families with JLNS may follow an autosomal dominant inheritance pattern, it is important that family members at risk undergo electrocardiographic testing for evidence of LQTS early in life. Individuals with LQTS are at increased risk for sudden death and thus require cardiologic intervention. The actual risk for LQTS in family members of individuals with JLNS is not known. Individuals who are heterozygous for a JLNS-related pathogenic variant have a single pathogenic variant in a gene associated with LQTS that may cause QTc prolongation or LQTS in either a clinically significant or clinically insignificant form. Whether the variant is clinically significant or insignificant, it may be transmitted in a clinically significant fashion to future generations as either autosomal dominant LQTS (i.e., The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. 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. • Parents of a child with JLNS are usually obligate heterozygotes (i.e., carriers of one • Parents may or may not have the long QT syndrome (LQTS) phenotype. Studies have documented autosomal dominant inheritance of moderately prolonged QTc intervals in some, but not all, families in which one or more sibs have JLNS [ • Recommendations for evaluation of the parents of a child with JLNS include: • Molecular genetic testing if the pathogenic variants have been identified; • Comprehensive electrocardiographic testing for evidence of QTc prolongation by a physician familiar with LQTS. • Molecular genetic testing if the pathogenic variants have been identified; • Comprehensive electrocardiographic testing for evidence of QTc prolongation by a physician familiar with LQTS. • Molecular genetic testing if the pathogenic variants have been identified; • Comprehensive electrocardiographic testing for evidence of QTc prolongation by a physician familiar with LQTS. • If both parents of the proband are heterozygous for a JLNS-related pathogenic variant (i.e., both of the variants identified in the proband are inherited), the typical risks at conception to each sib are: • A 25% chance of inheriting two pathogenic variants and being affected with JLNS; • A 50% chance of inheriting one pathogenic variant. A sib who inherits one pathogenic variant would not be expected to have JLNS but is at risk for LQTS if the inherited pathogenic variant is associated with the LQTS phenotype (approximately 67% of JLNS-associated pathogenic variants are also known to also be associated with autosomal dominant LQTS) [ • A 25% chance of inheriting neither of the pathogenic variants identified in the proband. A sib who inherits neither of the JLNS-related pathogenic variants is not at increased risk for JLNS or, potentially, LQTS. • A 25% chance of inheriting two pathogenic variants and being affected with JLNS; • A 50% chance of inheriting one pathogenic variant. A sib who inherits one pathogenic variant would not be expected to have JLNS but is at risk for LQTS if the inherited pathogenic variant is associated with the LQTS phenotype (approximately 67% of JLNS-associated pathogenic variants are also known to also be associated with autosomal dominant LQTS) [ • A 25% chance of inheriting neither of the pathogenic variants identified in the proband. A sib who inherits neither of the JLNS-related pathogenic variants is not at increased risk for JLNS or, potentially, LQTS. • If only one parent of the proband is heterozygous for a JLNS-related pathogenic variant (i.e., the proband has one inherited and one • Recommendations for evaluation of sibs of a proband with JLNS include: • Audiology evaluation; • Electrophysiologic evaluation for evidence of LQTS; • Molecular genetic testing if the pathogenic variants in the proband are known; • Comprehensive electrocardiographic testing for evidence of QTc prolongation by a physician familiar with LQTS. • Audiology evaluation; • Electrophysiologic evaluation for evidence of LQTS; • Molecular genetic testing if the pathogenic variants in the proband are known; • Comprehensive electrocardiographic testing for evidence of QTc prolongation by a physician familiar with LQTS. • A 25% chance of inheriting two pathogenic variants and being affected with JLNS; • A 50% chance of inheriting one pathogenic variant. A sib who inherits one pathogenic variant would not be expected to have JLNS but is at risk for LQTS if the inherited pathogenic variant is associated with the LQTS phenotype (approximately 67% of JLNS-associated pathogenic variants are also known to also be associated with autosomal dominant LQTS) [ • A 25% chance of inheriting neither of the pathogenic variants identified in the proband. A sib who inherits neither of the JLNS-related pathogenic variants is not at increased risk for JLNS or, potentially, LQTS. • Audiology evaluation; • Electrophysiologic evaluation for evidence of LQTS; • Molecular genetic testing if the pathogenic variants in the proband are known; • Comprehensive electrocardiographic testing for evidence of QTc prolongation by a physician familiar with LQTS. • The offspring of an individual with JLNS inherit one pathogenic variant; thus, 100% of the proband's offspring are potentially at risk for LQTS. • In the event that the reproductive partner of the proband is also heterozygous for a pathogenic variant in the same gene in which two pathogenic variants have been identified in the proband, the risk to offspring of having JLNS is 50%. • Recommendations for evaluation of the offspring of an individual with JLNS include comprehensive electrocardiographic testing for evidence of QTc prolongation by a physician familiar with LQTS. • The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. ## Mode of Inheritance Jervell and Lange-Nielsen syndrome (JLNS) is inherited in an autosomal recessive manner. ## Risk to Family Members Parents of a child with JLNS are usually obligate heterozygotes (i.e., carriers of one Parents may or may not have the long QT syndrome (LQTS) phenotype. Studies have documented autosomal dominant inheritance of moderately prolonged QTc intervals in some, but not all, families in which one or more sibs have JLNS [ Recommendations for evaluation of the parents of a child with JLNS include: Molecular genetic testing if the pathogenic variants have been identified; Comprehensive electrocardiographic testing for evidence of QTc prolongation by a physician familiar with LQTS. If both parents of the proband are heterozygous for a JLNS-related pathogenic variant (i.e., both of the variants identified in the proband are inherited), the typical risks at conception to each sib are: A 25% chance of inheriting two pathogenic variants and being affected with JLNS; A 50% chance of inheriting one pathogenic variant. A sib who inherits one pathogenic variant would not be expected to have JLNS but is at risk for LQTS if the inherited pathogenic variant is associated with the LQTS phenotype (approximately 67% of JLNS-associated pathogenic variants are also known to also be associated with autosomal dominant LQTS) [ A 25% chance of inheriting neither of the pathogenic variants identified in the proband. A sib who inherits neither of the JLNS-related pathogenic variants is not at increased risk for JLNS or, potentially, LQTS. If only one parent of the proband is heterozygous for a JLNS-related pathogenic variant (i.e., the proband has one inherited and one Recommendations for evaluation of sibs of a proband with JLNS include: Audiology evaluation; Electrophysiologic evaluation for evidence of LQTS; Molecular genetic testing if the pathogenic variants in the proband are known; Comprehensive electrocardiographic testing for evidence of QTc prolongation by a physician familiar with LQTS. The offspring of an individual with JLNS inherit one pathogenic variant; thus, 100% of the proband's offspring are potentially at risk for LQTS. In the event that the reproductive partner of the proband is also heterozygous for a pathogenic variant in the same gene in which two pathogenic variants have been identified in the proband, the risk to offspring of having JLNS is 50%. Recommendations for evaluation of the offspring of an individual with JLNS include comprehensive electrocardiographic testing for evidence of QTc prolongation by a physician familiar with LQTS. • Parents of a child with JLNS are usually obligate heterozygotes (i.e., carriers of one • Parents may or may not have the long QT syndrome (LQTS) phenotype. Studies have documented autosomal dominant inheritance of moderately prolonged QTc intervals in some, but not all, families in which one or more sibs have JLNS [ • Recommendations for evaluation of the parents of a child with JLNS include: • Molecular genetic testing if the pathogenic variants have been identified; • Comprehensive electrocardiographic testing for evidence of QTc prolongation by a physician familiar with LQTS. • Molecular genetic testing if the pathogenic variants have been identified; • Comprehensive electrocardiographic testing for evidence of QTc prolongation by a physician familiar with LQTS. • Molecular genetic testing if the pathogenic variants have been identified; • Comprehensive electrocardiographic testing for evidence of QTc prolongation by a physician familiar with LQTS. • If both parents of the proband are heterozygous for a JLNS-related pathogenic variant (i.e., both of the variants identified in the proband are inherited), the typical risks at conception to each sib are: • A 25% chance of inheriting two pathogenic variants and being affected with JLNS; • A 50% chance of inheriting one pathogenic variant. A sib who inherits one pathogenic variant would not be expected to have JLNS but is at risk for LQTS if the inherited pathogenic variant is associated with the LQTS phenotype (approximately 67% of JLNS-associated pathogenic variants are also known to also be associated with autosomal dominant LQTS) [ • A 25% chance of inheriting neither of the pathogenic variants identified in the proband. A sib who inherits neither of the JLNS-related pathogenic variants is not at increased risk for JLNS or, potentially, LQTS. • A 25% chance of inheriting two pathogenic variants and being affected with JLNS; • A 50% chance of inheriting one pathogenic variant. A sib who inherits one pathogenic variant would not be expected to have JLNS but is at risk for LQTS if the inherited pathogenic variant is associated with the LQTS phenotype (approximately 67% of JLNS-associated pathogenic variants are also known to also be associated with autosomal dominant LQTS) [ • A 25% chance of inheriting neither of the pathogenic variants identified in the proband. A sib who inherits neither of the JLNS-related pathogenic variants is not at increased risk for JLNS or, potentially, LQTS. • If only one parent of the proband is heterozygous for a JLNS-related pathogenic variant (i.e., the proband has one inherited and one • Recommendations for evaluation of sibs of a proband with JLNS include: • Audiology evaluation; • Electrophysiologic evaluation for evidence of LQTS; • Molecular genetic testing if the pathogenic variants in the proband are known; • Comprehensive electrocardiographic testing for evidence of QTc prolongation by a physician familiar with LQTS. • Audiology evaluation; • Electrophysiologic evaluation for evidence of LQTS; • Molecular genetic testing if the pathogenic variants in the proband are known; • Comprehensive electrocardiographic testing for evidence of QTc prolongation by a physician familiar with LQTS. • A 25% chance of inheriting two pathogenic variants and being affected with JLNS; • A 50% chance of inheriting one pathogenic variant. A sib who inherits one pathogenic variant would not be expected to have JLNS but is at risk for LQTS if the inherited pathogenic variant is associated with the LQTS phenotype (approximately 67% of JLNS-associated pathogenic variants are also known to also be associated with autosomal dominant LQTS) [ • A 25% chance of inheriting neither of the pathogenic variants identified in the proband. A sib who inherits neither of the JLNS-related pathogenic variants is not at increased risk for JLNS or, potentially, LQTS. • Audiology evaluation; • Electrophysiologic evaluation for evidence of LQTS; • Molecular genetic testing if the pathogenic variants in the proband are known; • Comprehensive electrocardiographic testing for evidence of QTc prolongation by a physician familiar with LQTS. • The offspring of an individual with JLNS inherit one pathogenic variant; thus, 100% of the proband's offspring are potentially at risk for LQTS. • In the event that the reproductive partner of the proband is also heterozygous for a pathogenic variant in the same gene in which two pathogenic variants have been identified in the proband, the risk to offspring of having JLNS is 50%. • Recommendations for evaluation of the offspring of an individual with JLNS include comprehensive electrocardiographic testing for evidence of QTc prolongation by a physician familiar with LQTS. ## Carrier (Heterozygote) Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues See Management, Because prolonged QTc interval in families with JLNS may follow an autosomal dominant inheritance pattern, it is important that family members at risk undergo electrocardiographic testing for evidence of LQTS early in life. Individuals with LQTS are at increased risk for sudden death and thus require cardiologic intervention. The actual risk for LQTS in family members of individuals with JLNS is not known. Individuals who are heterozygous for a JLNS-related pathogenic variant have a single pathogenic variant in a gene associated with LQTS that may cause QTc prolongation or LQTS in either a clinically significant or clinically insignificant form. Whether the variant is clinically significant or insignificant, it may be transmitted in a clinically significant fashion to future generations as either autosomal dominant LQTS (i.e., The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. • The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. ## 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 Heart Research Follow-Up Program • • • • • • Heart Research Follow-Up Program • ## Molecular Genetics Jervell and Lange-Nielsen Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Jervell and Lange-Nielsen Syndrome ( Jervell and Lange-Nielsen syndrome (JLNS) is caused by an aberration in a potassium channel found in the stria vascularis of the cochlea (inner ear) and the heart. Note that a minority of pathogenic variants in When stimulated by sound, potassium from the scala media of the cochlea passes through the apex of the hair cells, depolarizing the hair cells and causing a calcium-channel-induced release of neurotransmitter onto the auditory nerve. Depolarizations of the auditory nerve are sent centrally where they are perceived as sound. The maintenance of high potassium concentration in the endolymphatic fluid of the inner ear is required for normal hearing. The potassium-rich fluid of the scala media is created by the I Malfunction in these channels in the cochlea causes deafness. Malfunction in these channels in the heart results in abnormal ventricular electrical activity and LQTS. In individuals of Norwegian descent, it is important to confirm that molecular genetic testing includes detection of the most common Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions See • When stimulated by sound, potassium from the scala media of the cochlea passes through the apex of the hair cells, depolarizing the hair cells and causing a calcium-channel-induced release of neurotransmitter onto the auditory nerve. Depolarizations of the auditory nerve are sent centrally where they are perceived as sound. The maintenance of high potassium concentration in the endolymphatic fluid of the inner ear is required for normal hearing. The potassium-rich fluid of the scala media is created by the I • Malfunction in these channels in the cochlea causes deafness. • Malfunction in these channels in the heart results in abnormal ventricular electrical activity and LQTS. ## Molecular Pathogenesis Jervell and Lange-Nielsen syndrome (JLNS) is caused by an aberration in a potassium channel found in the stria vascularis of the cochlea (inner ear) and the heart. Note that a minority of pathogenic variants in When stimulated by sound, potassium from the scala media of the cochlea passes through the apex of the hair cells, depolarizing the hair cells and causing a calcium-channel-induced release of neurotransmitter onto the auditory nerve. Depolarizations of the auditory nerve are sent centrally where they are perceived as sound. The maintenance of high potassium concentration in the endolymphatic fluid of the inner ear is required for normal hearing. The potassium-rich fluid of the scala media is created by the I Malfunction in these channels in the cochlea causes deafness. Malfunction in these channels in the heart results in abnormal ventricular electrical activity and LQTS. In individuals of Norwegian descent, it is important to confirm that molecular genetic testing includes detection of the most common Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions See • When stimulated by sound, potassium from the scala media of the cochlea passes through the apex of the hair cells, depolarizing the hair cells and causing a calcium-channel-induced release of neurotransmitter onto the auditory nerve. Depolarizations of the auditory nerve are sent centrally where they are perceived as sound. The maintenance of high potassium concentration in the endolymphatic fluid of the inner ear is required for normal hearing. The potassium-rich fluid of the scala media is created by the I • Malfunction in these channels in the cochlea causes deafness. • Malfunction in these channels in the heart results in abnormal ventricular electrical activity and LQTS. ## In individuals of Norwegian descent, it is important to confirm that molecular genetic testing includes detection of the most common Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions See ## ## Chapter Notes Shane M Daley, MD; Mayo Clinic-Scottsdale (2002-2010) Glenn Edward Green, MD (2002-present) Ricardo A Samson, MD (2002-present) Lisbeth Tranebjærg, MD, PhD (2002-present) 17 August 2017 (sw) Comprehensive update posted live 20 November 2014 (me) Comprehensive update posted live 4 October 2012 (me) Comprehensive update posted live 23 February 2010 (me) Comprehensive update posted live 19 March 2007 (me) Comprehensive update posted live 29 July 2004 (me) Comprehensive update posted live 13 January 2003 (gg) Revision: Molecular Genetic Testing 29 July 2002 (me) Review posted live 8 October 2001 (gg) Original submission • 17 August 2017 (sw) Comprehensive update posted live • 20 November 2014 (me) Comprehensive update posted live • 4 October 2012 (me) Comprehensive update posted live • 23 February 2010 (me) Comprehensive update posted live • 19 March 2007 (me) Comprehensive update posted live • 29 July 2004 (me) Comprehensive update posted live • 13 January 2003 (gg) Revision: Molecular Genetic Testing • 29 July 2002 (me) Review posted live • 8 October 2001 (gg) Original submission ## Author History Shane M Daley, MD; Mayo Clinic-Scottsdale (2002-2010) Glenn Edward Green, MD (2002-present) Ricardo A Samson, MD (2002-present) Lisbeth Tranebjærg, MD, PhD (2002-present) ## Revision History 17 August 2017 (sw) Comprehensive update posted live 20 November 2014 (me) Comprehensive update posted live 4 October 2012 (me) Comprehensive update posted live 23 February 2010 (me) Comprehensive update posted live 19 March 2007 (me) Comprehensive update posted live 29 July 2004 (me) Comprehensive update posted live 13 January 2003 (gg) Revision: Molecular Genetic Testing 29 July 2002 (me) Review posted live 8 October 2001 (gg) Original submission • 17 August 2017 (sw) Comprehensive update posted live • 20 November 2014 (me) Comprehensive update posted live • 4 October 2012 (me) Comprehensive update posted live • 23 February 2010 (me) Comprehensive update posted live • 19 March 2007 (me) Comprehensive update posted live • 29 July 2004 (me) Comprehensive update posted live • 13 January 2003 (gg) Revision: Molecular Genetic Testing • 29 July 2002 (me) Review posted live • 8 October 2001 (gg) 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	[]	29/7/2002	17/8/2017	13/1/2003	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
jmc	jmc	[ "Jansen Disease", "Jansen Metaphyseal Dysplasia", "Murk Jansen Metaphyseal Chondrodysplasia", "PTH1R-Related Metaphyseal Dysplasia, Jansen Type", "Jansen Disease", "Jansen Metaphyseal Dysplasia", "Murk Jansen Metaphyseal Chondrodysplasia", "PTH1R-Related Metaphyseal Dysplasia, Jansen Type", "Parathyroid hormone/parathyroid hormone-related peptide receptor", "PTH1R", "PTH1R-Related Jansen Metaphyseal Chondrodysplasia" ]		Fiona Obiezu, Alison Boyce, Harald Jüppner, Smita Jha	Summary The diagnosis of	## Diagnosis No consensus clinical diagnostic criteria for Growth deceleration of postnatal onset or severe short-limb short stature Skeletal deformities: short limbs, swelling of the joints of the extremities, bowing of the lower extremities (see History of kidney stones Craniofacial features: scaphocephaly, prominent forehead and supraorbital ridge, downslanted palpebral fissures, hypertelorism, telecanthus, wide nasal bridge, low-set ears, and retrognathia (See Dental findings: delayed eruption with impaction, crowding, and malocclusion (See Hypertension or elevated blood pressure Normal intellect Hypercalcemia (or high-normal serum calcium levels) with low or suppressed serum PTH Increased bone turnover markers such as bone-specific alkaline phosphatase (ALK), osteocalcin, and serum N-terminal telopeptide (NTx) Serum phosphorus may be low or low-normal Hypercalciuria Rickets-like metaphyseal changes may be evident prenatally or in infancy [ Radiographs of the extremities show bowing of long bones, flaring or widening of the metaphyses, and short phalanges (see Radiographs of the axial skeleton reveal sclerosis of the skull base, fragmented vertebra, and, in some individuals, scoliosis [ Head CT shows bilateral expansile bony lesions of the skull base (i.e., sphenoid, temporal) and facial bones. There may be obliteration of the sinuses (e.g., sphenoid, maxillary, mastoid air cells) and irregular, abnormal-appearing atlantooccipital and temporomandibular joints [ Kidney ultrasound may show mild-to-moderate nephrocalcinosis with increased echogenicity of the renal pyramids. The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click When the phenotype is indistinguishable from many 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 missense, nonsense, and splice site variants and small 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. To date, all pathogenic variants reported to date are constitutively active variants in • Growth deceleration of postnatal onset or severe short-limb short stature • Skeletal deformities: short limbs, swelling of the joints of the extremities, bowing of the lower extremities (see • History of kidney stones • Craniofacial features: scaphocephaly, prominent forehead and supraorbital ridge, downslanted palpebral fissures, hypertelorism, telecanthus, wide nasal bridge, low-set ears, and retrognathia (See • Dental findings: delayed eruption with impaction, crowding, and malocclusion (See • Hypertension or elevated blood pressure • Normal intellect • Hypercalcemia (or high-normal serum calcium levels) with low or suppressed serum PTH • Increased bone turnover markers such as bone-specific alkaline phosphatase (ALK), osteocalcin, and serum N-terminal telopeptide (NTx) • Serum phosphorus may be low or low-normal • Hypercalciuria • Rickets-like metaphyseal changes may be evident prenatally or in infancy [ • Radiographs of the extremities show bowing of long bones, flaring or widening of the metaphyses, and short phalanges (see • Radiographs of the axial skeleton reveal sclerosis of the skull base, fragmented vertebra, and, in some individuals, scoliosis [ • Head CT shows bilateral expansile bony lesions of the skull base (i.e., sphenoid, temporal) and facial bones. There may be obliteration of the sinuses (e.g., sphenoid, maxillary, mastoid air cells) and irregular, abnormal-appearing atlantooccipital and temporomandibular joints [ • Kidney ultrasound may show mild-to-moderate nephrocalcinosis with increased echogenicity of the renal pyramids. ## Suggestive Findings Growth deceleration of postnatal onset or severe short-limb short stature Skeletal deformities: short limbs, swelling of the joints of the extremities, bowing of the lower extremities (see History of kidney stones Craniofacial features: scaphocephaly, prominent forehead and supraorbital ridge, downslanted palpebral fissures, hypertelorism, telecanthus, wide nasal bridge, low-set ears, and retrognathia (See Dental findings: delayed eruption with impaction, crowding, and malocclusion (See Hypertension or elevated blood pressure Normal intellect Hypercalcemia (or high-normal serum calcium levels) with low or suppressed serum PTH Increased bone turnover markers such as bone-specific alkaline phosphatase (ALK), osteocalcin, and serum N-terminal telopeptide (NTx) Serum phosphorus may be low or low-normal Hypercalciuria Rickets-like metaphyseal changes may be evident prenatally or in infancy [ Radiographs of the extremities show bowing of long bones, flaring or widening of the metaphyses, and short phalanges (see Radiographs of the axial skeleton reveal sclerosis of the skull base, fragmented vertebra, and, in some individuals, scoliosis [ Head CT shows bilateral expansile bony lesions of the skull base (i.e., sphenoid, temporal) and facial bones. There may be obliteration of the sinuses (e.g., sphenoid, maxillary, mastoid air cells) and irregular, abnormal-appearing atlantooccipital and temporomandibular joints [ Kidney ultrasound may show mild-to-moderate nephrocalcinosis with increased echogenicity of the renal pyramids. • Growth deceleration of postnatal onset or severe short-limb short stature • Skeletal deformities: short limbs, swelling of the joints of the extremities, bowing of the lower extremities (see • History of kidney stones • Craniofacial features: scaphocephaly, prominent forehead and supraorbital ridge, downslanted palpebral fissures, hypertelorism, telecanthus, wide nasal bridge, low-set ears, and retrognathia (See • Dental findings: delayed eruption with impaction, crowding, and malocclusion (See • Hypertension or elevated blood pressure • Normal intellect • Hypercalcemia (or high-normal serum calcium levels) with low or suppressed serum PTH • Increased bone turnover markers such as bone-specific alkaline phosphatase (ALK), osteocalcin, and serum N-terminal telopeptide (NTx) • Serum phosphorus may be low or low-normal • Hypercalciuria • Rickets-like metaphyseal changes may be evident prenatally or in infancy [ • Radiographs of the extremities show bowing of long bones, flaring or widening of the metaphyses, and short phalanges (see • Radiographs of the axial skeleton reveal sclerosis of the skull base, fragmented vertebra, and, in some individuals, scoliosis [ • Head CT shows bilateral expansile bony lesions of the skull base (i.e., sphenoid, temporal) and facial bones. There may be obliteration of the sinuses (e.g., sphenoid, maxillary, mastoid air cells) and irregular, abnormal-appearing atlantooccipital and temporomandibular joints [ • Kidney ultrasound may show mild-to-moderate nephrocalcinosis with increased echogenicity of the renal pyramids. ## Establishing the Diagnosis The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click When the phenotype is indistinguishable from many 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 missense, nonsense, and splice site variants and small 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. To date, all pathogenic variants reported to date are constitutively active variants in ## Option 1 For an introduction to multigene panels click ## Option 2 When the phenotype is indistinguishable from many other skeletal dysplasias, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small 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. To date, all pathogenic variants reported to date are constitutively active variants in ## Clinical Characteristics In addition to the distinctive craniofacial appearance (see The craniofacial anomalies may result in functional deficits such as hearing loss [ Given the ultra-rare nature of In the 2023 revision of the Nosology of Genetic Skeletal Disorders, ## Clinical Description In addition to the distinctive craniofacial appearance (see The craniofacial anomalies may result in functional deficits such as hearing loss [ ## Genotype-Phenotype Correlations Given the ultra-rare nature of ## Penetrance ## Nomenclature In the 2023 revision of the Nosology of Genetic Skeletal Disorders, ## Prevalence ## Genetically Related (Allelic) Disorders Other phenotypes associated with germline pathogenic variants in AD = autosomal dominant; AR = autosomal recessive; LOF = loss-of-function; MOI = mode of inheritance ## Differential Diagnosis Genetic disorders of interest in the differential diagnosis of Genes of Interest in the Differential Diagnosis of Short stature Metaphyseal dysplasia Short stature Irregular metaphysis Bowed legs Short stature Bowed legs Short stature Bowed legs Hypophosphatemia Short stature Irregular metaphysis AD = autosomal dominant; AR = autosomal recessive; FGF23 = fibroblast growth factor 23; MOI = mode of inheritance; Pathogenic variants in • Short stature • Metaphyseal dysplasia • Short stature • Irregular metaphysis • Bowed legs • Short stature • Bowed legs • Short stature • Bowed legs • Hypophosphatemia • Short stature • Irregular metaphysis ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with Referral to orthopedist & physiatrist for mgmt Skeletal radiographs to determine timing & extent of surgical procedures to improve alignment & range of motion CT skull to help determine need for intervention in those w/craniosynostosis Referral to oromaxillofacial surgeon or neurosurgeon for mgmt in those w/craniosynostosis Dental exam & radiographs Referral to oromaxillofacial specialist as needed Referral to endocrinologist for laboratory assessment incl serum calcium, serum phosphorus, & 24-hour urine calcium Kidney & urinary tract ultrasound to evaluate for nephrocalcinosis & nephrolithiasis Assess for signs & symptoms of respiratory insufficiency. Airway assessment prior to anesthesia Sleep study to evaluate for obstructive sleep apnea MOI = mode of inheritance; Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Physical therapy, shoe lifts for limb length discrepancy, assistive devices for mobility, or surgical intervention for alignment/mobility, if indicated Encourage healthy diet & physical activity as tolerated. Assure intake of plenty of fluids to ↓ risk of hypercalcemia, hypercalciuria, nephrolithiasis, & nephrocalcinosis. Consider bisphosphonates if necessary for severe hypercalcemia w/dosing intervals determined by symptoms &/or serum calcium concentration. Effects of long-term bisphosphonates on growing skeleton & other organs such as eyes need to be considered. Cinacalcet is unlikely to be of benefit since underlying defect is below level of calcium-sensing receptor. Treatment per pulmonologist for dyspnea w/use of rescue inhalers if indicated Continuous positive airway pressure for obstructive sleep apnea if indicated Encourage watchful sodium intake to reduce risk of hypertension. Consider drugs targeting angiotensin receptor pathway in those w/↑ blood pressure. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Radiographs of extremities & spine (to monitor scoliosis) Skull CT Exam of dental/orthodontic issues to evaluate for malocclusion &/or impactions Dental radiographs Visual field exam Optical coherence tomography Laboratory assessment incl serum calcium, serum phosphorus, & 24-hour urine calcium Kidney & urinary tract ultrasound for nephrocalcinosis & nephrolithiasis Contact sports and other high-risk activities should likely be avoided in those with significant skeletal involvement. Individuals with See Although women with See Search • Referral to orthopedist & physiatrist for mgmt • Skeletal radiographs to determine timing & extent of surgical procedures to improve alignment & range of motion • CT skull to help determine need for intervention in those w/craniosynostosis • Referral to oromaxillofacial surgeon or neurosurgeon for mgmt in those w/craniosynostosis • Dental exam & radiographs • Referral to oromaxillofacial specialist as needed • Referral to endocrinologist for laboratory assessment incl serum calcium, serum phosphorus, & 24-hour urine calcium • Kidney & urinary tract ultrasound to evaluate for nephrocalcinosis & nephrolithiasis • Assess for signs & symptoms of respiratory insufficiency. • Airway assessment prior to anesthesia • Sleep study to evaluate for obstructive sleep apnea • Physical therapy, shoe lifts for limb length discrepancy, assistive devices for mobility, or surgical intervention for alignment/mobility, if indicated • Encourage healthy diet & physical activity as tolerated. • Assure intake of plenty of fluids to ↓ risk of hypercalcemia, hypercalciuria, nephrolithiasis, & nephrocalcinosis. • Consider bisphosphonates if necessary for severe hypercalcemia w/dosing intervals determined by symptoms &/or serum calcium concentration. • Effects of long-term bisphosphonates on growing skeleton & other organs such as eyes need to be considered. • Cinacalcet is unlikely to be of benefit since underlying defect is below level of calcium-sensing receptor. • Treatment per pulmonologist for dyspnea w/use of rescue inhalers if indicated • Continuous positive airway pressure for obstructive sleep apnea if indicated • Encourage watchful sodium intake to reduce risk of hypertension. • Consider drugs targeting angiotensin receptor pathway in those w/↑ blood pressure. • Radiographs of extremities & spine (to monitor scoliosis) • Skull CT • Exam of dental/orthodontic issues to evaluate for malocclusion &/or impactions • Dental radiographs • Visual field exam • Optical coherence tomography • Laboratory assessment incl serum calcium, serum phosphorus, & 24-hour urine calcium • Kidney & urinary tract ultrasound for nephrocalcinosis & nephrolithiasis ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Referral to orthopedist & physiatrist for mgmt Skeletal radiographs to determine timing & extent of surgical procedures to improve alignment & range of motion CT skull to help determine need for intervention in those w/craniosynostosis Referral to oromaxillofacial surgeon or neurosurgeon for mgmt in those w/craniosynostosis Dental exam & radiographs Referral to oromaxillofacial specialist as needed Referral to endocrinologist for laboratory assessment incl serum calcium, serum phosphorus, & 24-hour urine calcium Kidney & urinary tract ultrasound to evaluate for nephrocalcinosis & nephrolithiasis Assess for signs & symptoms of respiratory insufficiency. Airway assessment prior to anesthesia Sleep study to evaluate for obstructive sleep apnea MOI = mode of inheritance; Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Referral to orthopedist & physiatrist for mgmt • Skeletal radiographs to determine timing & extent of surgical procedures to improve alignment & range of motion • CT skull to help determine need for intervention in those w/craniosynostosis • Referral to oromaxillofacial surgeon or neurosurgeon for mgmt in those w/craniosynostosis • Dental exam & radiographs • Referral to oromaxillofacial specialist as needed • Referral to endocrinologist for laboratory assessment incl serum calcium, serum phosphorus, & 24-hour urine calcium • Kidney & urinary tract ultrasound to evaluate for nephrocalcinosis & nephrolithiasis • Assess for signs & symptoms of respiratory insufficiency. • Airway assessment prior to anesthesia • Sleep study to evaluate for obstructive sleep apnea ## 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 Physical therapy, shoe lifts for limb length discrepancy, assistive devices for mobility, or surgical intervention for alignment/mobility, if indicated Encourage healthy diet & physical activity as tolerated. Assure intake of plenty of fluids to ↓ risk of hypercalcemia, hypercalciuria, nephrolithiasis, & nephrocalcinosis. Consider bisphosphonates if necessary for severe hypercalcemia w/dosing intervals determined by symptoms &/or serum calcium concentration. Effects of long-term bisphosphonates on growing skeleton & other organs such as eyes need to be considered. Cinacalcet is unlikely to be of benefit since underlying defect is below level of calcium-sensing receptor. Treatment per pulmonologist for dyspnea w/use of rescue inhalers if indicated Continuous positive airway pressure for obstructive sleep apnea if indicated Encourage watchful sodium intake to reduce risk of hypertension. Consider drugs targeting angiotensin receptor pathway in those w/↑ blood pressure. • Physical therapy, shoe lifts for limb length discrepancy, assistive devices for mobility, or surgical intervention for alignment/mobility, if indicated • Encourage healthy diet & physical activity as tolerated. • Assure intake of plenty of fluids to ↓ risk of hypercalcemia, hypercalciuria, nephrolithiasis, & nephrocalcinosis. • Consider bisphosphonates if necessary for severe hypercalcemia w/dosing intervals determined by symptoms &/or serum calcium concentration. • Effects of long-term bisphosphonates on growing skeleton & other organs such as eyes need to be considered. • Cinacalcet is unlikely to be of benefit since underlying defect is below level of calcium-sensing receptor. • Treatment per pulmonologist for dyspnea w/use of rescue inhalers if indicated • Continuous positive airway pressure for obstructive sleep apnea if indicated • Encourage watchful sodium intake to reduce risk of hypertension. • Consider drugs targeting angiotensin receptor pathway in those w/↑ blood pressure. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Radiographs of extremities & spine (to monitor scoliosis) Skull CT Exam of dental/orthodontic issues to evaluate for malocclusion &/or impactions Dental radiographs Visual field exam Optical coherence tomography Laboratory assessment incl serum calcium, serum phosphorus, & 24-hour urine calcium Kidney & urinary tract ultrasound for nephrocalcinosis & nephrolithiasis • Radiographs of extremities & spine (to monitor scoliosis) • Skull CT • Exam of dental/orthodontic issues to evaluate for malocclusion &/or impactions • Dental radiographs • Visual field exam • Optical coherence tomography • Laboratory assessment incl serum calcium, serum phosphorus, & 24-hour urine calcium • Kidney & urinary tract ultrasound for nephrocalcinosis & nephrolithiasis ## Agents/Circumstances to Avoid Contact sports and other high-risk activities should likely be avoided in those with significant skeletal involvement. Individuals with ## Evaluation of Relatives at Risk See ## Pregnancy Management Although women with See ## Therapies Under Investigation Search ## Genetic Counseling Some individuals diagnosed with Most individuals diagnosed with If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing of the parents of the proband can establish their genetic status and inform recurrence risk assessment. Note: Parental molecular genetic testing is typically not required in the absence of any clinical features but can help to confirm the If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism (gonadal mosaicism has not been reported in * A parent with somatic and gonadal 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 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. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • Some individuals diagnosed with • Most individuals diagnosed with • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing of the parents of the proband can establish their genetic status and inform recurrence risk assessment. Note: Parental molecular genetic testing is typically not required in the absence of any clinical features but can help to confirm the • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism (gonadal mosaicism has not been reported in • * A parent with somatic and gonadal mosaicism for a • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism (gonadal mosaicism has not been reported in • * A parent with somatic and gonadal mosaicism for a • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism (gonadal mosaicism has not been reported in • * A parent with somatic and gonadal 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 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. ## Mode of Inheritance ## Risk to Family Members Some individuals diagnosed with Most individuals diagnosed with If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing of the parents of the proband can establish their genetic status and inform recurrence risk assessment. Note: Parental molecular genetic testing is typically not required in the absence of any clinical features but can help to confirm the If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism (gonadal mosaicism has not been reported in * A parent with somatic and gonadal 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 proband has a known If the parents have not been tested for the • Some individuals diagnosed with • Most individuals diagnosed with • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing of the parents of the proband can establish their genetic status and inform recurrence risk assessment. Note: Parental molecular genetic testing is typically not required in the absence of any clinical features but can help to confirm the • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism (gonadal mosaicism has not been reported in • * A parent with somatic and gonadal mosaicism for a • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism (gonadal mosaicism has not been reported in • * A parent with somatic and gonadal mosaicism for a • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism (gonadal mosaicism has not been reported in • * A parent with somatic and gonadal 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 proband has a known • If the parents have not been tested for the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 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 PTH1R-Related Jansen Metaphyseal Chondrodysplasia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for PTH1R-Related Jansen Metaphyseal Chondrodysplasia ( In the distal convoluted tubules of the kidney results in calcium reabsorption; In osteoblasts results in upregulation of RANKL, which stimulates osteoclast precursor cells to differentiate to mature osteoclasts; In the pre-hypertrophic growth plate chondrocytes slows their differentiation into hypertrophic chondrocytes, thus regulating bone lengthening and linear growth. Variants listed in the table have been provided by the authors. • In the distal convoluted tubules of the kidney results in calcium reabsorption; • In osteoblasts results in upregulation of RANKL, which stimulates osteoclast precursor cells to differentiate to mature osteoclasts; • In the pre-hypertrophic growth plate chondrocytes slows their differentiation into hypertrophic chondrocytes, thus regulating bone lengthening and linear growth. ## Molecular Pathogenesis In the distal convoluted tubules of the kidney results in calcium reabsorption; In osteoblasts results in upregulation of RANKL, which stimulates osteoclast precursor cells to differentiate to mature osteoclasts; In the pre-hypertrophic growth plate chondrocytes slows their differentiation into hypertrophic chondrocytes, thus regulating bone lengthening and linear growth. Variants listed in the table have been provided by the authors. • In the distal convoluted tubules of the kidney results in calcium reabsorption; • In osteoblasts results in upregulation of RANKL, which stimulates osteoclast precursor cells to differentiate to mature osteoclasts; • In the pre-hypertrophic growth plate chondrocytes slows their differentiation into hypertrophic chondrocytes, thus regulating bone lengthening and linear growth. ## Chapter Notes Fiona Obiezu, MD, is an incoming Plastic Surgery Resident at University of Las Vegas who completed the Medical Research Scholars Program at National Institutes of Health. She is an aspiring craniofacial surgeon with an interest in rare skeletal disorders. Alison Boyce, MD, is a pediatric endocrinologist at the National Institutes of Health with an interest in rare and pediatric skeletal disorders. Web page: Harald Jüppner, MD, is a nephrologist at Massachusetts General Hospital with an interest in genetic disorders affecting calcium and phosphate homeostasis as well as bone disorders. Web page: Smita Jha, MD, is an endocrinologist at the National Institutes of Health with a special interest in disorders of parathyroid hormone signaling or function such as Drs Smita Jha ( This research was supported by the Intramural and Extramural Research Program of the NIH/NIDDK. We wish to express our gratitude to the patients and their families for participation in the research and to the trainees and staff at the NIH Clinical Research Center for providing clinical care to the study participants. 10 July 2025 (sw) Review posted live 2 April 2025 (sj) Original submission • 10 July 2025 (sw) Review posted live • 2 April 2025 (sj) Original submission ## Author Notes Fiona Obiezu, MD, is an incoming Plastic Surgery Resident at University of Las Vegas who completed the Medical Research Scholars Program at National Institutes of Health. She is an aspiring craniofacial surgeon with an interest in rare skeletal disorders. Alison Boyce, MD, is a pediatric endocrinologist at the National Institutes of Health with an interest in rare and pediatric skeletal disorders. Web page: Harald Jüppner, MD, is a nephrologist at Massachusetts General Hospital with an interest in genetic disorders affecting calcium and phosphate homeostasis as well as bone disorders. Web page: Smita Jha, MD, is an endocrinologist at the National Institutes of Health with a special interest in disorders of parathyroid hormone signaling or function such as Drs Smita Jha ( ## Acknowledgments This research was supported by the Intramural and Extramural Research Program of the NIH/NIDDK. We wish to express our gratitude to the patients and their families for participation in the research and to the trainees and staff at the NIH Clinical Research Center for providing clinical care to the study participants. ## Revision History 10 July 2025 (sw) Review posted live 2 April 2025 (sj) Original submission • 10 July 2025 (sw) Review posted live • 2 April 2025 (sj) Original submission ## References ## Literature Cited Skeletal deformities in individuals with Craniofacial phenotype in individuals with A, B. Male age 12 years C, D. Male age 14 years E, F. Male age 16 years G, H. Female age 39 years I, J. Female age 45 years Note sloped forehead, prominent supraorbital ridge, downslanted palpebral fissures, hypertelorism, wide nasal bridge, and low-set ears. Lateral views show retrognathia (B, D). Reproduced from Dental manifestations in individuals with A. Male age 16 years with multiple submerged primary molars and impacted permanent canines, premolars, and molars; B. Male age 14 years with several impacted teeth and a few teeth with enamel hypoplasia; C. Male age 11 years with severe maxillary crowding; D. Panoramic radiograph of female age 39 years with no specific pathologic findings. Reproduced from CT and radiographs of skeletal manifestations of A. Axial CT of the cranial base in a male age 17 years with diffuse expansile lesions in anterior skull base with extensive involvement of the sphenoid and temporal bones B. Radiograph of the right upper extremity in a male age 11 years showing short limb, bowing of the long bones, and metaphyseal flaring C. Radiographs of the lower limbs of a male age 17 years showing short limbs, bowing of the long bones, metaphyseal flaring, and plate and nail implants used to help correct the deformities D. Coronal CT of the skull in a male age 14 years showing fragmented appearance of the vertebrae and wide, irregular, abnormal-appearing atlantooccipital joint	[]	10/7/2025			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
joubert	joubert	[ "JBTS", "Joubert Syndrome and Related Disorders (JSRD)", "JBTS", "Joubert Syndrome and Related Disorders (JSRD)", "Varadi-Papp Syndrome", "COACH Syndrome", "Arima Syndrome", "ADP-ribosylation factor-like protein 13B", "B9 domain-containing protein 1", "B9 domain-containing protein 2", "C2 domain-containing protein 3", "Centriole and centriolar satellite protein OFD1", "Centrosomal protein of 104 kDa", "Centrosomal protein of 120 kDa", "Centrosomal protein of 290 kDa", "Centrosomal protein of 41 kDa", "Centrosome and spindle pole-associated protein 1", "Ciliogenesis and planar polarity effector 1", "Coiled-coil and C2 domain-containing protein 2A", "Intraflagellar transport protein 172 homolog", "Jouberin", "Katanin-interacting protein", "Kinesin-like protein KIF7", "Meckelin", "Nephrocystin-1", "Phosphatidylinositol polyphosphate 5-phosphatase type IV", "POC1 centriolar protein homolog B", "Protein fantom", "Protein TALPID3", "Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta", "Tectonic-1", "Tectonic-2", "Tectonic-3", "Tectonic-like complex member MKS1", "Tetratricopeptide repeat protein 21B", "Transmembrane protein 107", "Transmembrane protein 138", "Transmembrane protein 216", "Transmembrane protein 231", "Transmembrane protein 237", "Zinc finger protein 423", "AHI1", "ARL13B", "B9D1", "B9D2", "C2CD3", "CC2D2A", "CEP104", "CEP120", "CEP290", "CEP41", "CPLANE1", "CSPP1", "IFT172", "INPP5E", "KATNIP", "KIAA0586", "KIF7", "MKS1", "NPHP1", "OFD1", "PDE6D", "POC1B", "RPGRIP1L", "TCTN1", "TCTN2", "TCTN3", "TMEM107", "TMEM138", "TMEM216", "TMEM231", "TMEM237", "TMEM67", "TTC21B", "ZNF423", "Joubert Syndrome", "Overview" ]	Joubert Syndrome	Ian A Glass, Jennifer C Dempsey, Melissa Parisi, Dan Doherty	Summary The purpose of this overview is to: Briefly describe the Review the Provide Review Inform	## Clinical Characteristics of Joubert Syndrome Joubert syndrome (JS) is, with rare exceptions, an autosomal recessive neurodevelopmental disorder defined by a characteristic cerebellar and brain stem malformation recognizable on axial brain magnetic resonance imaging (MRI) as the "molar tooth sign" (MTS). Clinically, individuals with JS typically present as infants with hypotonia, abnormal eye movements, respiratory disturbance, and, as children or adults, ataxia and/or cognitive impairment. In addition to these core features, most individuals with JS also have involvement of other body systems including the eye, kidney, liver, and skeleton. JS is a multisystem disorder in which several of the additional features may be progressive, complicating medical management [ An abnormally deep interpeduncular fossa Prominent, straight, and thickened superior cerebellar peduncles Hypoplasia of the vermis (the midline portion of the cerebellum) (See An additional proposed near-universal feature is superior cerebellar dysplasia characterized by absence of the superior cerebellar peduncle decussation, which can be identified on fractional anisotropy imaging [ To ensure the most accurate imaging to establish the diagnosis of MTS, both high-quality MRI with thin (≤3 mm) axial cuts through the posterior fossa from the midbrain to the pons and standard axial, coronal, and sagittal cuts are recommended [ Note: (1) Because a subset of individuals with pathogenic variants in JS-associated genes (see Cerebellar hemisphere enlargement Malrotation of the hippocampi Ventriculomegaly Dandy-Walker malformation Dysgenesis of the corpus callosum Polymicrogyria Heterotopia Occipital encephalocele (See Abnormal brain stem and/or hypothalamic hamartomas, particularly in those with oral-facial-digital features [ Dysphagia that may manifest as excess drooling and feeding difficulties predisposing to aspiration and respiratory complications. A substantial minority of individuals require gastrostomy tube placement. Speech apraxia, a nearly universal finding that may account (at least in part) for the discrepancy between expressive and receptive communication abilities [ Dystonic movements, which often include facial grimacing and/or biting the tongue and cheeks (perhaps self-injurious), for which there are no established treatments [ Early hypotonia often evolves with time to become Some degree of functional visual impairment from OMA, even when visual acuity is retained. OMA often improves over time. Ptosis, strabismus, refractive errors, and/or amblyopia are also common [ Chorioretinal coloboma and optic nerve coloboma (17% of individuals) and optic atrophy [ Retinal dystrophy (30% of individuals) ranging from congenital retinal blindness diagnosed in infancy with an attenuated or extinguished electroretinogram (ERG) (i.e., Leber congenital amaurosis) to retinitis pigmentosa (see Both chorioretinal coloboma and retinal dystrophy (2%-3% of individuals) [ Unilateral or bilateral ptosis (19% of individuals) [ In early-onset kidney disease, findings may be consistent with cystic dysplasia (i.e., multiple variably sized cysts in immature kidneys with fetal lobulations). In the first or second decade of life, kidney disease often presents as a urine-concentrating defect that results in polyuria and polydipsia (i.e., juvenile nephronophthisis) that may go undetected until manifestations of end-stage kidney disease (ESKD) become evident, such as fatigue, growth restriction, and/or anemia. Ultrasound examination typically shows small, scarred kidneys with increased echogenicity and occasional cysts at the corticomedullary junction. Progression to ESKD, occurring on average by age 13 years, is the leading cause of death in individuals with JS after age one year [ Although various skeletal features and related short-rib thoracic dysplasias have been reported in JS, it is rare for this to be the primary presentation [ Neuromuscular scoliosis (minimal prevalence of 5%) requires monitoring and may require further intervention [ Polydactyly (reported in 8%-19% of individuals) can be unilateral or bilateral and can involve hands and/or feet [ Multiple clinical subtypes of JS have been proposed in the past to designate specific phenotypes in individuals with MTS. These designations include the following: Cerebellar-oculo-renal syndrome (CORS) Arima syndrome (Joubert syndrome with oculorenal disease [retinopathy and cystic dysplastic kidneys]) COACH syndrome ( Varadi-Papp syndrome (Joubert syndrome with oral-facial-digital features [tongue hamartomas, oral frenulae, and polydactyly with a Y-shaped metacarpal]) In recognition of the extreme clinical heterogeneity of manifestations in individuals with MTS and the variable age of onset of many of these features, the term "Joubert syndrome" is now used to refer to all forms of Joubert syndrome listed above. • An abnormally deep interpeduncular fossa • Prominent, straight, and thickened superior cerebellar peduncles • Hypoplasia of the vermis (the midline portion of the cerebellum) (See • Cerebellar hemisphere enlargement • Malrotation of the hippocampi • Ventriculomegaly • Dandy-Walker malformation • Dysgenesis of the corpus callosum • Polymicrogyria • Heterotopia • Occipital encephalocele (See • Abnormal brain stem and/or hypothalamic hamartomas, particularly in those with oral-facial-digital features [ • Dysphagia that may manifest as excess drooling and feeding difficulties predisposing to aspiration and respiratory complications. A substantial minority of individuals require gastrostomy tube placement. • Speech apraxia, a nearly universal finding that may account (at least in part) for the discrepancy between expressive and receptive communication abilities [ • Dystonic movements, which often include facial grimacing and/or biting the tongue and cheeks (perhaps self-injurious), for which there are no established treatments [ • Early hypotonia often evolves with time to become • Some degree of functional visual impairment from OMA, even when visual acuity is retained. OMA often improves over time. Ptosis, strabismus, refractive errors, and/or amblyopia are also common [ • Chorioretinal coloboma and optic nerve coloboma (17% of individuals) and optic atrophy [ • Retinal dystrophy (30% of individuals) ranging from congenital retinal blindness diagnosed in infancy with an attenuated or extinguished electroretinogram (ERG) (i.e., Leber congenital amaurosis) to retinitis pigmentosa (see • Both chorioretinal coloboma and retinal dystrophy (2%-3% of individuals) [ • Unilateral or bilateral ptosis (19% of individuals) [ • Although various skeletal features and related short-rib thoracic dysplasias have been reported in JS, it is rare for this to be the primary presentation [ • Neuromuscular scoliosis (minimal prevalence of 5%) requires monitoring and may require further intervention [ • Polydactyly (reported in 8%-19% of individuals) can be unilateral or bilateral and can involve hands and/or feet [ • Cerebellar-oculo-renal syndrome (CORS) • Arima syndrome (Joubert syndrome with oculorenal disease [retinopathy and cystic dysplastic kidneys]) • COACH syndrome ( • Varadi-Papp syndrome (Joubert syndrome with oral-facial-digital features [tongue hamartomas, oral frenulae, and polydactyly with a Y-shaped metacarpal]) • Cerebellar-oculo-renal syndrome (CORS) • Arima syndrome (Joubert syndrome with oculorenal disease [retinopathy and cystic dysplastic kidneys]) • COACH syndrome ( • Varadi-Papp syndrome (Joubert syndrome with oral-facial-digital features [tongue hamartomas, oral frenulae, and polydactyly with a Y-shaped metacarpal]) • Cerebellar-oculo-renal syndrome (CORS) • Arima syndrome (Joubert syndrome with oculorenal disease [retinopathy and cystic dysplastic kidneys]) • COACH syndrome ( • Varadi-Papp syndrome (Joubert syndrome with oral-facial-digital features [tongue hamartomas, oral frenulae, and polydactyly with a Y-shaped metacarpal]) ## Brain Anomalies An abnormally deep interpeduncular fossa Prominent, straight, and thickened superior cerebellar peduncles Hypoplasia of the vermis (the midline portion of the cerebellum) (See An additional proposed near-universal feature is superior cerebellar dysplasia characterized by absence of the superior cerebellar peduncle decussation, which can be identified on fractional anisotropy imaging [ To ensure the most accurate imaging to establish the diagnosis of MTS, both high-quality MRI with thin (≤3 mm) axial cuts through the posterior fossa from the midbrain to the pons and standard axial, coronal, and sagittal cuts are recommended [ Note: (1) Because a subset of individuals with pathogenic variants in JS-associated genes (see Cerebellar hemisphere enlargement Malrotation of the hippocampi Ventriculomegaly Dandy-Walker malformation Dysgenesis of the corpus callosum Polymicrogyria Heterotopia Occipital encephalocele (See Abnormal brain stem and/or hypothalamic hamartomas, particularly in those with oral-facial-digital features [ • An abnormally deep interpeduncular fossa • Prominent, straight, and thickened superior cerebellar peduncles • Hypoplasia of the vermis (the midline portion of the cerebellum) (See • Cerebellar hemisphere enlargement • Malrotation of the hippocampi • Ventriculomegaly • Dandy-Walker malformation • Dysgenesis of the corpus callosum • Polymicrogyria • Heterotopia • Occipital encephalocele (See • Abnormal brain stem and/or hypothalamic hamartomas, particularly in those with oral-facial-digital features [ ## Clinical Findings Dysphagia that may manifest as excess drooling and feeding difficulties predisposing to aspiration and respiratory complications. A substantial minority of individuals require gastrostomy tube placement. Speech apraxia, a nearly universal finding that may account (at least in part) for the discrepancy between expressive and receptive communication abilities [ Dystonic movements, which often include facial grimacing and/or biting the tongue and cheeks (perhaps self-injurious), for which there are no established treatments [ Early hypotonia often evolves with time to become Some degree of functional visual impairment from OMA, even when visual acuity is retained. OMA often improves over time. Ptosis, strabismus, refractive errors, and/or amblyopia are also common [ Chorioretinal coloboma and optic nerve coloboma (17% of individuals) and optic atrophy [ Retinal dystrophy (30% of individuals) ranging from congenital retinal blindness diagnosed in infancy with an attenuated or extinguished electroretinogram (ERG) (i.e., Leber congenital amaurosis) to retinitis pigmentosa (see Both chorioretinal coloboma and retinal dystrophy (2%-3% of individuals) [ Unilateral or bilateral ptosis (19% of individuals) [ In early-onset kidney disease, findings may be consistent with cystic dysplasia (i.e., multiple variably sized cysts in immature kidneys with fetal lobulations). In the first or second decade of life, kidney disease often presents as a urine-concentrating defect that results in polyuria and polydipsia (i.e., juvenile nephronophthisis) that may go undetected until manifestations of end-stage kidney disease (ESKD) become evident, such as fatigue, growth restriction, and/or anemia. Ultrasound examination typically shows small, scarred kidneys with increased echogenicity and occasional cysts at the corticomedullary junction. Progression to ESKD, occurring on average by age 13 years, is the leading cause of death in individuals with JS after age one year [ Although various skeletal features and related short-rib thoracic dysplasias have been reported in JS, it is rare for this to be the primary presentation [ Neuromuscular scoliosis (minimal prevalence of 5%) requires monitoring and may require further intervention [ Polydactyly (reported in 8%-19% of individuals) can be unilateral or bilateral and can involve hands and/or feet [ • Dysphagia that may manifest as excess drooling and feeding difficulties predisposing to aspiration and respiratory complications. A substantial minority of individuals require gastrostomy tube placement. • Speech apraxia, a nearly universal finding that may account (at least in part) for the discrepancy between expressive and receptive communication abilities [ • Dystonic movements, which often include facial grimacing and/or biting the tongue and cheeks (perhaps self-injurious), for which there are no established treatments [ • Early hypotonia often evolves with time to become • Some degree of functional visual impairment from OMA, even when visual acuity is retained. OMA often improves over time. Ptosis, strabismus, refractive errors, and/or amblyopia are also common [ • Chorioretinal coloboma and optic nerve coloboma (17% of individuals) and optic atrophy [ • Retinal dystrophy (30% of individuals) ranging from congenital retinal blindness diagnosed in infancy with an attenuated or extinguished electroretinogram (ERG) (i.e., Leber congenital amaurosis) to retinitis pigmentosa (see • Both chorioretinal coloboma and retinal dystrophy (2%-3% of individuals) [ • Unilateral or bilateral ptosis (19% of individuals) [ • Although various skeletal features and related short-rib thoracic dysplasias have been reported in JS, it is rare for this to be the primary presentation [ • Neuromuscular scoliosis (minimal prevalence of 5%) requires monitoring and may require further intervention [ • Polydactyly (reported in 8%-19% of individuals) can be unilateral or bilateral and can involve hands and/or feet [ ## Nomenclature Multiple clinical subtypes of JS have been proposed in the past to designate specific phenotypes in individuals with MTS. These designations include the following: Cerebellar-oculo-renal syndrome (CORS) Arima syndrome (Joubert syndrome with oculorenal disease [retinopathy and cystic dysplastic kidneys]) COACH syndrome ( Varadi-Papp syndrome (Joubert syndrome with oral-facial-digital features [tongue hamartomas, oral frenulae, and polydactyly with a Y-shaped metacarpal]) In recognition of the extreme clinical heterogeneity of manifestations in individuals with MTS and the variable age of onset of many of these features, the term "Joubert syndrome" is now used to refer to all forms of Joubert syndrome listed above. • Cerebellar-oculo-renal syndrome (CORS) • Arima syndrome (Joubert syndrome with oculorenal disease [retinopathy and cystic dysplastic kidneys]) • COACH syndrome ( • Varadi-Papp syndrome (Joubert syndrome with oral-facial-digital features [tongue hamartomas, oral frenulae, and polydactyly with a Y-shaped metacarpal]) • Cerebellar-oculo-renal syndrome (CORS) • Arima syndrome (Joubert syndrome with oculorenal disease [retinopathy and cystic dysplastic kidneys]) • COACH syndrome ( • Varadi-Papp syndrome (Joubert syndrome with oral-facial-digital features [tongue hamartomas, oral frenulae, and polydactyly with a Y-shaped metacarpal]) • Cerebellar-oculo-renal syndrome (CORS) • Arima syndrome (Joubert syndrome with oculorenal disease [retinopathy and cystic dysplastic kidneys]) • COACH syndrome ( • Varadi-Papp syndrome (Joubert syndrome with oral-facial-digital features [tongue hamartomas, oral frenulae, and polydactyly with a Y-shaped metacarpal]) ## Genetic Causes of Joubert Syndrome Establishing the molecular diagnosis of Joubert syndrome (JS) confirms the clinical diagnosis of JS and informs genetic counseling (i.e., recurrence risk/family planning). The molecular diagnosis also informs management related to known gene-phenotype correlations that include (1) the frequency of monitoring for progressive features such as retinal dystrophy, kidney disease, and liver disease and (2) recommendations to avoid use of nephrotoxic medications in individuals at the highest risk for kidney involvement while not unnecessarily restricting these medications in those at low risk [ More than 40 genes are known to be associated with Joubert syndrome. Joubert Syndrome: Genes and Distinguishing Clinical Features Encephalocele, oral-facial-digital features, primary ciliary dyskinesia XL inheritance AR inheritance: mild JS w/craniofacial features AD inheritance of monoallelic variants: OMA ± mild JS features w/macrocephaly; unclear of exact overlap w/ Adapted from AD = autosomal dominant; AR = autosomal recessive; NBCC = nevoid basal cell carcinoma; OMA = oculomotor apraxia; XL = X-linked Genes are listed in alphabetic order. • Encephalocele, oral-facial-digital features, primary ciliary dyskinesia • XL inheritance • AR inheritance: mild JS w/craniofacial features • AD inheritance of monoallelic variants: OMA ± mild JS features w/macrocephaly; unclear of exact overlap w/ ## Evaluation Strategies to Identify the Genetic Cause of Joubert Syndrome in a Proband Establishing a specific genetic cause of Joubert syndrome (JS): Can aid in discussions of Usually involves a medical history, physical examination, family history, and genomic/genetic testing. The genetic basis of JS 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 Note: (1) Single-gene testing for the diagnosis of Joubert syndrome is rarely useful and typically NOT recommended. (2) Given the large number of causative genes and the broad phenotypic spectrum of Joubert syndrome, use of a multigene panel may also be too restrictive. For an introduction to comprehensive genomic testing click For an introduction to multigene panels click • Can aid in discussions of • Usually involves a medical history, physical examination, family history, and genomic/genetic testing. • For an introduction to comprehensive genomic testing click • For an introduction to multigene panels click ## Genomic/Genetic Testing The genetic basis of JS 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 Note: (1) Single-gene testing for the diagnosis of Joubert syndrome is rarely useful and typically NOT recommended. (2) Given the large number of causative genes and the broad phenotypic spectrum of Joubert syndrome, use of a multigene panel may also be too restrictive. For an introduction to comprehensive genomic testing click For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click • For an introduction to multigene panels click ## Management Management recommendations based on consensus of expert opinion have been published to minimize medical complications and maximize quality of life for individuals with Joubert syndrome (JS) [ To establish the extent of disease and needs in an individual diagnosed with JS, the evaluations summarized in Joubert Syndrome: Recommended Evaluations Following Initial Diagnosis Hypotonia, present in infants, often becomes cerebellar ataxia in older persons. Consider EEG if seizures are a concern. Evaluate aspiration risk & nutritional status. Consider eval for gastrostomy tube placement in persons w/dysphagia &/or when aspiration risk is increased. Ptosis, abnormal ocular movement, reduced vision, best corrected visual acuity, refractive errors, & strabismus; Findings such as coloboma &/or retinal dystrophy. 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) Physical exam; if suspicion of skeletal dysplasia, obtain skeletal survey &/or limb radiographs. Evaluate polydactyly re need for surgery. Evaluate for spinal curvature per standard practice. Consult w/orthopedist if scoliosis is progressing &/or significant. To incl motor, adaptive, cognitive, & speech-language eval Evaluate for early intervention / special education. Monitor blood pressure, BUN, serum creatinine concentration, CBC, & urinalysis from 1st am void for specific gravity to test concentrating ability (if feasible). Abdominal ultrasound for kidney size, cysts, &/or findings consistent w/nephronophthisis (e.g., loss of corticomedullary differentiation) Monitor blood concentrations of transaminases, albumin, bilirubin, & prothrombin time. Abdominal ultrasound to evaluate for hepatic fibrosis, anomalies of bile duct 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; BUN = blood urea nitrogen; CBC = complete blood count; JS = Joubert syndrome; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Now commonly confirmed by ocular coherence tomography (OCT) rather than electroretinogram (ERG) 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 Joubert Syndrome: Treatment of Manifestations Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education for parents/caregivers Stimulatory medications (e.g., caffeine) &/or supplemental oxygen (particularly newborns); Rarely, mechanical support &/or tracheostomy. Assure adequate dietary intake. Consider gastrostomy tube placement if aspiration risk is increased. Children: through early intervention programs &/or school district Adults: low vision clinic &/or community vision services /OT / mobility services For oral motor dysfunction Consider augmentative or alternate means of communication. Incl stretching to help avoid contractures & falls Consider need for positioning and mobility devices, disability parking placard. Scoliosis detection & monitoring Surgical repair as recommended by orthopedist If needed, incl special programs for visually impaired. Determine if IEP or 504 plan is needed. Medication mgmt per standard care Counsel re ↑ risk for emotional lability, anxiety, & ADHD By nephrologist familiar w/nephronophthisis Agents/circumstances to avoid incl nephrotoxic agents/medications for those w/molecular diagnosis that puts them at ↑ risk (see Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASMs = anti-seizure medications; ESKD = end-stage kidney disease; IEP = individual education plan; OT = occupational therapy; PT = physical therapy; SLP = speech-language pathologist Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in Joubert Syndrome: Recommended Surveillance Measure growth parameters. Assess nutritional status & safety of oral intake. Monitor those w/seizures as clinically indicated. Assess for new manifestations such as seizures, changes in tone, & ataxia. ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ALT = alanine transaminase; ASD = autism spectrum disorder; GGT = gamma-glutamyl transferase; OT = occupational therapy; PT = physical therapy; SLP = speech-language pathologist See also • Hypotonia, present in infants, often becomes cerebellar ataxia in older persons. • Consider EEG if seizures are a concern. • Evaluate aspiration risk & nutritional status. • Consider eval for gastrostomy tube placement in persons w/dysphagia &/or when aspiration risk is increased. • Ptosis, abnormal ocular movement, reduced vision, best corrected visual acuity, refractive errors, & strabismus; • Findings such as coloboma &/or retinal dystrophy. • 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) • Physical exam; if suspicion of skeletal dysplasia, obtain skeletal survey &/or limb radiographs. • Evaluate polydactyly re need for surgery. • Evaluate for spinal curvature per standard practice. • Consult w/orthopedist if scoliosis is progressing &/or significant. • To incl motor, adaptive, cognitive, & speech-language eval • Evaluate for early intervention / special education. • Monitor blood pressure, BUN, serum creatinine concentration, CBC, & urinalysis from 1st am void for specific gravity to test concentrating ability (if feasible). • Abdominal ultrasound for kidney size, cysts, &/or findings consistent w/nephronophthisis (e.g., loss of corticomedullary differentiation) • Monitor blood concentrations of transaminases, albumin, bilirubin, & prothrombin time. • Abdominal ultrasound to evaluate for hepatic fibrosis, anomalies of bile duct • 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 for parents/caregivers • Stimulatory medications (e.g., caffeine) &/or supplemental oxygen (particularly newborns); • Rarely, mechanical support &/or tracheostomy. • Assure adequate dietary intake. • Consider gastrostomy tube placement if aspiration risk is increased. • Children: through early intervention programs &/or school district • Adults: low vision clinic &/or community vision services /OT / mobility services • For oral motor dysfunction • Consider augmentative or alternate means of communication. • Incl stretching to help avoid contractures & falls • Consider need for positioning and mobility devices, disability parking placard. • Scoliosis detection & monitoring • Surgical repair as recommended by orthopedist • If needed, incl special programs for visually impaired. • Determine if IEP or 504 plan is needed. • Medication mgmt per standard care • Counsel re ↑ risk for emotional lability, anxiety, & ADHD • By nephrologist familiar w/nephronophthisis • Agents/circumstances to avoid incl nephrotoxic agents/medications for those w/molecular diagnosis that puts them at ↑ risk (see • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • Measure growth parameters. • Assess nutritional status & safety of oral intake. • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as seizures, changes in tone, & ataxia. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with JS, the evaluations summarized in Joubert Syndrome: Recommended Evaluations Following Initial Diagnosis Hypotonia, present in infants, often becomes cerebellar ataxia in older persons. Consider EEG if seizures are a concern. Evaluate aspiration risk & nutritional status. Consider eval for gastrostomy tube placement in persons w/dysphagia &/or when aspiration risk is increased. Ptosis, abnormal ocular movement, reduced vision, best corrected visual acuity, refractive errors, & strabismus; Findings such as coloboma &/or retinal dystrophy. 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) Physical exam; if suspicion of skeletal dysplasia, obtain skeletal survey &/or limb radiographs. Evaluate polydactyly re need for surgery. Evaluate for spinal curvature per standard practice. Consult w/orthopedist if scoliosis is progressing &/or significant. To incl motor, adaptive, cognitive, & speech-language eval Evaluate for early intervention / special education. Monitor blood pressure, BUN, serum creatinine concentration, CBC, & urinalysis from 1st am void for specific gravity to test concentrating ability (if feasible). Abdominal ultrasound for kidney size, cysts, &/or findings consistent w/nephronophthisis (e.g., loss of corticomedullary differentiation) Monitor blood concentrations of transaminases, albumin, bilirubin, & prothrombin time. Abdominal ultrasound to evaluate for hepatic fibrosis, anomalies of bile duct 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; BUN = blood urea nitrogen; CBC = complete blood count; JS = Joubert syndrome; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Now commonly confirmed by ocular coherence tomography (OCT) rather than electroretinogram (ERG) Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Hypotonia, present in infants, often becomes cerebellar ataxia in older persons. • Consider EEG if seizures are a concern. • Evaluate aspiration risk & nutritional status. • Consider eval for gastrostomy tube placement in persons w/dysphagia &/or when aspiration risk is increased. • Ptosis, abnormal ocular movement, reduced vision, best corrected visual acuity, refractive errors, & strabismus; • Findings such as coloboma &/or retinal dystrophy. • 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) • Physical exam; if suspicion of skeletal dysplasia, obtain skeletal survey &/or limb radiographs. • Evaluate polydactyly re need for surgery. • Evaluate for spinal curvature per standard practice. • Consult w/orthopedist if scoliosis is progressing &/or significant. • To incl motor, adaptive, cognitive, & speech-language eval • Evaluate for early intervention / special education. • Monitor blood pressure, BUN, serum creatinine concentration, CBC, & urinalysis from 1st am void for specific gravity to test concentrating ability (if feasible). • Abdominal ultrasound for kidney size, cysts, &/or findings consistent w/nephronophthisis (e.g., loss of corticomedullary differentiation) • Monitor blood concentrations of transaminases, albumin, bilirubin, & prothrombin time. • Abdominal ultrasound to evaluate for hepatic fibrosis, anomalies of bile duct • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Joubert Syndrome: Treatment of Manifestations Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education for parents/caregivers Stimulatory medications (e.g., caffeine) &/or supplemental oxygen (particularly newborns); Rarely, mechanical support &/or tracheostomy. Assure adequate dietary intake. Consider gastrostomy tube placement if aspiration risk is increased. Children: through early intervention programs &/or school district Adults: low vision clinic &/or community vision services /OT / mobility services For oral motor dysfunction Consider augmentative or alternate means of communication. Incl stretching to help avoid contractures & falls Consider need for positioning and mobility devices, disability parking placard. Scoliosis detection & monitoring Surgical repair as recommended by orthopedist If needed, incl special programs for visually impaired. Determine if IEP or 504 plan is needed. Medication mgmt per standard care Counsel re ↑ risk for emotional lability, anxiety, & ADHD By nephrologist familiar w/nephronophthisis Agents/circumstances to avoid incl nephrotoxic agents/medications for those w/molecular diagnosis that puts them at ↑ risk (see Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASMs = anti-seizure medications; ESKD = end-stage kidney disease; IEP = individual education plan; OT = occupational therapy; PT = physical therapy; SLP = speech-language pathologist 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 • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education for parents/caregivers • Stimulatory medications (e.g., caffeine) &/or supplemental oxygen (particularly newborns); • Rarely, mechanical support &/or tracheostomy. • Assure adequate dietary intake. • Consider gastrostomy tube placement if aspiration risk is increased. • Children: through early intervention programs &/or school district • Adults: low vision clinic &/or community vision services /OT / mobility services • For oral motor dysfunction • Consider augmentative or alternate means of communication. • Incl stretching to help avoid contractures & falls • Consider need for positioning and mobility devices, disability parking placard. • Scoliosis detection & monitoring • Surgical repair as recommended by orthopedist • If needed, incl special programs for visually impaired. • Determine if IEP or 504 plan is needed. • Medication mgmt per standard care • Counsel re ↑ risk for emotional lability, anxiety, & ADHD • By nephrologist familiar w/nephronophthisis • Agents/circumstances to avoid incl nephrotoxic agents/medications for those w/molecular diagnosis that puts them at ↑ risk (see • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in Joubert Syndrome: Recommended Surveillance Measure growth parameters. Assess nutritional status & safety of oral intake. Monitor those w/seizures as clinically indicated. Assess for new manifestations such as seizures, changes in tone, & ataxia. ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ALT = alanine transaminase; ASD = autism spectrum disorder; GGT = gamma-glutamyl transferase; OT = occupational therapy; PT = physical therapy; SLP = speech-language pathologist See also • Measure growth parameters. • Assess nutritional status & safety of oral intake. • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as seizures, changes in tone, & ataxia. ## Genetic Counseling Joubert syndrome (JS) is predominantly inherited in an autosomal recessive manner. Note: Oligogenic inheritance has also been proposed; however, more recent data have not supported oligogenic inheritance in JS [ The parents of an affected child are presumed to be heterozygous for an autosomal recessive JS-related pathogenic variant. If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an autosomal recessive JS-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including 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 JS-related pathogenic variant(s) have been identified in an affected family member, If the JS-related pathogenic variant(s) in the family are unknown, When detection of cerebellar vermis hypoplasia by routine prenatal ultrasound examination raises the possibility of JS, fetal MRI may detect the typical molar tooth sign (MTS); however, the sensitivity and specificity of this prenatal finding remain unknown [ Note: Other disorders with posterior fossa anomalies such as Dandy-Walker malformation, Poretti-Boltshauser syndrome (OMIM 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 autosomal recessive JS-related pathogenic variant. • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a pathogenic variant and to allow reliable recurrence risk assessment. • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an autosomal recessive JS-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including 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 JS-related pathogenic variant(s) have been identified in an affected family member, • If the JS-related pathogenic variant(s) in the family are unknown, • When detection of cerebellar vermis hypoplasia by routine prenatal ultrasound examination raises the possibility of JS, fetal MRI may detect the typical molar tooth sign (MTS); however, the sensitivity and specificity of this prenatal finding remain unknown [ • Note: Other disorders with posterior fossa anomalies such as Dandy-Walker malformation, Poretti-Boltshauser syndrome (OMIM ## Mode of Inheritance Joubert syndrome (JS) is predominantly inherited in an autosomal recessive manner. Note: Oligogenic inheritance has also been proposed; however, more recent data have not supported oligogenic inheritance in JS [ ## Risk to Family Members (Autosomal Recessive Inheritance) The parents of an affected child are presumed to be heterozygous for an autosomal recessive JS-related pathogenic variant. If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an autosomal recessive JS-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The parents of an affected child are presumed to be heterozygous for an autosomal recessive JS-related pathogenic variant. • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a pathogenic variant and to allow reliable recurrence risk assessment. • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an autosomal recessive JS-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## 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 JS-related pathogenic variant(s) have been identified in an affected family member, If the JS-related pathogenic variant(s) in the family are unknown, When detection of cerebellar vermis hypoplasia by routine prenatal ultrasound examination raises the possibility of JS, fetal MRI may detect the typical molar tooth sign (MTS); however, the sensitivity and specificity of this prenatal finding remain unknown [ Note: Other disorders with posterior fossa anomalies such as Dandy-Walker malformation, Poretti-Boltshauser syndrome (OMIM 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. • Once the JS-related pathogenic variant(s) have been identified in an affected family member, • If the JS-related pathogenic variant(s) in the family are unknown, • When detection of cerebellar vermis hypoplasia by routine prenatal ultrasound examination raises the possibility of JS, fetal MRI may detect the typical molar tooth sign (MTS); however, the sensitivity and specificity of this prenatal finding remain unknown [ • Note: Other disorders with posterior fossa anomalies such as Dandy-Walker malformation, Poretti-Boltshauser syndrome (OMIM ## Resources United Kingdom • • • • • • • • • • United Kingdom • ## Chapter Notes The following groups are actively involved in clinical research regarding individuals with Joubert syndrome (JS). They would be happy to communicate with persons who have any questions regarding diagnosis of JS and/or would like to enroll in a research study. University of Washington Hindbrain Malformation Research Program, USAPrincipal Investigator: Dr Dan DohertyContact: North East Genomics ClinicThe Newcastle Upon Tyne NHS Foundation Trust, UKPrincipal Investigator: Dr John SayerContact: The following groups are interested in hearing from clinicians treating families affected by JS in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders. University of Washington Hindbrain Malformation Research Program, USAPrincipal Investigator: Dr Dan DohertyContact: University of Pavia and IRCCS Mondino Foundation, ItalyPrincipal Investigator: Dr Enza Maria ValenteContact: North East Genomics ClinicThe Newcastle Upon Tyne NHS Foundation Trust, UKPrincipal Investigator: Dr John SayerContact: Contact the following groups to inquire about review of variants of uncertain significance in genes associated with JS. University of Washington Hindbrain Malformation Research Program, USAPrincipal Investigator: Dr Dan DohertyContact: University of Pavia and IRCCS Mondino Foundation, ItalyPrincipal Investigator: Dr Enza Maria ValenteContact: North East Genomics ClinicThe Newcastle Upon Tyne NHS Foundation Trust, UKPrincipal Investigator: Dr John SayerContact: Ruxandra Bachmann-Gagescu, University of Zurich, Switzerland 13 March 2025 (bp) Comprehensive update posted live 29 June 2017 (bp) Comprehensive update posted live 29 March 2012 (me) Comprehensive update posted live 24 February 2006 (me) Comprehensive update posted live 9 July 2003 (me) Review posted live 27 January 2003 (mp) Original submission • University of Washington Hindbrain Malformation Research Program, USAPrincipal Investigator: Dr Dan DohertyContact: • North East Genomics ClinicThe Newcastle Upon Tyne NHS Foundation Trust, UKPrincipal Investigator: Dr John SayerContact: • University of Washington Hindbrain Malformation Research Program, USAPrincipal Investigator: Dr Dan DohertyContact: • University of Pavia and IRCCS Mondino Foundation, ItalyPrincipal Investigator: Dr Enza Maria ValenteContact: • North East Genomics ClinicThe Newcastle Upon Tyne NHS Foundation Trust, UKPrincipal Investigator: Dr John SayerContact: • University of Washington Hindbrain Malformation Research Program, USAPrincipal Investigator: Dr Dan DohertyContact: • University of Pavia and IRCCS Mondino Foundation, ItalyPrincipal Investigator: Dr Enza Maria ValenteContact: • North East Genomics ClinicThe Newcastle Upon Tyne NHS Foundation Trust, UKPrincipal Investigator: Dr John SayerContact: • 13 March 2025 (bp) Comprehensive update posted live • 29 June 2017 (bp) Comprehensive update posted live • 29 March 2012 (me) Comprehensive update posted live • 24 February 2006 (me) Comprehensive update posted live • 9 July 2003 (me) Review posted live • 27 January 2003 (mp) Original submission ## Author Notes The following groups are actively involved in clinical research regarding individuals with Joubert syndrome (JS). They would be happy to communicate with persons who have any questions regarding diagnosis of JS and/or would like to enroll in a research study. University of Washington Hindbrain Malformation Research Program, USAPrincipal Investigator: Dr Dan DohertyContact: North East Genomics ClinicThe Newcastle Upon Tyne NHS Foundation Trust, UKPrincipal Investigator: Dr John SayerContact: The following groups are interested in hearing from clinicians treating families affected by JS in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders. University of Washington Hindbrain Malformation Research Program, USAPrincipal Investigator: Dr Dan DohertyContact: University of Pavia and IRCCS Mondino Foundation, ItalyPrincipal Investigator: Dr Enza Maria ValenteContact: North East Genomics ClinicThe Newcastle Upon Tyne NHS Foundation Trust, UKPrincipal Investigator: Dr John SayerContact: Contact the following groups to inquire about review of variants of uncertain significance in genes associated with JS. University of Washington Hindbrain Malformation Research Program, USAPrincipal Investigator: Dr Dan DohertyContact: University of Pavia and IRCCS Mondino Foundation, ItalyPrincipal Investigator: Dr Enza Maria ValenteContact: North East Genomics ClinicThe Newcastle Upon Tyne NHS Foundation Trust, UKPrincipal Investigator: Dr John SayerContact: • University of Washington Hindbrain Malformation Research Program, USAPrincipal Investigator: Dr Dan DohertyContact: • North East Genomics ClinicThe Newcastle Upon Tyne NHS Foundation Trust, UKPrincipal Investigator: Dr John SayerContact: • University of Washington Hindbrain Malformation Research Program, USAPrincipal Investigator: Dr Dan DohertyContact: • University of Pavia and IRCCS Mondino Foundation, ItalyPrincipal Investigator: Dr Enza Maria ValenteContact: • North East Genomics ClinicThe Newcastle Upon Tyne NHS Foundation Trust, UKPrincipal Investigator: Dr John SayerContact: • University of Washington Hindbrain Malformation Research Program, USAPrincipal Investigator: Dr Dan DohertyContact: • University of Pavia and IRCCS Mondino Foundation, ItalyPrincipal Investigator: Dr Enza Maria ValenteContact: • North East Genomics ClinicThe Newcastle Upon Tyne NHS Foundation Trust, UKPrincipal Investigator: Dr John SayerContact: ## Acknowledgments Ruxandra Bachmann-Gagescu, University of Zurich, Switzerland ## Revision History 13 March 2025 (bp) Comprehensive update posted live 29 June 2017 (bp) Comprehensive update posted live 29 March 2012 (me) Comprehensive update posted live 24 February 2006 (me) Comprehensive update posted live 9 July 2003 (me) Review posted live 27 January 2003 (mp) Original submission • 13 March 2025 (bp) Comprehensive update posted live • 29 June 2017 (bp) Comprehensive update posted live • 29 March 2012 (me) Comprehensive update posted live • 24 February 2006 (me) Comprehensive update posted live • 9 July 2003 (me) Review posted live • 27 January 2003 (mp) Original submission ## References ## Literature Cited Molar tooth sign (MTS) in Joubert syndrome (JS) A. Axial MRI image through the cerebellum and brain stem of a control showing intact cerebellar vermis (outlined by white arrows) B. Axial MRI image through the cerebellum and brain stem of a child with JS. Arrows indicate the three key components of the MTS. Clinical features in Joubert syndrome (JS) A. Facial features in a girl with JS at age 27 months showing broad forehead, arched eyebrows, strabismus, eyelid ptosis (on right eye), and open mouth configuration indicating reduced facial tone B. Oral findings in a child with oral-facial-digital features of JS showing midline upper lip cleft (arrowhead), midline groove of tongue, and bumps of the lower alveolar ridge (arrow) C. Left hand of an infant with JS and postaxial polydactyly (arrow) D. Left foot of an infant with JS and preaxial polydactyly of the hallux E. View from above of an infant with a small occipital encephalocele with protrusion of the occiput of the skull (arrow) Reproduced with permission from	[]	9/7/2003	13/3/2025	11/4/2013	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
jpd	jpd	[ "PARK-Parkin", "PRKN Parkinson Disease", "PRKN Parkinson Disease", "PARK-Parkin", "E3 ubiquitin-protein ligase parkin", "PRKN", "Parkin Type of Early-Onset Parkinson Disease" ]	Parkin Type of Early-Onset Parkinson Disease	Norbert Brüggemann, Christine Klein	Summary Parkin type of early-onset Parkinson disease (PARK- The diagnosis of PARK- PARK-	## Diagnosis Parkin type of early-onset Parkinson disease (PARK- Onset before age 40 years in most individuals (median age: 31 years; range: 3-81 years) or, rarely, juvenile onset (age <20 years). Lower-limb dystonia (may be a presenting sign or may occur during disease progression), which sometimes remains an isolated finding for years Slow disease progression Absence of dementia in most individuals (present in <3%) Well-preserved sense of smell Marked and sustained response to oral administration of levodopa, which is frequently associated with levodopa-induced motor fluctuations and dyskinesias (abnormal involuntary movements) The diagnosis of PARK- Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas exome or genome testing does not. Because the phenotype of PARK- For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Parkin Type of Early-Onset Parkinson Disease See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. The frequency of exon rearrangements is likely underestimated given that early variant screening studies did not include methods to detect large deletions and duplications. • Onset before age 40 years in most individuals (median age: 31 years; range: 3-81 years) or, rarely, juvenile onset (age <20 years). • Lower-limb dystonia (may be a presenting sign or may occur during disease progression), which sometimes remains an isolated finding for years • Slow disease progression • Absence of dementia in most individuals (present in <3%) • Well-preserved sense of smell • Marked and sustained response to oral administration of levodopa, which is frequently associated with levodopa-induced motor fluctuations and dyskinesias (abnormal involuntary movements) • ## Suggestive Findings Parkin type of early-onset Parkinson disease (PARK- Onset before age 40 years in most individuals (median age: 31 years; range: 3-81 years) or, rarely, juvenile onset (age <20 years). Lower-limb dystonia (may be a presenting sign or may occur during disease progression), which sometimes remains an isolated finding for years Slow disease progression Absence of dementia in most individuals (present in <3%) Well-preserved sense of smell Marked and sustained response to oral administration of levodopa, which is frequently associated with levodopa-induced motor fluctuations and dyskinesias (abnormal involuntary movements) • Onset before age 40 years in most individuals (median age: 31 years; range: 3-81 years) or, rarely, juvenile onset (age <20 years). • Lower-limb dystonia (may be a presenting sign or may occur during disease progression), which sometimes remains an isolated finding for years • Slow disease progression • Absence of dementia in most individuals (present in <3%) • Well-preserved sense of smell • Marked and sustained response to oral administration of levodopa, which is frequently associated with levodopa-induced motor fluctuations and dyskinesias (abnormal involuntary movements) ## Establishing the Diagnosis The diagnosis of PARK- Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas exome or genome testing does not. Because the phenotype of PARK- For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Parkin Type of Early-Onset Parkinson Disease See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. The frequency of exon rearrangements is likely underestimated given that early variant screening studies did not include methods to detect large deletions and 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 Parkin Type of Early-Onset Parkinson Disease See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. The frequency of exon rearrangements is likely underestimated given that early variant screening studies did not include methods to detect large deletions and duplications. • ## Clinical Characteristics Parkin type of early-onset Parkinson disease (PARK- Women and men are affected with equal frequency. Age at onset is highly variable, even among individuals with the same pathogenic variant [ Clinical findings vary; however, tremor, bradykinesia, and dystonia are the most common presenting signs. Dystonia is observed in 65% (177/271) of affected individuals for whom this information is available. Almost half of affected individuals present with hyperreflexia. The diagnosis of PD may be delayed due to unusual clinical features, especially in patients with an early manifestation [ PARK- The disease is slowly progressive: disease duration of greater than 50 years has been reported. In later disease stages, freezing of gait, postural deformities, and motor fluctuations may be common features, whereas dementia usually does not develop [ Routine cranial CT and MRI scans are usually normal. PET/SPECT studies have revealed a reduced striatal Voxel-based morphometry revealed a decrease of putaminal gray matter volume and a slight increase of gray matter in the right pallidum in individuals with PARK- To date, detailed postmortem studies of nine individuals with biallelic No clear-cut genotype-phenotype correlations have been observed. Based on the International Parkinson and Movement Disorder Society Task Force for Nomenclature of Genetic Movement Disorders, the recommended name for Parkinson disease caused by Families with PARK- The population-based prevalence of PARK- The percentage of PARK- Prevalence of PARK- ## Clinical Description Parkin type of early-onset Parkinson disease (PARK- Women and men are affected with equal frequency. Age at onset is highly variable, even among individuals with the same pathogenic variant [ Clinical findings vary; however, tremor, bradykinesia, and dystonia are the most common presenting signs. Dystonia is observed in 65% (177/271) of affected individuals for whom this information is available. Almost half of affected individuals present with hyperreflexia. The diagnosis of PD may be delayed due to unusual clinical features, especially in patients with an early manifestation [ PARK- The disease is slowly progressive: disease duration of greater than 50 years has been reported. In later disease stages, freezing of gait, postural deformities, and motor fluctuations may be common features, whereas dementia usually does not develop [ Routine cranial CT and MRI scans are usually normal. PET/SPECT studies have revealed a reduced striatal Voxel-based morphometry revealed a decrease of putaminal gray matter volume and a slight increase of gray matter in the right pallidum in individuals with PARK- To date, detailed postmortem studies of nine individuals with biallelic ## Neuroimaging Routine cranial CT and MRI scans are usually normal. PET/SPECT studies have revealed a reduced striatal Voxel-based morphometry revealed a decrease of putaminal gray matter volume and a slight increase of gray matter in the right pallidum in individuals with PARK- ## Neuropathology To date, detailed postmortem studies of nine individuals with biallelic ## Genotype-Phenotype Correlations No clear-cut genotype-phenotype correlations have been observed. ## Nomenclature Based on the International Parkinson and Movement Disorder Society Task Force for Nomenclature of Genetic Movement Disorders, the recommended name for Parkinson disease caused by Families with PARK- ## Prevalence The population-based prevalence of PARK- The percentage of PARK- Prevalence of PARK- ## Genetically Related (Allelic) Disorders Multimodal neuroimaging and electrophysiologic studies disclosed latent nigrostriatal impairment, compensatory hypertrophy of the putamen and pallidum, and increased iron deposition in the substantia nigra in asymptomatic individuals heterozygous for a PET/SPECT studies have revealed that asymptomatic individuals heterozygous for a Using functional MRI, asymptomatic individuals heterozygous for a However, based on the currently available data (and lack of prospective evaluations), the role of heterozygous ## Differential Diagnosis Parkin type of early-onset Parkinson disease (PARK- PARK- Genes Associated with Early-Onset Autosomal Recessive Parkinson Disease in the Differential Diagnosis of PARK- 2nd most common cause of EOPD, after PARK- Non-motor manifestations incl psychiatric features may be more common. Heterozygotes may have ↑ risk for PD. Phenotype similar to PARK- IDD &/or seizures occasionally Risk to heterozygotes unknown Pyramidal signs IDD / early cognitive impairment Early & vivid hallucinations on intake of dopamine agonists Early falls Saccadic abnormalities Pyramidal signs IDD / early cognitive impairment Early & vivid hallucinations & behavioral abnormalities on intake of dopamine agonists Early falls Saccadic abnormalities Gaze palsy Oculogyric spasms Pyramidal signs Autonomic dysfunction Early cognitive impairment Early falls Saccadic abnormalities Gaze palsy Pyramidal signs Ataxia Autonomic dysfunction Early cognitive impairment Early falls Pyramidal signs Autonomic dysfunction EOPD = early-onset Parkinson disease; IDD = intellectual developmental disorder Nomenclature based on Data from For individuals with juvenile-onset parkinsonism, especially those with prominent dystonia, dopa-responsive dystonia should be considered: • 2nd most common cause of EOPD, after • PARK- • Non-motor manifestations incl psychiatric features may be more common. • Heterozygotes may have ↑ risk for PD. • Phenotype similar to PARK- • IDD &/or seizures occasionally • Risk to heterozygotes unknown • Pyramidal signs • IDD / early cognitive impairment • Early & vivid hallucinations on intake of dopamine agonists • Early falls • Saccadic abnormalities • Pyramidal signs • IDD / early cognitive impairment • Early & vivid hallucinations & behavioral abnormalities on intake of dopamine agonists • Early falls • Saccadic abnormalities • Gaze palsy • Oculogyric spasms • Pyramidal signs • Autonomic dysfunction • Early cognitive impairment • Early falls • Saccadic abnormalities • Gaze palsy • Pyramidal signs • Ataxia • Autonomic dysfunction • Early cognitive impairment • Early falls • Pyramidal signs • Autonomic dysfunction ## Early-Onset Parkinson Disease Parkin type of early-onset Parkinson disease (PARK- PARK- Genes Associated with Early-Onset Autosomal Recessive Parkinson Disease in the Differential Diagnosis of PARK- 2nd most common cause of EOPD, after PARK- Non-motor manifestations incl psychiatric features may be more common. Heterozygotes may have ↑ risk for PD. Phenotype similar to PARK- IDD &/or seizures occasionally Risk to heterozygotes unknown Pyramidal signs IDD / early cognitive impairment Early & vivid hallucinations on intake of dopamine agonists Early falls Saccadic abnormalities Pyramidal signs IDD / early cognitive impairment Early & vivid hallucinations & behavioral abnormalities on intake of dopamine agonists Early falls Saccadic abnormalities Gaze palsy Oculogyric spasms Pyramidal signs Autonomic dysfunction Early cognitive impairment Early falls Saccadic abnormalities Gaze palsy Pyramidal signs Ataxia Autonomic dysfunction Early cognitive impairment Early falls Pyramidal signs Autonomic dysfunction EOPD = early-onset Parkinson disease; IDD = intellectual developmental disorder Nomenclature based on Data from • 2nd most common cause of EOPD, after • PARK- • Non-motor manifestations incl psychiatric features may be more common. • Heterozygotes may have ↑ risk for PD. • Phenotype similar to PARK- • IDD &/or seizures occasionally • Risk to heterozygotes unknown • Pyramidal signs • IDD / early cognitive impairment • Early & vivid hallucinations on intake of dopamine agonists • Early falls • Saccadic abnormalities • Pyramidal signs • IDD / early cognitive impairment • Early & vivid hallucinations & behavioral abnormalities on intake of dopamine agonists • Early falls • Saccadic abnormalities • Gaze palsy • Oculogyric spasms • Pyramidal signs • Autonomic dysfunction • Early cognitive impairment • Early falls • Saccadic abnormalities • Gaze palsy • Pyramidal signs • Ataxia • Autonomic dysfunction • Early cognitive impairment • Early falls • Pyramidal signs • Autonomic dysfunction ## Dopa-Responsive Dystonia For individuals with juvenile-onset parkinsonism, especially those with prominent dystonia, dopa-responsive dystonia should be considered: ## Management To establish the extent of disease and needs in an individual diagnosed with Parkin type early-onset Parkinson disease (PARK- Assess the presence and the severity of parkinsonian signs, non-motor features, and treatment-related complications using the Unified Parkinson's disease rating scale (UPDRS) [ Assess the presence of atypical signs, such as hyperreflexia and dystonia. Evaluate the degree of response to treatment. Assess for cognitive or behavioral problems. Consider consultation with a clinical geneticist and/or genetic counselor. To date, the treatment of PARK- The motor impairment usually responds very well to low doses of dopaminergic medication; the response is typically sustained even after long disease duration. To reduce or delay side effects, levodopa doses should not exceed the levels required for satisfactory clinical response. On average, the response to low doses of levodopa is excellent and sustained. The likelihood of developing levodopa-induced dyskinesias is higher than in individuals with parkinsonism resulting from other etiologies. The most relevant treatment-related problem is the early occurrence of levodopa-induced dyskinesias (abnormal involuntary movements) and motor fluctuations. The management of treatment-related complications is not different from the strategies applied in Parkinson disease of other etiologies, and includes deep brain stimulation (DBS) in selected cases. Given its rarity, PARK- The response to DBS is favorable, including in patients with a long disease duration [ Neurologic follow up every six to 12 months to modify treatment as needed is appropriate. Neuroleptic treatment may exacerbate parkinsonism. See Pregnancy is rare in women with Parkinson disease. Only one instance of a successful pregnancy in a woman with PARK- Both levodopa and carbidopa have the ability to cross the placenta. Limited data from case reports and pregnancy registries do not suggest an increased risk of major malformations in fetuses exposed to levodopa [ Data on the risk of adverse fetal outcome from the use of other medications (e.g., dopamine agonists and anticholinergics) to treat PD manifestations during pregnancy are limited, but generally reassuring [ Worsening of parkinsonian manifestations could in part be explained by the reduction of dopaminergic replacement therapy. If possible, dopaminergic medication should be limited to levodopa/decarboxylase inhibitor to minimize the potential risk for teratogenicity at least over the course of the embryonic phase. See Search • Assess the presence and the severity of parkinsonian signs, non-motor features, and treatment-related complications using the Unified Parkinson's disease rating scale (UPDRS) [ • Assess the presence of atypical signs, such as hyperreflexia and dystonia. • Evaluate the degree of response to treatment. • Assess for cognitive or behavioral problems. • Consider consultation with a clinical geneticist and/or genetic counselor. • The motor impairment usually responds very well to low doses of dopaminergic medication; the response is typically sustained even after long disease duration. To reduce or delay side effects, levodopa doses should not exceed the levels required for satisfactory clinical response. • On average, the response to low doses of levodopa is excellent and sustained. The likelihood of developing levodopa-induced dyskinesias is higher than in individuals with parkinsonism resulting from other etiologies. • The most relevant treatment-related problem is the early occurrence of levodopa-induced dyskinesias (abnormal involuntary movements) and motor fluctuations. The management of treatment-related complications is not different from the strategies applied in Parkinson disease of other etiologies, and includes deep brain stimulation (DBS) in selected cases. Given its rarity, PARK- • The response to DBS is favorable, including in patients with a long disease duration [ ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Parkin type early-onset Parkinson disease (PARK- Assess the presence and the severity of parkinsonian signs, non-motor features, and treatment-related complications using the Unified Parkinson's disease rating scale (UPDRS) [ Assess the presence of atypical signs, such as hyperreflexia and dystonia. Evaluate the degree of response to treatment. Assess for cognitive or behavioral problems. Consider consultation with a clinical geneticist and/or genetic counselor. • Assess the presence and the severity of parkinsonian signs, non-motor features, and treatment-related complications using the Unified Parkinson's disease rating scale (UPDRS) [ • Assess the presence of atypical signs, such as hyperreflexia and dystonia. • Evaluate the degree of response to treatment. • Assess for cognitive or behavioral problems. • Consider consultation with a clinical geneticist and/or genetic counselor. ## Treatment of Manifestations To date, the treatment of PARK- The motor impairment usually responds very well to low doses of dopaminergic medication; the response is typically sustained even after long disease duration. To reduce or delay side effects, levodopa doses should not exceed the levels required for satisfactory clinical response. On average, the response to low doses of levodopa is excellent and sustained. The likelihood of developing levodopa-induced dyskinesias is higher than in individuals with parkinsonism resulting from other etiologies. The most relevant treatment-related problem is the early occurrence of levodopa-induced dyskinesias (abnormal involuntary movements) and motor fluctuations. The management of treatment-related complications is not different from the strategies applied in Parkinson disease of other etiologies, and includes deep brain stimulation (DBS) in selected cases. Given its rarity, PARK- The response to DBS is favorable, including in patients with a long disease duration [ • The motor impairment usually responds very well to low doses of dopaminergic medication; the response is typically sustained even after long disease duration. To reduce or delay side effects, levodopa doses should not exceed the levels required for satisfactory clinical response. • On average, the response to low doses of levodopa is excellent and sustained. The likelihood of developing levodopa-induced dyskinesias is higher than in individuals with parkinsonism resulting from other etiologies. • The most relevant treatment-related problem is the early occurrence of levodopa-induced dyskinesias (abnormal involuntary movements) and motor fluctuations. The management of treatment-related complications is not different from the strategies applied in Parkinson disease of other etiologies, and includes deep brain stimulation (DBS) in selected cases. Given its rarity, PARK- • The response to DBS is favorable, including in patients with a long disease duration [ ## Surveillance Neurologic follow up every six to 12 months to modify treatment as needed is appropriate. ## Agents/Circumstances to Avoid Neuroleptic treatment may exacerbate parkinsonism. ## Evaluation of Relatives at Risk See ## Pregnancy Management Pregnancy is rare in women with Parkinson disease. Only one instance of a successful pregnancy in a woman with PARK- Both levodopa and carbidopa have the ability to cross the placenta. Limited data from case reports and pregnancy registries do not suggest an increased risk of major malformations in fetuses exposed to levodopa [ Data on the risk of adverse fetal outcome from the use of other medications (e.g., dopamine agonists and anticholinergics) to treat PD manifestations during pregnancy are limited, but generally reassuring [ Worsening of parkinsonian manifestations could in part be explained by the reduction of dopaminergic replacement therapy. If possible, dopaminergic medication should be limited to levodopa/decarboxylase inhibitor to minimize the potential risk for teratogenicity at least over the course of the embryonic phase. See ## Therapies Under Investigation Search ## Genetic Counseling Parkin type of early-onset Parkinson disease (PARK- 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 the genetic status of each parent and to allow reliable recurrence risk assessment. Although the parents of a proband with PARK- Only one parent is heterozygous for a One parent is affected (based on the presence of biallelic The risk to heterozygotes of developing manifestations is not yet conclusively determined (see If each parent is known to be heterozygous for a The risk to heterozygotes of developing symptoms is not yet conclusively determined (see Unless an individual with PARK- The empiric recurrence risk to offspring of a proband depends on the frequency of heterozygotes, which is ≤3.7% in the general population [ Heterozygote testing for at-risk relatives requires prior identification of the 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, heterozygous, or at risk of being heterozygous. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The 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 the genetic status of each parent and to allow reliable recurrence risk assessment. Although the parents of a proband with PARK- • Only one parent is heterozygous for a • One parent is affected (based on the presence of biallelic • Only one parent is heterozygous for a • One parent is affected (based on the presence of biallelic • The risk to heterozygotes of developing manifestations is not yet conclusively determined (see • Only one parent is heterozygous for a • One parent is affected (based on the presence of biallelic • If each parent is known to be heterozygous for a • The risk to heterozygotes of developing symptoms is not yet conclusively determined (see • Unless an individual with PARK- • The empiric recurrence risk to offspring of a proband depends on the frequency of heterozygotes, which is ≤3.7% in the general population [ • 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, heterozygous, or at risk of being heterozygous. ## Mode of Inheritance Parkin type of early-onset Parkinson disease (PARK- ## Risk to Family Members The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm the genetic status of each parent and to allow reliable recurrence risk assessment. Although the parents of a proband with PARK- Only one parent is heterozygous for a One parent is affected (based on the presence of biallelic The risk to heterozygotes of developing manifestations is not yet conclusively determined (see If each parent is known to be heterozygous for a The risk to heterozygotes of developing symptoms is not yet conclusively determined (see Unless an individual with PARK- The empiric recurrence risk to offspring of a proband depends on the frequency of heterozygotes, which is ≤3.7% in the general population [ • 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 the genetic status of each parent and to allow reliable recurrence risk assessment. Although the parents of a proband with PARK- • Only one parent is heterozygous for a • One parent is affected (based on the presence of biallelic • Only one parent is heterozygous for a • One parent is affected (based on the presence of biallelic • The risk to heterozygotes of developing manifestations is not yet conclusively determined (see • Only one parent is heterozygous for a • One parent is affected (based on the presence of biallelic • If each parent is known to be heterozygous for a • The risk to heterozygotes of developing symptoms is not yet conclusively determined (see • Unless an individual with PARK- • The empiric recurrence risk to offspring of a proband depends on the frequency of heterozygotes, which is ≤3.7% in the general population [ ## 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, 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, heterozygous, or at risk of being heterozygous. • 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, heterozygous, or at risk of being heterozygous. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom • • • • • • • • • • United Kingdom • • • • • ## Molecular Genetics Parkin Type of Early-Onset Parkinson Disease: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Parkin Type of Early-Onset Parkinson Disease ( Parkin is also involved in the maintenance of mitochondrial function and integrity, and protection from multiple stressors, hence acting as neuroprotectant. Parkin works in a pathway with its companion protein PINK1, another protein associated with autosomal recessive early-onset parkinsonism [ Pathogenic variants may result in the accumulation of its substrates no longer appropriately targeted for degradation; however, this has not been confirmed. Notable Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions ## Molecular Pathogenesis Parkin is also involved in the maintenance of mitochondrial function and integrity, and protection from multiple stressors, hence acting as neuroprotectant. Parkin works in a pathway with its companion protein PINK1, another protein associated with autosomal recessive early-onset parkinsonism [ Pathogenic variants may result in the accumulation of its substrates no longer appropriately targeted for degradation; however, this has not been confirmed. Notable Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions ## References ## Published Guidelines / Consensus Statements ## Literature Cited ## Chapter Notes Alexis Brice, MD; Hôpital de la Pitié-Salpêtrière (2001-2013)Norbert Brüggemann, MD (2013-present)Alexandra Dürr, MD, PhD; Hôpital de la Pitié-Salpêtrière (2001-2013)Christine Klein, MD (2013-present) Christoph Lücking, MD; Ludwig-Maximilians University (2001-2013) 23 April 2020 (bp) Comprehensive update posted live 4 April 2013 (me) Comprehensive update posted live 1 October 2007 (me) Comprehensive update posted live 6 November 2006 (cd) Revision: prenatal diagnosis available 8 July 2005 (me) Comprehensive update posted live 14 November 2003 (ab) Revisions 3 October 2003 (cd) Revision: change in test availability 6 June 2003 (ca) Comprehensive update posted live 17 April 2001 (me) Review posted live November 2000 (ab) Original submission • 23 April 2020 (bp) Comprehensive update posted live • 4 April 2013 (me) Comprehensive update posted live • 1 October 2007 (me) Comprehensive update posted live • 6 November 2006 (cd) Revision: prenatal diagnosis available • 8 July 2005 (me) Comprehensive update posted live • 14 November 2003 (ab) Revisions • 3 October 2003 (cd) Revision: change in test availability • 6 June 2003 (ca) Comprehensive update posted live • 17 April 2001 (me) Review posted live • November 2000 (ab) Original submission ## Author History Alexis Brice, MD; Hôpital de la Pitié-Salpêtrière (2001-2013)Norbert Brüggemann, MD (2013-present)Alexandra Dürr, MD, PhD; Hôpital de la Pitié-Salpêtrière (2001-2013)Christine Klein, MD (2013-present) Christoph Lücking, MD; Ludwig-Maximilians University (2001-2013) ## Revision History 23 April 2020 (bp) Comprehensive update posted live 4 April 2013 (me) Comprehensive update posted live 1 October 2007 (me) Comprehensive update posted live 6 November 2006 (cd) Revision: prenatal diagnosis available 8 July 2005 (me) Comprehensive update posted live 14 November 2003 (ab) Revisions 3 October 2003 (cd) Revision: change in test availability 6 June 2003 (ca) Comprehensive update posted live 17 April 2001 (me) Review posted live November 2000 (ab) Original submission • 23 April 2020 (bp) Comprehensive update posted live • 4 April 2013 (me) Comprehensive update posted live • 1 October 2007 (me) Comprehensive update posted live • 6 November 2006 (cd) Revision: prenatal diagnosis available • 8 July 2005 (me) Comprehensive update posted live • 14 November 2003 (ab) Revisions • 3 October 2003 (cd) Revision: change in test availability • 6 June 2003 (ca) Comprehensive update posted live • 17 April 2001 (me) Review posted live • November 2000 (ab) Original submission	[]	17/4/2001	23/4/2020		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
jps	jps	[ "Juvenile Polyposis Syndrome / Hereditary Hemorrhagic Telangiectasia (JPS/HHT)", "Bone morphogenetic protein receptor type-1A", "Mothers against decapentaplegic homolog 4", "BMPR1A", "SMAD4", "Juvenile Polyposis Syndrome" ]	Juvenile Polyposis Syndrome	Joy Larsen Haidle, Suzanne P MacFarland, James R Howe	Summary Juvenile polyposis syndrome (JPS) is characterized by predisposition to hamartomatous polyps in the gastrointestinal (GI) tract, specifically in the stomach, small intestine, colon, and rectum. The term "juvenile" refers to the type of polyp rather than to the age of onset of polyps. Most individuals with JPS have some polyps by age 20 years; some may have only four or five polyps over their lifetime, whereas others in the same family may have more than 100. If the polyps are left untreated, they may cause bleeding and anemia. Most juvenile polyps are benign; however, malignant transformation can occur. Risk for GI cancers ranges from 11% to 86%. Most of this increased risk is attributed to colon cancer, but cancers of the stomach, upper GI tract, and pancreas have also been reported. A combined syndrome of JPS and hereditary hemorrhagic telangiectasia (HHT) is present in most individuals with an The diagnosis of JPS is established in a proband with any of the following: more than five juvenile polyps of the colorectum; multiple juvenile polyps throughout the GI tract; or any number of juvenile polyps and a family history of juvenile polyposis. Identification of a heterozygous pathogenic variant in JPS is inherited in an autosomal dominant manner. Up to half of individuals with JPS have an affected parent; approximately 50% of probands with JPS have no previous history of polyps in the family and may have the disorder as the result of a	Juvenile polyposis syndrome (JPS) Juvenile polyposis syndrome / hereditary hemorrhagic telangiectasia (JPS/HHT) For synonyms and outdated names see • Juvenile polyposis syndrome (JPS) • Juvenile polyposis syndrome / hereditary hemorrhagic telangiectasia (JPS/HHT) ## Diagnosis Juvenile polyposis syndrome (JPS) Anemia, rectal bleeding, or prolapse of rectal polyp More than one juvenile polyp One or more juvenile polyps and a family history of JPS Note: "Juvenile" refers to the polyp histopathology, not the age of onset of polyps. Note: Variability in histopathology has been reported in polyps associated with juvenile polyposis syndrome / hereditary hemorrhagic telangiectasia (JPS/HHT) (see The diagnosis of JPS More than five juvenile polyps of the colon or rectum Multiple juvenile polyps of the upper and lower gastrointestinal tract Any number of juvenile polyps and a family history of juvenile polyposis Identification of a heterozygous pathogenic (or likely pathogenic) variant in one of the genes listed in Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include Sequence analysis and deletion/duplication analysis of Sequence analysis and deletion/duplication analysis of Consider molecular genetic testing of additional HHT-related genes if an Deletions of 10q22-q23 detectable by * If no pathogenic variant is found, molecular genetic testing of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Juvenile Polyposis Syndrome NA = not applicable See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 the Two individuals with early-onset JPS have been found to have • Anemia, rectal bleeding, or prolapse of rectal polyp • More than one juvenile polyp • One or more juvenile polyps and a family history of JPS • More than five juvenile polyps of the colon or rectum • Multiple juvenile polyps of the upper and lower gastrointestinal tract • Any number of juvenile polyps and a family history of juvenile polyposis • Identification of a heterozygous pathogenic (or likely pathogenic) variant in one of the genes listed in • Sequence analysis and deletion/duplication analysis of • Sequence analysis and deletion/duplication analysis of • Consider molecular genetic testing of additional HHT-related genes if an • Sequence analysis and deletion/duplication analysis of • Sequence analysis and deletion/duplication analysis of • Consider molecular genetic testing of additional HHT-related genes if an • Deletions of 10q22-q23 detectable by • * If no pathogenic variant is found, molecular genetic testing of • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click • Sequence analysis and deletion/duplication analysis of • Sequence analysis and deletion/duplication analysis of • Consider molecular genetic testing of additional HHT-related genes if an ## Suggestive Findings Juvenile polyposis syndrome (JPS) Anemia, rectal bleeding, or prolapse of rectal polyp More than one juvenile polyp One or more juvenile polyps and a family history of JPS Note: "Juvenile" refers to the polyp histopathology, not the age of onset of polyps. Note: Variability in histopathology has been reported in polyps associated with juvenile polyposis syndrome / hereditary hemorrhagic telangiectasia (JPS/HHT) (see • Anemia, rectal bleeding, or prolapse of rectal polyp • More than one juvenile polyp • One or more juvenile polyps and a family history of JPS ## Establishing the Diagnosis The diagnosis of JPS More than five juvenile polyps of the colon or rectum Multiple juvenile polyps of the upper and lower gastrointestinal tract Any number of juvenile polyps and a family history of juvenile polyposis Identification of a heterozygous pathogenic (or likely pathogenic) variant in one of the genes listed in Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include Sequence analysis and deletion/duplication analysis of Sequence analysis and deletion/duplication analysis of Consider molecular genetic testing of additional HHT-related genes if an Deletions of 10q22-q23 detectable by * If no pathogenic variant is found, molecular genetic testing of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Juvenile Polyposis Syndrome NA = not applicable See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 the Two individuals with early-onset JPS have been found to have • More than five juvenile polyps of the colon or rectum • Multiple juvenile polyps of the upper and lower gastrointestinal tract • Any number of juvenile polyps and a family history of juvenile polyposis • Identification of a heterozygous pathogenic (or likely pathogenic) variant in one of the genes listed in • Sequence analysis and deletion/duplication analysis of • Sequence analysis and deletion/duplication analysis of • Consider molecular genetic testing of additional HHT-related genes if an • Sequence analysis and deletion/duplication analysis of • Sequence analysis and deletion/duplication analysis of • Consider molecular genetic testing of additional HHT-related genes if an • Deletions of 10q22-q23 detectable by • * If no pathogenic variant is found, molecular genetic testing of • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click • Sequence analysis and deletion/duplication analysis of • Sequence analysis and deletion/duplication analysis of • Consider molecular genetic testing of additional HHT-related genes if an ## Clinical Characteristics JPS is characterized by predisposition to hamartomatous polyps in the gastrointestinal (GI) tract, specifically in the stomach, small intestine, colon, and rectum. "Generalized juvenile polyposis" refers to polyps of the upper and lower GI tract. "Juvenile polyposis coli" refers to polyps of the colon only. The polyps vary in size and shape: some are flat (sessile), whereas others have a stalk (pedunculated). The number of polyps in individuals with JPS varies. Some individuals may have only four or five polyps over their lifetime; others in the same family may have more than 100. Bleeding may result from sloughing of the polyp or its surface epithelium with the passage of stool. If the polyps are left untreated, they may cause bleeding and anemia. Juvenile polyps develop from infancy through adulthood. Most individuals with JPS have some polyps by age 20 years. In juvenile polyposis of infancy, associated with a contiguous deletion of The incidence of colorectal cancer is 17%-22% by age 35 years and approaches 68% by age 60 years. The median age at diagnosis is 42 years. The incidence of gastric cancer is 21% in those with gastric polyps. The relative risk for colorectal cancer was 34.0% in individuals with JPS. The mean age of diagnosis of colorectal cancer was 43.9 years, with a cumulative lifetime risk of 38.7% [ Historically, the cancer incidence in one large family with a germline Individuals with JPS/HHT have variable findings of juvenile polyposis and Clinical Features of AVM = arteriovenous malformation See Thoracic aortic disease (e.g., aortic root dilatation, aneurysm, and aortic dissection) and mitral valve dysfunction have been reported in individuals with Genotype-phenotype correlations in general are weak; family members with JPS and the same pathogenic variant can have a few polyps or more than 100. The age at which polyps develop can vary from the first decade to beyond the fourth decade among affected members of the same family. Some generalizations: Individuals with Colorectal cancer occurs more frequently than other cancers in Individuals with either an There is some evidence that in individuals without a germline JPS/HHT is associated with One study evaluating 34 affected individuals with an Familial juvenile polyposis is an older term used to distinguish between simplex (i.e., a single affected individual in a family) and familial cases. The incidence of JPS has been estimated to range between 1:16,000 and 1:100,000. • The incidence of colorectal cancer is 17%-22% by age 35 years and approaches 68% by age 60 years. The median age at diagnosis is 42 years. • The incidence of gastric cancer is 21% in those with gastric polyps. • The relative risk for colorectal cancer was 34.0% in individuals with JPS. The mean age of diagnosis of colorectal cancer was 43.9 years, with a cumulative lifetime risk of 38.7% [ • Individuals with • Colorectal cancer occurs more frequently than other cancers in • Individuals with either an • There is some evidence that in individuals without a germline • JPS/HHT is associated with ## Clinical Description JPS is characterized by predisposition to hamartomatous polyps in the gastrointestinal (GI) tract, specifically in the stomach, small intestine, colon, and rectum. "Generalized juvenile polyposis" refers to polyps of the upper and lower GI tract. "Juvenile polyposis coli" refers to polyps of the colon only. The polyps vary in size and shape: some are flat (sessile), whereas others have a stalk (pedunculated). The number of polyps in individuals with JPS varies. Some individuals may have only four or five polyps over their lifetime; others in the same family may have more than 100. Bleeding may result from sloughing of the polyp or its surface epithelium with the passage of stool. If the polyps are left untreated, they may cause bleeding and anemia. Juvenile polyps develop from infancy through adulthood. Most individuals with JPS have some polyps by age 20 years. In juvenile polyposis of infancy, associated with a contiguous deletion of The incidence of colorectal cancer is 17%-22% by age 35 years and approaches 68% by age 60 years. The median age at diagnosis is 42 years. The incidence of gastric cancer is 21% in those with gastric polyps. The relative risk for colorectal cancer was 34.0% in individuals with JPS. The mean age of diagnosis of colorectal cancer was 43.9 years, with a cumulative lifetime risk of 38.7% [ Historically, the cancer incidence in one large family with a germline Individuals with JPS/HHT have variable findings of juvenile polyposis and Clinical Features of AVM = arteriovenous malformation See Thoracic aortic disease (e.g., aortic root dilatation, aneurysm, and aortic dissection) and mitral valve dysfunction have been reported in individuals with • The incidence of colorectal cancer is 17%-22% by age 35 years and approaches 68% by age 60 years. The median age at diagnosis is 42 years. • The incidence of gastric cancer is 21% in those with gastric polyps. • The relative risk for colorectal cancer was 34.0% in individuals with JPS. The mean age of diagnosis of colorectal cancer was 43.9 years, with a cumulative lifetime risk of 38.7% [ ## Juvenile Polyposis Syndrome (JPS) JPS is characterized by predisposition to hamartomatous polyps in the gastrointestinal (GI) tract, specifically in the stomach, small intestine, colon, and rectum. "Generalized juvenile polyposis" refers to polyps of the upper and lower GI tract. "Juvenile polyposis coli" refers to polyps of the colon only. The polyps vary in size and shape: some are flat (sessile), whereas others have a stalk (pedunculated). The number of polyps in individuals with JPS varies. Some individuals may have only four or five polyps over their lifetime; others in the same family may have more than 100. Bleeding may result from sloughing of the polyp or its surface epithelium with the passage of stool. If the polyps are left untreated, they may cause bleeding and anemia. Juvenile polyps develop from infancy through adulthood. Most individuals with JPS have some polyps by age 20 years. In juvenile polyposis of infancy, associated with a contiguous deletion of The incidence of colorectal cancer is 17%-22% by age 35 years and approaches 68% by age 60 years. The median age at diagnosis is 42 years. The incidence of gastric cancer is 21% in those with gastric polyps. The relative risk for colorectal cancer was 34.0% in individuals with JPS. The mean age of diagnosis of colorectal cancer was 43.9 years, with a cumulative lifetime risk of 38.7% [ Historically, the cancer incidence in one large family with a germline • The incidence of colorectal cancer is 17%-22% by age 35 years and approaches 68% by age 60 years. The median age at diagnosis is 42 years. • The incidence of gastric cancer is 21% in those with gastric polyps. • The relative risk for colorectal cancer was 34.0% in individuals with JPS. The mean age of diagnosis of colorectal cancer was 43.9 years, with a cumulative lifetime risk of 38.7% [ ## Juvenile Polyposis Syndrome / Hereditary Hemorrhagic Telangiectasia (JPS/HHT) Individuals with JPS/HHT have variable findings of juvenile polyposis and Clinical Features of AVM = arteriovenous malformation See Thoracic aortic disease (e.g., aortic root dilatation, aneurysm, and aortic dissection) and mitral valve dysfunction have been reported in individuals with ## Genotype-Phenotype Correlations Genotype-phenotype correlations in general are weak; family members with JPS and the same pathogenic variant can have a few polyps or more than 100. The age at which polyps develop can vary from the first decade to beyond the fourth decade among affected members of the same family. Some generalizations: Individuals with Colorectal cancer occurs more frequently than other cancers in Individuals with either an There is some evidence that in individuals without a germline JPS/HHT is associated with • Individuals with • Colorectal cancer occurs more frequently than other cancers in • Individuals with either an • There is some evidence that in individuals without a germline • JPS/HHT is associated with ## Penetrance One study evaluating 34 affected individuals with an ## Nomenclature Familial juvenile polyposis is an older term used to distinguish between simplex (i.e., a single affected individual in a family) and familial cases. ## Prevalence The incidence of JPS has been estimated to range between 1:16,000 and 1:100,000. ## Genetically Related (Allelic) Disorders Germline Deletions of 10q22-q23 that include One individual with an intragenic Homozygous Heterozygous gain-of-function ## Germline Deletions of 10q22-q23 that include One individual with an intragenic Homozygous ## Heterozygous gain-of-function ## Differential Diagnosis A juvenile polyp can result from genetic predisposition or chance. It should be noted that 1% to 2% of individuals in the general population develop a solitary juvenile polyp and do not meet diagnostic criteria for juvenile polyposis syndrome (JPS). Genetic predisposition syndromes characterized by the presence of polyps are summarized in Polyp Predisposition Syndromes in the Differential Diagnosis of Juvenile Polyposis Syndrome Significant colorectal cancer risk AD = autosomal dominant; AR = autosomal recessive; ASD = autism spectrum disorder; DD = developmental delay; GI = gastrointestinal; MOI = mode of inheritance Duplications of 15q13-q14 lead to overexpression of ## Management Clinical practice guidelines for juvenile polyposis syndrome have been published [ To establish the extent of disease and needs in an individual diagnosed with juvenile polyposis syndrome (JPS), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Juvenile Polyposis Syndrome Complete blood count Colonoscopy Upper endoscopy Evaluate for complications related to Consider transthoracic echocardiogram. At diagnosis in those w/ Note: Recommended age at first transthoracic echocardiogram has not been determined. HHT = hereditary hemorrhagic telangiectasia; MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse Treatment of Manifestations in Individuals with Juvenile Polyposis Syndrome Partial or total gastrectomy Partial or total colectomy (subtotal colectomy w/ileorectal anastomosis or proctocolectomy w/ileoanal pouch) Iron replacement (oral or parenteral if needed) Red blood cell transfusion as needed AVM = arteriovenous malformation; GI = gastrointestinal The preferred procedure is debated. The number of colonic or rectal polyps does not appear to correlate with the need for proctectomy [ The surveillance recommended in Recommended Surveillance for Individuals with Juvenile Polyposis Syndrome Colonoscopy Upper endoscopy Note: Following surgical bowel resection, continue screening for polyps in remaining colon, rectum, & ileal pouch. Every 3 yrs beginning at age 15 yrs or earlier if symptomatic If polyps are found: following polyp treatment, annual screening until no polyps are found, then screening every 3 yrs In those w/o germline See Consider transthoracic echocardiogram. Individuals with significant epistaxis are advised to avoid vigorous nose blowing, lifting of heavy objects, straining during bowel movements, and finger manipulation in the nose. Some individuals with HHT experience increased epistaxis after drinking alcohol. Most otolaryngologists with experience treating individuals with HHT advise against electric and chemical cautery and transcatheter embolotherapy for treatment of recurrent nosebleeds. Anticoagulants including aspirin and nonsteroidal anti-inflammatory agents such as ibuprofen that interfere with normal clotting should be avoided unless required for treatment of other medical conditions. In one study, lower-dose agents, particularly anti-platelet agents, were not associated with hemorrhage in a high proportion of affected individuals. The findings support the use of antiplatelet or anticoagulant agents, with caution, if there is a very strong indication for their use [ Scuba diving should be avoided unless contrast echocardiography performed within the last five years was negative for evidence of a right-to-left shunt. Liver biopsy should be avoided [ It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from early surveillance and intervention. In families in which findings suggest JPS or families with a known Molecular genetic testing at or prior to age 15 years if the pathogenic variant in the family is known; If the familial pathogenic variant is not known, complete blood count (CBC) and lower intestinal endoscopy in individuals age 15 years an older. Normal results do not rule out a diagnosis of JPS (see In families in which findings suggest juvenile polyposis syndrome / hereditary hemorrhagic telangiectasia (JPS/HHT) or families with a known Molecular genetic testing before age 15 years for children at risk for a known familial In families in which findings suggest JPS/HHT but the familial pathogenic variant is not known: CBC and lower intestinal endoscopy in individuals age 15 years an older, or earlier if symptoms of polyposis. Normal results do not rule out a diagnosis of JPS (see In individuals older than age 40 years, targeted medical history and clinical examination for features of HHT. The absence of mild but recurrent epistaxis and subtle telangiectases in characteristic locations on careful examination is reassuring (see In individuals age 40 years and younger, targeted medical history and clinical examination for features of HHT as well as initial evaluation for brain and pulmonary arteriovenous malformations, as features of HHT may not be identified by medical history and clinical examination in younger individuals See See In individuals with juvenile polyposis of infancy due to deletion of both Search No known chemoprevention options are effective for juvenile polyps. • Complete blood count • Colonoscopy • Upper endoscopy • Evaluate for complications related to • Consider transthoracic echocardiogram. • At diagnosis in those w/ • Note: Recommended age at first transthoracic echocardiogram has not been determined. • Partial or total gastrectomy • Partial or total colectomy (subtotal colectomy w/ileorectal anastomosis or proctocolectomy w/ileoanal pouch) • Iron replacement (oral or parenteral if needed) • Red blood cell transfusion as needed • Colonoscopy • Upper endoscopy • Note: Following surgical bowel resection, continue screening for polyps in remaining colon, rectum, & ileal pouch. • Every 3 yrs beginning at age 15 yrs or earlier if symptomatic • If polyps are found: following polyp treatment, annual screening until no polyps are found, then screening every 3 yrs • In those w/o germline • See • Consider transthoracic echocardiogram. • Individuals with significant epistaxis are advised to avoid vigorous nose blowing, lifting of heavy objects, straining during bowel movements, and finger manipulation in the nose. Some individuals with HHT experience increased epistaxis after drinking alcohol. • Most otolaryngologists with experience treating individuals with HHT advise against electric and chemical cautery and transcatheter embolotherapy for treatment of recurrent nosebleeds. • Anticoagulants including aspirin and nonsteroidal anti-inflammatory agents such as ibuprofen that interfere with normal clotting should be avoided unless required for treatment of other medical conditions. In one study, lower-dose agents, particularly anti-platelet agents, were not associated with hemorrhage in a high proportion of affected individuals. The findings support the use of antiplatelet or anticoagulant agents, with caution, if there is a very strong indication for their use [ • Scuba diving should be avoided unless contrast echocardiography performed within the last five years was negative for evidence of a right-to-left shunt. • Liver biopsy should be avoided [ • Molecular genetic testing at or prior to age 15 years if the pathogenic variant in the family is known; • If the familial pathogenic variant is not known, complete blood count (CBC) and lower intestinal endoscopy in individuals age 15 years an older. Normal results do not rule out a diagnosis of JPS (see • Molecular genetic testing before age 15 years for children at risk for a known familial • In families in which findings suggest JPS/HHT but the familial pathogenic variant is not known: • CBC and lower intestinal endoscopy in individuals age 15 years an older, or earlier if symptoms of polyposis. Normal results do not rule out a diagnosis of JPS (see • In individuals older than age 40 years, targeted medical history and clinical examination for features of HHT. The absence of mild but recurrent epistaxis and subtle telangiectases in characteristic locations on careful examination is reassuring (see • In individuals age 40 years and younger, targeted medical history and clinical examination for features of HHT as well as initial evaluation for brain and pulmonary arteriovenous malformations, as features of HHT may not be identified by medical history and clinical examination in younger individuals • CBC and lower intestinal endoscopy in individuals age 15 years an older, or earlier if symptoms of polyposis. Normal results do not rule out a diagnosis of JPS (see • In individuals older than age 40 years, targeted medical history and clinical examination for features of HHT. The absence of mild but recurrent epistaxis and subtle telangiectases in characteristic locations on careful examination is reassuring (see • In individuals age 40 years and younger, targeted medical history and clinical examination for features of HHT as well as initial evaluation for brain and pulmonary arteriovenous malformations, as features of HHT may not be identified by medical history and clinical examination in younger individuals • CBC and lower intestinal endoscopy in individuals age 15 years an older, or earlier if symptoms of polyposis. Normal results do not rule out a diagnosis of JPS (see • In individuals older than age 40 years, targeted medical history and clinical examination for features of HHT. The absence of mild but recurrent epistaxis and subtle telangiectases in characteristic locations on careful examination is reassuring (see • In individuals age 40 years and younger, targeted medical history and clinical examination for features of HHT as well as initial evaluation for brain and pulmonary arteriovenous malformations, as features of HHT may not be identified by medical history and clinical examination in younger individuals ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with juvenile polyposis syndrome (JPS), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Juvenile Polyposis Syndrome Complete blood count Colonoscopy Upper endoscopy Evaluate for complications related to Consider transthoracic echocardiogram. At diagnosis in those w/ Note: Recommended age at first transthoracic echocardiogram has not been determined. HHT = hereditary hemorrhagic telangiectasia; MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Complete blood count • Colonoscopy • Upper endoscopy • Evaluate for complications related to • Consider transthoracic echocardiogram. • At diagnosis in those w/ • Note: Recommended age at first transthoracic echocardiogram has not been determined. ## Treatment of Manifestations Treatment of Manifestations in Individuals with Juvenile Polyposis Syndrome Partial or total gastrectomy Partial or total colectomy (subtotal colectomy w/ileorectal anastomosis or proctocolectomy w/ileoanal pouch) Iron replacement (oral or parenteral if needed) Red blood cell transfusion as needed AVM = arteriovenous malformation; GI = gastrointestinal The preferred procedure is debated. The number of colonic or rectal polyps does not appear to correlate with the need for proctectomy [ • Partial or total gastrectomy • Partial or total colectomy (subtotal colectomy w/ileorectal anastomosis or proctocolectomy w/ileoanal pouch) • Iron replacement (oral or parenteral if needed) • Red blood cell transfusion as needed ## Surveillance The surveillance recommended in Recommended Surveillance for Individuals with Juvenile Polyposis Syndrome Colonoscopy Upper endoscopy Note: Following surgical bowel resection, continue screening for polyps in remaining colon, rectum, & ileal pouch. Every 3 yrs beginning at age 15 yrs or earlier if symptomatic If polyps are found: following polyp treatment, annual screening until no polyps are found, then screening every 3 yrs In those w/o germline See Consider transthoracic echocardiogram. • Colonoscopy • Upper endoscopy • Note: Following surgical bowel resection, continue screening for polyps in remaining colon, rectum, & ileal pouch. • Every 3 yrs beginning at age 15 yrs or earlier if symptomatic • If polyps are found: following polyp treatment, annual screening until no polyps are found, then screening every 3 yrs • In those w/o germline • See • Consider transthoracic echocardiogram. ## Agents/Circumstances to Avoid Individuals with significant epistaxis are advised to avoid vigorous nose blowing, lifting of heavy objects, straining during bowel movements, and finger manipulation in the nose. Some individuals with HHT experience increased epistaxis after drinking alcohol. Most otolaryngologists with experience treating individuals with HHT advise against electric and chemical cautery and transcatheter embolotherapy for treatment of recurrent nosebleeds. Anticoagulants including aspirin and nonsteroidal anti-inflammatory agents such as ibuprofen that interfere with normal clotting should be avoided unless required for treatment of other medical conditions. In one study, lower-dose agents, particularly anti-platelet agents, were not associated with hemorrhage in a high proportion of affected individuals. The findings support the use of antiplatelet or anticoagulant agents, with caution, if there is a very strong indication for their use [ Scuba diving should be avoided unless contrast echocardiography performed within the last five years was negative for evidence of a right-to-left shunt. Liver biopsy should be avoided [ • Individuals with significant epistaxis are advised to avoid vigorous nose blowing, lifting of heavy objects, straining during bowel movements, and finger manipulation in the nose. Some individuals with HHT experience increased epistaxis after drinking alcohol. • Most otolaryngologists with experience treating individuals with HHT advise against electric and chemical cautery and transcatheter embolotherapy for treatment of recurrent nosebleeds. • Anticoagulants including aspirin and nonsteroidal anti-inflammatory agents such as ibuprofen that interfere with normal clotting should be avoided unless required for treatment of other medical conditions. In one study, lower-dose agents, particularly anti-platelet agents, were not associated with hemorrhage in a high proportion of affected individuals. The findings support the use of antiplatelet or anticoagulant agents, with caution, if there is a very strong indication for their use [ • Scuba diving should be avoided unless contrast echocardiography performed within the last five years was negative for evidence of a right-to-left shunt. • Liver biopsy should be avoided [ ## Evaluation of Relatives at Risk It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from early surveillance and intervention. In families in which findings suggest JPS or families with a known Molecular genetic testing at or prior to age 15 years if the pathogenic variant in the family is known; If the familial pathogenic variant is not known, complete blood count (CBC) and lower intestinal endoscopy in individuals age 15 years an older. Normal results do not rule out a diagnosis of JPS (see In families in which findings suggest juvenile polyposis syndrome / hereditary hemorrhagic telangiectasia (JPS/HHT) or families with a known Molecular genetic testing before age 15 years for children at risk for a known familial In families in which findings suggest JPS/HHT but the familial pathogenic variant is not known: CBC and lower intestinal endoscopy in individuals age 15 years an older, or earlier if symptoms of polyposis. Normal results do not rule out a diagnosis of JPS (see In individuals older than age 40 years, targeted medical history and clinical examination for features of HHT. The absence of mild but recurrent epistaxis and subtle telangiectases in characteristic locations on careful examination is reassuring (see In individuals age 40 years and younger, targeted medical history and clinical examination for features of HHT as well as initial evaluation for brain and pulmonary arteriovenous malformations, as features of HHT may not be identified by medical history and clinical examination in younger individuals See • Molecular genetic testing at or prior to age 15 years if the pathogenic variant in the family is known; • If the familial pathogenic variant is not known, complete blood count (CBC) and lower intestinal endoscopy in individuals age 15 years an older. Normal results do not rule out a diagnosis of JPS (see • Molecular genetic testing before age 15 years for children at risk for a known familial • In families in which findings suggest JPS/HHT but the familial pathogenic variant is not known: • CBC and lower intestinal endoscopy in individuals age 15 years an older, or earlier if symptoms of polyposis. Normal results do not rule out a diagnosis of JPS (see • In individuals older than age 40 years, targeted medical history and clinical examination for features of HHT. The absence of mild but recurrent epistaxis and subtle telangiectases in characteristic locations on careful examination is reassuring (see • In individuals age 40 years and younger, targeted medical history and clinical examination for features of HHT as well as initial evaluation for brain and pulmonary arteriovenous malformations, as features of HHT may not be identified by medical history and clinical examination in younger individuals • CBC and lower intestinal endoscopy in individuals age 15 years an older, or earlier if symptoms of polyposis. Normal results do not rule out a diagnosis of JPS (see • In individuals older than age 40 years, targeted medical history and clinical examination for features of HHT. The absence of mild but recurrent epistaxis and subtle telangiectases in characteristic locations on careful examination is reassuring (see • In individuals age 40 years and younger, targeted medical history and clinical examination for features of HHT as well as initial evaluation for brain and pulmonary arteriovenous malformations, as features of HHT may not be identified by medical history and clinical examination in younger individuals • CBC and lower intestinal endoscopy in individuals age 15 years an older, or earlier if symptoms of polyposis. Normal results do not rule out a diagnosis of JPS (see • In individuals older than age 40 years, targeted medical history and clinical examination for features of HHT. The absence of mild but recurrent epistaxis and subtle telangiectases in characteristic locations on careful examination is reassuring (see • In individuals age 40 years and younger, targeted medical history and clinical examination for features of HHT as well as initial evaluation for brain and pulmonary arteriovenous malformations, as features of HHT may not be identified by medical history and clinical examination in younger individuals ## Pregnancy Management See ## Therapies Under Investigation In individuals with juvenile polyposis of infancy due to deletion of both Search ## Other No known chemoprevention options are effective for juvenile polyps. ## Genetic Counseling Juvenile polyposis syndrome (JPS) is inherited in an autosomal dominant manner. Up to half of individuals diagnosed with JPS have an affected parent. Approximately 50% of individuals diagnosed with JPS have no previous history of polyps in the family and 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), evaluation of the parents is recommended in order to clarify their genetic/clinical status and to assess the risk of JPS in sibs and other relatives. Recommendations for the evaluation of parents of a proband include the following: Molecular genetic testing if a causative Screening/ If the proband has a known pathogenic variant that cannot be identified in either parent and parental identified testing has confirmed 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 JPS may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance and variable expressivity, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or appropriate 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%. Intrafamilial variability (including variable symptoms, ages of onset, and cancer risks) has been reported among family members who are heterozygous for the same If the proband has a known JPS-causing pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [ If the genetic status of the parents is unknown (and/or a molecular diagnosis has not been established in the proband), sibs should be considered at risk for JPS (regardless of whether parents have had manifestations of the disorder) and offered molecular genetic testing and screening/ 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. If symptoms of JPS appear before age 15 years, surveillance should begin at that time and disclosure of molecular genetic test results may be a reasonable option. It is important to consider the risks and benefits for children of learning this information at a young age and to consider ways to discuss this information with children and to answer their questions. See Management, Once the JPS-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for JPS 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. • Up to half of individuals diagnosed with JPS have an affected parent. • Approximately 50% of individuals diagnosed with JPS have no previous history of polyps in the family and 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), evaluation of the parents is recommended in order to clarify their genetic/clinical status and to assess the risk of JPS in sibs and other relatives. Recommendations for the evaluation of parents of a proband include the following: • Molecular genetic testing if a causative • Screening/ • Molecular genetic testing if a causative • Screening/ • If the proband has a known pathogenic variant that cannot be identified in either parent and parental identified testing has confirmed 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 JPS may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance and variable expressivity, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or appropriate molecular genetic testing has been performed on the parents of the proband. • Molecular genetic testing if a causative • Screening/ • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. • Intrafamilial variability (including variable symptoms, ages of onset, and cancer risks) has been reported among family members who are heterozygous for the same • If the proband has a known JPS-causing pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [ • If the genetic status of the parents is unknown (and/or a molecular diagnosis has not been established in the proband), sibs should be considered at risk for JPS (regardless of whether parents have had manifestations of the disorder) and offered molecular genetic testing and screening/ • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • If symptoms of JPS appear before age 15 years, surveillance should begin at that time and disclosure of molecular genetic test results may be a reasonable option. It is important to consider the risks and benefits for children of learning this information at a young age and to consider ways to discuss this information with children and to answer their questions. ## Mode of Inheritance Juvenile polyposis syndrome (JPS) is inherited in an autosomal dominant manner. ## Risk to Family Members Up to half of individuals diagnosed with JPS have an affected parent. Approximately 50% of individuals diagnosed with JPS have no previous history of polyps in the family and 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), evaluation of the parents is recommended in order to clarify their genetic/clinical status and to assess the risk of JPS in sibs and other relatives. Recommendations for the evaluation of parents of a proband include the following: Molecular genetic testing if a causative Screening/ If the proband has a known pathogenic variant that cannot be identified in either parent and parental identified testing has confirmed 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 JPS may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance and variable expressivity, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or appropriate 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%. Intrafamilial variability (including variable symptoms, ages of onset, and cancer risks) has been reported among family members who are heterozygous for the same If the proband has a known JPS-causing pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [ If the genetic status of the parents is unknown (and/or a molecular diagnosis has not been established in the proband), sibs should be considered at risk for JPS (regardless of whether parents have had manifestations of the disorder) and offered molecular genetic testing and screening/ • Up to half of individuals diagnosed with JPS have an affected parent. • Approximately 50% of individuals diagnosed with JPS have no previous history of polyps in the family and 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), evaluation of the parents is recommended in order to clarify their genetic/clinical status and to assess the risk of JPS in sibs and other relatives. Recommendations for the evaluation of parents of a proband include the following: • Molecular genetic testing if a causative • Screening/ • Molecular genetic testing if a causative • Screening/ • If the proband has a known pathogenic variant that cannot be identified in either parent and parental identified testing has confirmed 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 JPS may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance and variable expressivity, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or appropriate molecular genetic testing has been performed on the parents of the proband. • Molecular genetic testing if a causative • Screening/ • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. • Intrafamilial variability (including variable symptoms, ages of onset, and cancer risks) has been reported among family members who are heterozygous for the same • If the proband has a known JPS-causing pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [ • If the genetic status of the parents is unknown (and/or a molecular diagnosis has not been established in the proband), sibs should be considered at risk for JPS (regardless of whether parents have had manifestations of the disorder) and offered molecular genetic testing and screening/ ## 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. If symptoms of JPS appear before age 15 years, surveillance should begin at that time and disclosure of molecular genetic test results may be a reasonable option. It is important to consider the risks and benefits for children of learning this information at a young age and to consider ways to discuss this information with children and to answer their questions. 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. • If symptoms of JPS appear before age 15 years, surveillance should begin at that time and disclosure of molecular genetic test results may be a reasonable option. It is important to consider the risks and benefits for children of learning this information at a young age and to consider ways to discuss this information with children and to answer their questions. ## Prenatal Testing and Preimplantation Genetic Testing Once the JPS-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for JPS are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • • • ## Molecular Genetics Juvenile Polyposis Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Juvenile Polyposis Syndrome ( The mechanism of juvenile polyp formation as a consequence of germline pathogenic variants in Most Most Somatic ## Molecular Pathogenesis The mechanism of juvenile polyp formation as a consequence of germline pathogenic variants in Most Most ## Cancer and Benign Tumors Somatic ## Chapter Notes Dr James R Howe is a surgical oncologist and primary researcher in the field of juvenile polyposis syndrome. Joy Larsen Haidle is a genetic counselor with the Cancer Genetics program at North Memorial Health Cancer Center who is actively involved in the development of genetic counseling guidelines with Dr Howe's research program. Dr Suzanne P MacFarland is a pediatric oncologist and cancer predisposition researcher in the field of juvenile polyposis syndrome. She runs a multidisciplinary polyposis clinic at the Children's Hospital of Philadelphia. 3 February 2022 (sw) Comprehensive update posted live 9 March 2017 (sw) Comprehensive update posted live 3 December 2015 (jrh) Revision: corrections to 22 May 2014 (me) Comprehensive update posted live 29 September 2011 (me) Comprehensive update posted live 9 September 2008 (me) Comprehensive update posted live 22 February 2007 (cd) Revision: prenatal diagnosis available for 2 November 2006 (cd) Revision: prenatal diagnosis available for 13 June 2005 (me) Comprehensive update posted live 20 May 2004 (cd) Revision: Genetic Counseling 27 October 2003 (cd) Revision: Statements and Policies 13 May 2003 (me) Review posted live 4 January 2003 (jrh) Original submission • 3 February 2022 (sw) Comprehensive update posted live • 9 March 2017 (sw) Comprehensive update posted live • 3 December 2015 (jrh) Revision: corrections to • 22 May 2014 (me) Comprehensive update posted live • 29 September 2011 (me) Comprehensive update posted live • 9 September 2008 (me) Comprehensive update posted live • 22 February 2007 (cd) Revision: prenatal diagnosis available for • 2 November 2006 (cd) Revision: prenatal diagnosis available for • 13 June 2005 (me) Comprehensive update posted live • 20 May 2004 (cd) Revision: Genetic Counseling • 27 October 2003 (cd) Revision: Statements and Policies • 13 May 2003 (me) Review posted live • 4 January 2003 (jrh) Original submission ## Author Notes Dr James R Howe is a surgical oncologist and primary researcher in the field of juvenile polyposis syndrome. Joy Larsen Haidle is a genetic counselor with the Cancer Genetics program at North Memorial Health Cancer Center who is actively involved in the development of genetic counseling guidelines with Dr Howe's research program. Dr Suzanne P MacFarland is a pediatric oncologist and cancer predisposition researcher in the field of juvenile polyposis syndrome. She runs a multidisciplinary polyposis clinic at the Children's Hospital of Philadelphia. ## Revision History 3 February 2022 (sw) Comprehensive update posted live 9 March 2017 (sw) Comprehensive update posted live 3 December 2015 (jrh) Revision: corrections to 22 May 2014 (me) Comprehensive update posted live 29 September 2011 (me) Comprehensive update posted live 9 September 2008 (me) Comprehensive update posted live 22 February 2007 (cd) Revision: prenatal diagnosis available for 2 November 2006 (cd) Revision: prenatal diagnosis available for 13 June 2005 (me) Comprehensive update posted live 20 May 2004 (cd) Revision: Genetic Counseling 27 October 2003 (cd) Revision: Statements and Policies 13 May 2003 (me) Review posted live 4 January 2003 (jrh) Original submission • 3 February 2022 (sw) Comprehensive update posted live • 9 March 2017 (sw) Comprehensive update posted live • 3 December 2015 (jrh) Revision: corrections to • 22 May 2014 (me) Comprehensive update posted live • 29 September 2011 (me) Comprehensive update posted live • 9 September 2008 (me) Comprehensive update posted live • 22 February 2007 (cd) Revision: prenatal diagnosis available for • 2 November 2006 (cd) Revision: prenatal diagnosis available for • 13 June 2005 (me) Comprehensive update posted live • 20 May 2004 (cd) Revision: Genetic Counseling • 27 October 2003 (cd) Revision: Statements and Policies • 13 May 2003 (me) Review posted live • 4 January 2003 (jrh) Original submission ## References Achatz MI, Porter CC, Brugières L, Druker H, Frebourg T, Foulkes WD, Kratz CP, Kuiper RP, Hansford JR, Hernandez HS, Nathanson KL, Kohlmann WK, Doros L, Onel K, Schneider KW, Scollon SR, Tabori U, Tomlinson GE, Evans DGR, Plon SE. Cancer screening recommendations and clinical management of inherited gastrointestinal cancer syndromes in childhood. Clin Cancer Res. 2017;23:e107-14. Cohen S, Hyer W, Mas E, Auth M, Attard TM, Spalinger J, Latchford A, Durno C. Management of juvenile polyposis syndromes in children and adolescents: a position paper from the ESPGHAN Polyposis Working Group. J Pediatr Gastroenterol Nutr. 2019;68:453-62. 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 Hampel H, Bennett RL, Buchanan A, Pearlman R, Wiesner GL, et al. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015;17:70-87. NCCN. Genetic/Familial High-Risk Assessment: Colorectal. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 1.2021 (May 11, 2021). Available • Achatz MI, Porter CC, Brugières L, Druker H, Frebourg T, Foulkes WD, Kratz CP, Kuiper RP, Hansford JR, Hernandez HS, Nathanson KL, Kohlmann WK, Doros L, Onel K, Schneider KW, Scollon SR, Tabori U, Tomlinson GE, Evans DGR, Plon SE. Cancer screening recommendations and clinical management of inherited gastrointestinal cancer syndromes in childhood. Clin Cancer Res. 2017;23:e107-14. • Cohen S, Hyer W, Mas E, Auth M, Attard TM, Spalinger J, Latchford A, Durno C. Management of juvenile polyposis syndromes in children and adolescents: a position paper from the ESPGHAN Polyposis Working Group. J Pediatr Gastroenterol Nutr. 2019;68:453-62. • 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 • Hampel H, Bennett RL, Buchanan A, Pearlman R, Wiesner GL, et al. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015;17:70-87. • NCCN. Genetic/Familial High-Risk Assessment: Colorectal. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 1.2021 (May 11, 2021). Available ## Published Guidelines / Consensus Statements Achatz MI, Porter CC, Brugières L, Druker H, Frebourg T, Foulkes WD, Kratz CP, Kuiper RP, Hansford JR, Hernandez HS, Nathanson KL, Kohlmann WK, Doros L, Onel K, Schneider KW, Scollon SR, Tabori U, Tomlinson GE, Evans DGR, Plon SE. Cancer screening recommendations and clinical management of inherited gastrointestinal cancer syndromes in childhood. Clin Cancer Res. 2017;23:e107-14. Cohen S, Hyer W, Mas E, Auth M, Attard TM, Spalinger J, Latchford A, Durno C. Management of juvenile polyposis syndromes in children and adolescents: a position paper from the ESPGHAN Polyposis Working Group. J Pediatr Gastroenterol Nutr. 2019;68:453-62. 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 Hampel H, Bennett RL, Buchanan A, Pearlman R, Wiesner GL, et al. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015;17:70-87. NCCN. Genetic/Familial High-Risk Assessment: Colorectal. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 1.2021 (May 11, 2021). Available • Achatz MI, Porter CC, Brugières L, Druker H, Frebourg T, Foulkes WD, Kratz CP, Kuiper RP, Hansford JR, Hernandez HS, Nathanson KL, Kohlmann WK, Doros L, Onel K, Schneider KW, Scollon SR, Tabori U, Tomlinson GE, Evans DGR, Plon SE. Cancer screening recommendations and clinical management of inherited gastrointestinal cancer syndromes in childhood. Clin Cancer Res. 2017;23:e107-14. • Cohen S, Hyer W, Mas E, Auth M, Attard TM, Spalinger J, Latchford A, Durno C. Management of juvenile polyposis syndromes in children and adolescents: a position paper from the ESPGHAN Polyposis Working Group. J Pediatr Gastroenterol Nutr. 2019;68:453-62. • 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 • Hampel H, Bennett RL, Buchanan A, Pearlman R, Wiesner GL, et al. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015;17:70-87. • NCCN. Genetic/Familial High-Risk Assessment: Colorectal. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 1.2021 (May 11, 2021). Available ## Literature Cited	[ "MI Achatz, CC Porter, L Brugières, H Druker, T Frebourg, WD Foulkes, CP Kratz, RP Kuiper, JR Hansford, HS Hernandez, KL Nathanson, WK Kohlmann, L Doros, K Onel, KW Schneider, SR Scollon, U Tabori, GE Tomlinson, DGR Evans, SE Plon. Cancer screening recommendations and clinical management of inherited gastrointestinal cancer syndromes in childhood.. Clin Cancer Res. 2017;23:e107-e114", "A Alimi, LA Weeth-Feinstein, A Stettner, F Caldera, JM Weiss. Overlap of Juvenile polyposis syndrome and Cowden syndrome due to de novo chromosome 10 deletion involving BMPR1A and PTEN: implications for treatment and surveillance.. Am J Med Genet A. 2015;167:1305-8", "S Aretz, D Stienen, S Uhlhaas, M Stolte, MM Entius, S Loff, W Back, A Kaufmann, KM Keller, SH Blaas, R Siebert, S Vogt, S Spranger, E Holinski-Feder, L Sunde, P Propping, W Friedl. High proportion of large genomic deletions and a genotype phenotype update in 80 unrelated families with juvenile polyposis syndrome.. J Med Genet 2007;44:702-9", "E Aytac, B Sulu, B Heald, M O'Malley, L LaGuardia, FH Remzi, MF Kalady, CA Burke, JM Church. Genotype-defined cancer risk in juvenile polyposis syndrome.. Br J Surg. 2015;102:114-8", "R Blatter, B Tschupp, S Aretz, I Bernstein, C Colas, DG Evans, M Genuardi, FJ Hes, R Hüneburg, H Järvinen, F Lalloo, G Moeslein, L Renkonen-Sinisalo, N Resta, I Spier, D Varvara, H Vasen, AR Latchford, K Heinimann. Disease expression in juvenile polyposis syndrome: a retrospective survey on a cohort of 221 European patients and comparison with a literature-derived cohort of 473 SMAD4/BMPR1A pathogenic variant carriers.. Genet Med. 2020;22:1524-32", "J Breckpot, LC Tranchevent, B Thienpont, M Bauters, E Troost, M Gewillig, JR Vermeesch, Y Moreau, K Devriendt, H Van Esch. BMPR1A is a candidate gene for congenital heart defects associated with the recurrent 10q22q23 deletion syndrome.. Eur J Med Genet 2012;55:12-6", "LA Brosens, A van Hattem, LM Hylind, C Iacobuzio-Donahue, KE Romans, J Axilbund, M Cruz-Correa, AC Tersmette, GJ Offerhaus, FM Giardiello. Risk of colorectal cancer in juvenile polyposis.. Gut 2007;56:965-7", "B Burger, S Uhlhaas, E Mangold, P Propping, W Friedl, D Jenne, G Dockter, W Back. Novel de novo mutation of MADH4/SMAD4 in a patient with juvenile polyposis.. Am J Med Genet 2002;110:289-91", "E Buscarini, H Plauchu, G Garcia Tsao, RI White, C Sabbà, F Miller, JC Saurin, JP Pelage, G Lesca, MJ Marion, A Perna, ME Faughnan. Liver involvement in hereditary hemorrhagic telangiectasia: consensus recommendations.. Liver Int. 2006;26:1040-6", "VB Busoni, M Orsi, PA Lobos, D D'Agostino, M Wagener, P De la Iglesia, VL Fox. Successful treatment of juvenile polyposis of infancy with sirolimus.. Pediatrics. 2019;144", "D Calva-Cerqueira, S Chinnathambi, B Pechman, J Bair, J Larsen-Haidle, JR Howe. The rate of germline mutations and large deletions of SMAD4 and BMPR1A in juvenile polyposis.. Clin Genet. 2009;75:79-85", "D Calva-Cerqueira, FS Dahdaleh, G Woodfield, S Chinnathambi, PL Nagy, J Larsen-Haidle, RJ Weigel, JR Howe. Discovery of the BMPR1A promoter and germline mutations that cause juvenile polyposis.. Hum Mol Genet. 2010;19:4654-62", "X Cao, KW Eu, MP Kumarasinghe, HH Li, C Loi, PY Cheah. Mapping of hereditary mixed polyposis syndrome (HMPS) to chromosome 10q23 by genomewide high-density single nucleotide polymorphism (SNP) scan and identification of BMPR1A loss of function.. J Med Genet 2006;43", "JC Carr, FS Dahdaleh, D Wang, JR Howe. Germline mutations in SMAD4 disrupt bone morphogenetic protein signaling.. J Surg Res. 2012;174:211-4", "PY Cheah, YH Wong, YP Chau, C Loi, KH Lim, JF Lim, PK Koh, KW Eu. Germline bone morphogenesis protein receptor 1A mutation causes colorectal tumorigenesis in hereditary mixed polyposis syndrome.. Am J Gastroenterol. 2009;104:3027-33", "YW Chen, PJ Hsiao, CC Weng, KK Kuo, TL Kuo, DC Wu, WC Hung, KH Cheng. SMAD4 loss triggers the phenotypic changes of pancreatic ductal adenocarcinoma cells.. BMC Cancer. 2014;14:181", "MC Coburn, VE Pricolo, FG DeLuca, KI Bland. Malignant potential in intestinal juvenile polyposis syndromes.. Ann Surg Oncol. 1995;2:386-91", "S Cohen, W Hyer, E Mas, M Auth, TM Attard, J Spalinger, A Latchford, C Durno. Management of juvenile polyposis syndromes in children and adolescents: a position paper from the ESPGHAN Polyposis Working Group.. J Pediatr Gastroenterol Nutr. 2019;68:453-62", "FS Dahdaleh, JC Carr, D Calva, JR Howe. Juvenile polyposis and other intestinal polyposis syndromes with microdeletions of chromosome 10q22-23.. Clin Genet. 2012;81:110-6", "C Delnatte, D Sanlaville, JF Mougenot, JR Vermeesch, C Houdayer, MC Blois, D Genevieve, O Goulet, JP Fryns, F Jaubert, M Vekemans, S Lyonnet, S Romana, C Eng, D Stoppa-Lyonnet. Contiguous gene deletion within chromosome arm 10q is associated with juvenile polyposis of infancy, reflecting cooperation between the BMPR1A and PTEN tumor-suppressor genes.. Am J Hum Genet 2006;78:1066-74", "HL Devlin, AE Hosman, CL Shovlin. Antiplatlet and anticoagulant agents in hereditary hemorrhagic telangiectasia.. N Engl J Med. 2013;368:876-8", "W Friedl, S Uhlhaas, K Schulmann, M Stolte, S Loff, W Back, E Mangold, M Stern, HP Knaebel, C Sutter, RG Weber, S Pistorius, B Burger, P Propping. Juvenile polyposis: massive gastric polyposis is more common in MADH4 mutation carriers than in BMPR1A mutation carriers.. Hum Genet 2002;111:108-11", "LI Gómez Pinto, D Rodriguez, AM Adamo, PA Mathieu. TGF-β pro-oligodendrogenic effects on adult SVZ progenitor cultures and its interaction with the Notch signaling pathway.. Glia. 2018;66:396-412", "B Heald, C Rigelsky, R Moran, L LaGuardia, M O'Malley, CA Burke, K Zahka. Prevalence of thoracic aortopathy in patients with juvenile polyposis syndrome-hereditary hemorrhagic telangiectasia due to SMAD4.. Am J Med Genet 2015;167A:1758-62", "CH Heldin, K Miyazono, P ten Dijke. TGF-beta signalling from cell membrane to nucleus through SMAD proteins.. Nature 1997;390:465-71", "JR Howe, JL Haidle, G Lal, J Bair, C Song, B Pechman, S Chinnathambi, HT Lynch. ENG mutations in MADH4.BMPR1A mutation negative patients with juvenile polyposis.. Clin Genet 2007;71:91-2", "JR Howe, S Roth, JC Ringold, RW Summers, HJ Jarvinen, P Sistonen, IP Tomlinson, RS Houlston, S Bevan, FA Mitros, EM Stone, LA Aaltonen. Mutations in the SMAD4/DPC4 gene in juvenile polyposis.. Science 1998;280:1086-8", "JR Howe, MG Sayed, AF Ahmed, J Ringold, J Larsen-Haidle, A Merg, FA Mitros, CA Vaccaro, GM Petersen, FM Giardiello, ST Tinley, LA Aaltonen, HT Lynch. The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations.. J Med Genet 2004;41:484-91", "JR Howe, FS Dahdaleh, JC Carr, D Wang, SK Sherman, JR Howe. BMPR1A mutations in juvenile polyposis affect cellular localization.. J Surg Res 2013;184:739-45", "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 Ishida, K Ishibashi, T Iwama. Malignant tumors associated with juvenile polyposis syndrome in Japan.. Surg Today. 2018;48:253-63", "AM Jelsig, PM Tørring, AD Kjeldsen, N Qvist, A Bojesen, UB Jensen, MK Andersen, AM Gerdes, K Brusgaard, LB Ousager. JP-HHT phenotype in Danish patients with SMAD4 mutations.. Clin Genet 2016;90:55-62", "T Lamireau, S Olschwang, C Rooryck, B Le Bail, JF Chateil, D Lacombe. SMAD4 germinal mosaicism in a family with juvenile polyposis and hypertrophic osteoarthropathy.. J Pediatr Gastroenterol Nutr. 2005;41:117-20", "AR Latchford, K Neale, RK Phillips, SK Clark. Juvenile polyposis syndrome: a study of genotype, phenotype, and long-term outcome.. Dis Colon Rectum 2012;55:1038-43", "AE Lin, A Alali, LJ Starr, N Shah, A Beavis, EM Pereira, ME Lindsay, S Klugman. Gain-of-function pathogenic variants in SMAD4 are associated with neoplasia in Myhre syndrome.. Am J Med Genet A. 2020;182:328-37", "SP MacFarland, JE Ebrahimzadeh, K Zelley, L Begum, LM Bass, RE Brand, B Dudley, DS Fishman, A Ganzak, E Karloski, A Latham, X Llor, S Plon, MK Riordan, SR Scollon, ZK Stadler, S Syngal, C Ukaegbu, JM Weiss, MB Yurgelun, GM Brodeur, P Mamula, BW Katona. Phenotypic differences in juvenile polyposis syndrome with or without a disease-causing SMAD4/BMPR1A variant.. Cancer Prev Res (Phila) 2021;14:215-22", "AJ McCarthy, R Chetty. Smad4/DPC4.. J Clin Pathol. 2018;71:661-4", "Y Miyahara, H Ishida, K Kawabe, H Eto, T Kasai, T Ito, K Kaneko, M Arai, N Kamae, S Momose, H Eguchi, Y. Okazaki. A novel germline BMPR1A variant (c.72_73delGA) in a Japanese family with hereditary mixed polyposis syndrome.. Jpn J Clin Oncol. 2020;50:826-9", "T Nishida, ME Faughnan, T Krings, M Chakinala, JR Gossage, WL Young, H Kim, T Pourmohamad, KJ Henderson, SD Schurm, M James, N Quinnine, A Bharatha, KG Terbrugge, RI White. Brain arteriovenous malformations associated with hereditary hemorrhagic telangiectasia: gene-phenotype correlations.. Am J Med Genet A. 2012;158A:2829-34", "PH Oliveira, C Cunha, S Almeida, R Ferreira, S Maia, JM Saraiva, MF Lopes. Juvenile polyposis of infancy in a child with deletion of BMPR1A and PTEN genes: surgical approach.. J Pediatr Surg. 2013;48:e33-7", "M Oncel, JM Church, FH Remzi, VW Fazio. Colonic surgery in patients with juvenile polyposis syndrome: a case series.. Dis Colon Rectum. 2005;48:49-55", "M O'Malley, L LaGuardia, MF Kalady, J Parambil, B Heald, C Eng, J Church, CA Burke. The prevalence of hereditary hemorrhagic telangiectasia in juvenile polyposis syndrome.. Dis Colon Rectum 2012;55:886-92", "JM O'Riordan, D O'Donoghue, A Green, D Keegan, LA Hawkes, SJ Payne, K Sheahan, DC Winter. Hereditary mixed polyposis syndrome due to a BMPR1A mutation.. Colorectal Dis. 2010;12:570-3", "C Restrepo, J Moreno, E Duque, C Cuello, J Amsel, P Correa. Juvenile colonic polyposis in Colombia.. Dis Colon Rectum. 1978;21:600-12", "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", "BE Russell, D Rigueur, KN Weaver, K Sund, JS Basil, RB Hufnagel, CA Prows, A Oestreich, L Al-Gazali, RJ Hopkin, HM Saal, K Lyons, A Dauber. Homozygous missense variant in BMPR1A resulting in BMPR signaling disruption and syndromic features.. Mol Genet Genomic Med. 2019;7", "L Salviati, M Patricelli, G Guariso, GC Sturniolo, R Alaggio, F Bernardi, O Zuffardi, R Tenconi. Deletion of PTEN and BMPR1A on chromosome 10q23 is not always associated with juvenile polyposis of infancy.. Am J Hum Genet 2006;79:593-6", "MG Sayed, AF Ahmed, JR Ringold, ME Anderson, JL Bair, FA Mitros, HT Lynch, ST Tinley, GM Petersen, FM Giardiello, B Vogelstein, JR Howe. Germline SMAD4 or BMPR1A mutations and phenotype of juvenile polyposis.. Ann Surg Oncol 2002;9:901-6", "K Sweet, J Willis, XP Zhou, C Gallione, T Sawada, P Alhopuro, SK Khoo, A Patocs, C Martin, S Bridgeman, J Heinz, R Pilarski, R Lehtonen, TW Prior, T Frebourg, BT Teh, DA Marchuk, LA Aaltonen, C Eng. Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis.. JAMA 2005;294:2465-73", "H Taylor, D Yerlioglu, C Phen, A Ballauff, N Nedelkopoulou, I Spier, I Loverdos, VB Busoni, J Heise, P Dale, T de Meij, K Sweet, MC Cohen, VL Fox, E Mas, S Aretz, C Eng, S Buderus, M Thomson, I Rojas, HH Uhlig. mTOR inhibitors reduce enteropathy, intestinal bleeding and colectomy rate in patients with juvenile polyposis of infancy with PTEN-BMPR1A deletion.. Hum Mol Genet. 2021;30:1273-82", "P Teekakirikul, DM Milewicz, DT Miller, RV Lacro, ES Regalado, AM Rosales, DP Ryan, TL Toler, AE Lin. Thoracic aortic disease in two patients with juvenile polyposis syndrome and SMAD4 mutations.. Am J Med Genet A 2013;161A:185-91", "WA van Hattem, LA Brosens, WW de Leng, FH Morsink, S Lens, R Carvalho, FM Giardiello, GJ Offerhaus. Large genomic deletions of SMAD4, BMPR1A and PTEN in juvenile polyposis.. Gut. 2008;57:623-7", "KE Wain, MS Ellingson, J McDonald, A Gammon, M Roberts, P Pichurin, I Winship, DL Riegert-Johnson, JN Weitzel, NM Lindor. Appreciating the broad clinical features of SMAD4 mutation carriers: a multicenter chart review.. Genet Med. 2014;16:588-93" ]	13/5/2003	3/2/2022	3/12/2015	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
kabuki	kabuki	[ "Kabuki Make-Up Syndrome", "Niikawa-Kuroki Syndrome", "Kabuki Make-Up Syndrome", "Niikawa-Kuroki Syndrome", "Histone-lysine N-methyltransferase 2D", "Lysine-specific demethylase 6A", "KDM6A", "KMT2D", "Kabuki Syndrome" ]	Kabuki Syndrome	Margaret P Adam, Mark Hannibal	Summary Kabuki syndrome (KS) is characterized by typical facial features (long palpebral fissures with eversion of the lateral third of the lower eyelid; arched and broad eyebrows; short columella with depressed nasal tip; large, prominent, or cupped ears), minor skeletal anomalies, persistence of fetal fingertip pads, mild-to-moderate intellectual disability, and postnatal growth deficiency. Other findings may include: congenital heart defects, genitourinary anomalies, cleft lip and/or palate, gastrointestinal anomalies including anal atresia, ptosis and strabismus, and widely spaced teeth and hypodontia. Functional differences can include: increased susceptibility to infections and autoimmune disorders, seizures, endocrinologic abnormalities (including isolated premature thelarche in females), feeding problems, and hearing loss. The diagnosis of KS is established in a proband of any age with a history of infantile hypotonia, developmental delay, and/or intellectual disability AND one or both of the following: Typical dysmorphic features (long palpebral fissures with eversion of the lateral third of the lower eyelid, and ≥2 of the following: arched and broad eyebrows with the lateral third displaying notching or sparseness; short columella with depressed nasal tip; large, prominent, or cupped ears; persistent fingertip pads) A heterozygous pathogenic variant in Once the causative pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for KS are possible.	## Diagnosis Consensus clinical diagnostic criteria for Kabuki syndrome (KS) have been published [ KS Typical facial features: Long palpebral fissures with eversion of the lateral third of the lower eyelid Highly arched and broad eyebrows with the lateral third displaying sparseness or notching Short columella with depressed nasal tip Large, prominent, and/or cupped ears Skeletal anomalies: Spine abnormalities including sagittal clefts, hemivertebrae, butterfly vertebrae, narrow intervertebral disc space, and/or scoliosis Brachydactyly V Brachymesophalangy Clinodactyly of fifth digits Dermatoglyphic abnormalities: persistence of fetal fingertip pads Note: While absence of digital triradius c and/or d and increased digital loop and hypothenar loop patterns can be observed, this type of analysis is not routinely done in clinical practice in most centers. Mild-to-moderate intellectual disability Postnatal growth deficiency Ophthalmologic anomalies including ptosis and strabismus Ear pits (a potentially helpful diagnostic clue when seen with other typical findings) Cleft lip and/or palate Dental anomalies including widely spaced teeth and hypodontia Congenital heart defects Gastrointestinal anomalies including anal atresia Genitourinary anomalies including cryptorchidism in males Hearing loss Feeding problems Endocrinologic abnormalities including hyperinsulinism and/or isolated premature thelarche in females Increased susceptibility to infections and autoimmune disorders Seizures The diagnosis of KS Typical dysmorphic features * at some point of life A heterozygous pathogenic (or likely pathogenic) variant in * Typical dysmorphic features include long palpebral fissures (a palpebral fissure measurement ≥2 SD above the mean for age) with eversion of the lateral third of the lower eyelid AND two or more of the following: Arched and broad eyebrows with the lateral third displaying notching or sparseness Short columella with depressed nasal tip Large, prominent, or cupped ears Persistent fingertip pads 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 Kabuki syndrome is broad, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of Kabuki syndrome, molecular genetic testing approaches can include Perform sequence analysis of Sequence analysis and gene-targeted deletion/duplication analysis of Note: Affected individuals with classic features who have a mosaic heterozygous pathogenic variant in For an introduction to multigene panels click When the diagnosis of Kabuki syndrome is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Kabuki Syndrome (KS) 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 missense, nonsense, and splice site variants and small 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 approximately 30% of individuals with a clinical diagnosis of Kabuki syndrome, the genetic cause remains unknown. Therefore, locus heterogeneity for one or more as-yet-unidentified genes remains a possibility [ Further candidate genes for KS or conditions with features that overlap with KS include • Typical facial features: • Long palpebral fissures with eversion of the lateral third of the lower eyelid • Highly arched and broad eyebrows with the lateral third displaying sparseness or notching • Short columella with depressed nasal tip • Large, prominent, and/or cupped ears • Long palpebral fissures with eversion of the lateral third of the lower eyelid • Highly arched and broad eyebrows with the lateral third displaying sparseness or notching • Short columella with depressed nasal tip • Large, prominent, and/or cupped ears • Skeletal anomalies: • Spine abnormalities including sagittal clefts, hemivertebrae, butterfly vertebrae, narrow intervertebral disc space, and/or scoliosis • Brachydactyly V • Brachymesophalangy • Clinodactyly of fifth digits • Spine abnormalities including sagittal clefts, hemivertebrae, butterfly vertebrae, narrow intervertebral disc space, and/or scoliosis • Brachydactyly V • Brachymesophalangy • Clinodactyly of fifth digits • Dermatoglyphic abnormalities: persistence of fetal fingertip pads • Note: While absence of digital triradius c and/or d and increased digital loop and hypothenar loop patterns can be observed, this type of analysis is not routinely done in clinical practice in most centers. • Mild-to-moderate intellectual disability • Postnatal growth deficiency • Long palpebral fissures with eversion of the lateral third of the lower eyelid • Highly arched and broad eyebrows with the lateral third displaying sparseness or notching • Short columella with depressed nasal tip • Large, prominent, and/or cupped ears • Spine abnormalities including sagittal clefts, hemivertebrae, butterfly vertebrae, narrow intervertebral disc space, and/or scoliosis • Brachydactyly V • Brachymesophalangy • Clinodactyly of fifth digits • Ophthalmologic anomalies including ptosis and strabismus • Ear pits (a potentially helpful diagnostic clue when seen with other typical findings) • Cleft lip and/or palate • Dental anomalies including widely spaced teeth and hypodontia • Congenital heart defects • Gastrointestinal anomalies including anal atresia • Genitourinary anomalies including cryptorchidism in males • Hearing loss • Feeding problems • Endocrinologic abnormalities including hyperinsulinism and/or isolated premature thelarche in females • Increased susceptibility to infections and autoimmune disorders • Seizures • Typical dysmorphic features * at some point of life • A heterozygous pathogenic (or likely pathogenic) variant in • Arched and broad eyebrows with the lateral third displaying notching or sparseness • Short columella with depressed nasal tip • Large, prominent, or cupped ears • Persistent fingertip pads • Perform sequence analysis of • Sequence analysis and gene-targeted deletion/duplication analysis of ## Suggestive Findings KS Typical facial features: Long palpebral fissures with eversion of the lateral third of the lower eyelid Highly arched and broad eyebrows with the lateral third displaying sparseness or notching Short columella with depressed nasal tip Large, prominent, and/or cupped ears Skeletal anomalies: Spine abnormalities including sagittal clefts, hemivertebrae, butterfly vertebrae, narrow intervertebral disc space, and/or scoliosis Brachydactyly V Brachymesophalangy Clinodactyly of fifth digits Dermatoglyphic abnormalities: persistence of fetal fingertip pads Note: While absence of digital triradius c and/or d and increased digital loop and hypothenar loop patterns can be observed, this type of analysis is not routinely done in clinical practice in most centers. Mild-to-moderate intellectual disability Postnatal growth deficiency Ophthalmologic anomalies including ptosis and strabismus Ear pits (a potentially helpful diagnostic clue when seen with other typical findings) Cleft lip and/or palate Dental anomalies including widely spaced teeth and hypodontia Congenital heart defects Gastrointestinal anomalies including anal atresia Genitourinary anomalies including cryptorchidism in males Hearing loss Feeding problems Endocrinologic abnormalities including hyperinsulinism and/or isolated premature thelarche in females Increased susceptibility to infections and autoimmune disorders Seizures • Typical facial features: • Long palpebral fissures with eversion of the lateral third of the lower eyelid • Highly arched and broad eyebrows with the lateral third displaying sparseness or notching • Short columella with depressed nasal tip • Large, prominent, and/or cupped ears • Long palpebral fissures with eversion of the lateral third of the lower eyelid • Highly arched and broad eyebrows with the lateral third displaying sparseness or notching • Short columella with depressed nasal tip • Large, prominent, and/or cupped ears • Skeletal anomalies: • Spine abnormalities including sagittal clefts, hemivertebrae, butterfly vertebrae, narrow intervertebral disc space, and/or scoliosis • Brachydactyly V • Brachymesophalangy • Clinodactyly of fifth digits • Spine abnormalities including sagittal clefts, hemivertebrae, butterfly vertebrae, narrow intervertebral disc space, and/or scoliosis • Brachydactyly V • Brachymesophalangy • Clinodactyly of fifth digits • Dermatoglyphic abnormalities: persistence of fetal fingertip pads • Note: While absence of digital triradius c and/or d and increased digital loop and hypothenar loop patterns can be observed, this type of analysis is not routinely done in clinical practice in most centers. • Mild-to-moderate intellectual disability • Postnatal growth deficiency • Long palpebral fissures with eversion of the lateral third of the lower eyelid • Highly arched and broad eyebrows with the lateral third displaying sparseness or notching • Short columella with depressed nasal tip • Large, prominent, and/or cupped ears • Spine abnormalities including sagittal clefts, hemivertebrae, butterfly vertebrae, narrow intervertebral disc space, and/or scoliosis • Brachydactyly V • Brachymesophalangy • Clinodactyly of fifth digits • Ophthalmologic anomalies including ptosis and strabismus • Ear pits (a potentially helpful diagnostic clue when seen with other typical findings) • Cleft lip and/or palate • Dental anomalies including widely spaced teeth and hypodontia • Congenital heart defects • Gastrointestinal anomalies including anal atresia • Genitourinary anomalies including cryptorchidism in males • Hearing loss • Feeding problems • Endocrinologic abnormalities including hyperinsulinism and/or isolated premature thelarche in females • Increased susceptibility to infections and autoimmune disorders • Seizures ## Establishing the Diagnosis The diagnosis of KS Typical dysmorphic features * at some point of life A heterozygous pathogenic (or likely pathogenic) variant in * Typical dysmorphic features include long palpebral fissures (a palpebral fissure measurement ≥2 SD above the mean for age) with eversion of the lateral third of the lower eyelid AND two or more of the following: Arched and broad eyebrows with the lateral third displaying notching or sparseness Short columella with depressed nasal tip Large, prominent, or cupped ears Persistent fingertip pads 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 Kabuki syndrome is broad, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of Kabuki syndrome, molecular genetic testing approaches can include Perform sequence analysis of Sequence analysis and gene-targeted deletion/duplication analysis of Note: Affected individuals with classic features who have a mosaic heterozygous pathogenic variant in For an introduction to multigene panels click When the diagnosis of Kabuki syndrome is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Kabuki Syndrome (KS) 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 missense, nonsense, and splice site variants and small 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 approximately 30% of individuals with a clinical diagnosis of Kabuki syndrome, the genetic cause remains unknown. Therefore, locus heterogeneity for one or more as-yet-unidentified genes remains a possibility [ Further candidate genes for KS or conditions with features that overlap with KS include • Typical dysmorphic features * at some point of life • A heterozygous pathogenic (or likely pathogenic) variant in • Arched and broad eyebrows with the lateral third displaying notching or sparseness • Short columella with depressed nasal tip • Large, prominent, or cupped ears • Persistent fingertip pads • Perform sequence analysis of • Sequence analysis and gene-targeted deletion/duplication analysis of ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of Kabuki syndrome, molecular genetic testing approaches can include Perform sequence analysis of Sequence analysis and gene-targeted deletion/duplication analysis of Note: Affected individuals with classic features who have a mosaic heterozygous pathogenic variant in For an introduction to multigene panels click • Perform sequence analysis of • Sequence analysis and gene-targeted deletion/duplication analysis of ## Option 2 When the diagnosis of Kabuki syndrome is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Kabuki Syndrome (KS) 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 missense, nonsense, and splice site variants and small 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 approximately 30% of individuals with a clinical diagnosis of Kabuki syndrome, the genetic cause remains unknown. Therefore, locus heterogeneity for one or more as-yet-unidentified genes remains a possibility [ Further candidate genes for KS or conditions with features that overlap with KS include ## Clinical Characteristics This section summarizes findings in more than 400 individuals with a molecularly confirmed diagnosis of Kabuki syndrome (KS). Individuals with KS typically exhibit normal growth parameters at birth. Infants with KS frequently exhibit failure to thrive for a variety of reasons (see In adolescence and adulthood, more than half of individuals with KS develop obesity [ Without treatment (see Ocular findings occur in more than one third of individuals with Kabuki syndrome and include blue sclerae, strabismus, ptosis, coloboma, Marcus Gunn phenomenon (also referred to as jaw winking), and corneal abnormalities such as Peters anomaly. Rarely, more severe eye anomalies may occur, such as optic nerve hypoplasia, colobomatous microphthalmia, and anophthalmia [ Functional visual problems may include difficulties with motor coordination, visuoperception, and visuomotor integration [ As a result of the everted lower eyelid, children with KS can demonstrate excessive tearing, which is not usually a significant problem. However, nocturnal lagophthalmos, which occurs in many children with KS, can predispose to corneal abrasion and scarring. Most individuals with KS have prominent and cup-shaped ears. Ear pits are also relatively common. From a medical standpoint, chronic otitis media is a major cause of morbidity, including conductive hearing loss. It is not clear, however, whether this finding is related to an underlying susceptibility to infection or to the craniofacial abnormalities, such as palatal insufficiency. Up to 50% of individuals with KS have hearing loss. Although chronic otitis media is the most common cause, sensorineural hearing loss can rarely occur and some individuals have progressive hearing loss. Inner-ear malformations including Mondini dysplasia, vestibular enlargement, aplastic cochlea and semicircular canals, and aqueductal enlargement have been reported. At least one individual with a clinical diagnosis of Kabuki syndrome who had profound progressive sensorineural hearing loss received a cochlear implant with a reported improvement in quality of life [ Cleft lip and/or palate affects approximately one third of individuals with KS. Submucous cleft palate may be underascertained [ The typical facial features (elongated palpebral fissures with eversion of the lateral third of the lower eyelid; arched and broad eyebrows; short columella with depressed nasal tip; and large, prominent, or cupped ears) are considered part of the diagnostic criteria of KS and are therefore present in almost all individuals who have a clinical diagnosis of KS. A majority of individuals with a molecularly confirmed diagnosis of KS are also found to have these characteristic facial features [ A number of different dental anomalies in individuals with KS have been noted [ Approximately 70% of individuals with KS have a congenital heart defect [ Eventration of the diaphragm has been rarely reported [ Laryngeal abnormalities may pose problems with anesthesia (see Management, Feeding difficulties are quite common (~70%) and may be related to hypotonia, poor oromotor coordination, and swallowing difficulties [ Abnormalities involving the gastrointestinal system are not common in KS; however, the following may be seen rarely: Anorectal anomalies including imperforate anus, anovestibular fistula, and anteriorly placed anus [ Congenital diaphragmatic hernia and eventration of the diaphragm Cholestasis from a variety of causes Chronic diarrhea from malabsorption and/or celiac disease Kidney and urinary tract anomalies are seen in more than 25% of affected individuals [ Joint hypermobility is seen in 50%-75% of individuals with KS. Joint dislocations, especially involving the hips, patellae, and shoulders, are not uncommon. As in most conditions with joint laxity, this finding improves with age. Variable degrees of scoliosis and kyphosis are seen and may be associated with vertebral anomalies (hemivertebrae, butterfly vertebrae, sagittal clefts). Persistent fetal fingertip pads are considered one of the five cardinal manifestations of KS and are therefore found in a large proportion of affected individuals [ Absence of digital triradius c and/or d and increased digital loop and hypothenar loop patterns can also be observed, although analysis for these features is not frequently done in current clinical practice. Other hand findings (brachydactyly V, brachymesophalangy, and clinodactyly of the 5th digits) can also be seen, but these features rarely lead to clinical issues and are used more as a clue to the diagnosis (see In a study by After one year of growth hormone treatment, the average height improved from 2.40 to 1.69 SD below the mean [ Those who initiated growth hormone therapy at an earlier age received the most benefit in terms of catch-up growth. After one year of growth hormone therapy, body proportions were not significantly affected. Failure to recognize and treat HI in a timely fashion can lead to irreversible neurologic damage and exacerbate developmental issues. It is estimated that about 1% of neonates with HI have a diagnosis of KS [ In a study of 33 individuals with HI and KS (29 of whom had a confirmed molecular diagnosis) seen in an HI specialty clinic, 25/33 (76%) had hypoglycemia that was identified on the first day of life [ The median age of diagnosis of HI in this study was 1.8 months, with 20/33 (61%) of affected individuals being diagnosed with KS after their diagnosis of HI. The latest age at which HI was diagnosed in this cohort was 28.3 months. This individual experienced resolution of HI at age 10.5 years. Diazoxide therapy was trialed in 25/33 of the individuals with HI, with a response rate of 92%. Treatment for HI was able to be discontinued in 15 individuals at a median age of 2.8 years. Of the affected individuals with HI and a molecular diagnosis of KS, 24/29 (83%) had a pathogenic variant in Adrenal insufficiency Combined pituitary hormone deficiency Diabetes insipidus Frank growth hormone deficiency Hypothyroidism Primary ovarian dysfunction True precocious puberty Immune dysfunction including both humoral immune deficiency and autoimmune disease has been described [ Frequent and recurrent infections, such as frequent sinopulmonary infections and recurrent otitis media, are found in a majority of affected individuals [ Hypogammaglobulinemia and IgA deficiency are common. Diminished B-cell populations have also been reported [ Autoimmune conditions such as vitiligo, immune thrombocytopenia (ITP), hemolytic anemia, and even diabetes mellitus have also been described in affected individuals, most commonly in childhood or adolescence [ Most children with KS are hypotonic and joint laxity may be a contributing factor. Hypotonia may contribute to significant feeding problems in infancy (see Seizures are seen more frequently in KS (10%-39%) than in the general population and represent a spectrum of findings including infantile spasms [ Although most people with Kabuki syndrome undergo brain imaging at some point for indications such as seizures and/or developmental delay, major structural brain anomalies are rare. Reported findings have included the following [ Cerebellar and brain stem atrophy Dandy-walker malformation Delayed myelination Mild ventriculomegaly Note: Prior to the identification of the genetic causes of KS, symptomatic Chiari I malformation was reported in multiple affected individuals [ Intellectual disability, usually in the mild to moderate range, has been reported in a majority of individuals; however, reports of rare individuals with pathogenic variants in either Average IQ scores in individuals with Neuropsychiatric testing has identified deficits in both comprehension and production of verbal language, but this may be related, in part, to hearing, neurologic, orofacial, and cognitive deficits [ No specific language profile has been identified. However, all language subdomains including syntax, morphology, pragmatics, and semantics may be affected. Dysarthria (reduced rate and stress, distorted pitch, harsh vocal quality, hypernasality, and imprecise consonants) has also been described. On formal neuropsychiatric testing, individuals with KS tend to score better in the areas of vocabulary comprehension and working memory and score lower in the areas of nonverbal reasoning and processing speed [ In terms of adaptive skills, individuals with KS have more difficulties with daily living than with communication. An educational environment that stresses audio-verbal learning over visual learning may beneficial (see Individuals with KS tend to be described as pleasant and outgoing. Attention-deficit disorder and/or hyperactivity are present in a subset of affected individuals. Other behavioral findings including anxiety disorder, self-harm, and sleep disturbance have been rarely reported [ Autism continues to be a rare but described finding in affected individuals [ Pilomatricomas, benign tumors of the hair shaft that commonly occur on the head and neck, have been described rarely in those with Kabuki syndrome [ Although pathogenic somatic variants in Those with a In general, those with a Hypoglycemia as a result of hyperinsulinism Note: The overall number of individuals with KS and hyperinsulinism is greater in individuals with a pathogenic variant in Hypertrichosis Long halluces Large central incisors Affected males are more likely to have moderate-to-severe developmental delay / cognitive impairment than are females, who may have mild-to-moderate intellectual disability. In general, females with a pathogenic variant in Individuals with KS caused by a heterozygous pathogenic missense variants in the terminal regions of Individuals with KS caused by a whole-gene deletion of Note: Individuals with a heterozygous pathogenic variant involving exons 38 or 39 potentially resulting in a gain of function may have some features similar to KS but otherwise have a phenotype that is noticeably different from KS (see Based on small numbers of individuals with Splice site variants, as compared to nonsense, missense, and small in/dels, are the most common type of single-nucleotide variant in individuals with Penetrance for pathogenic variants in The prevalence of KS in Japan is estimated at 1:32,000 live births [ • Infants with KS frequently exhibit failure to thrive for a variety of reasons (see • In adolescence and adulthood, more than half of individuals with KS develop obesity [ • Without treatment (see • Rarely, more severe eye anomalies may occur, such as optic nerve hypoplasia, colobomatous microphthalmia, and anophthalmia [ • Functional visual problems may include difficulties with motor coordination, visuoperception, and visuomotor integration [ • As a result of the everted lower eyelid, children with KS can demonstrate excessive tearing, which is not usually a significant problem. However, nocturnal lagophthalmos, which occurs in many children with KS, can predispose to corneal abrasion and scarring. • Anorectal anomalies including imperforate anus, anovestibular fistula, and anteriorly placed anus [ • Congenital diaphragmatic hernia and eventration of the diaphragm • Cholestasis from a variety of causes • Chronic diarrhea from malabsorption and/or celiac disease • Variable degrees of scoliosis and kyphosis are seen and may be associated with vertebral anomalies (hemivertebrae, butterfly vertebrae, sagittal clefts). • Persistent fetal fingertip pads are considered one of the five cardinal manifestations of KS and are therefore found in a large proportion of affected individuals [ • Absence of digital triradius c and/or d and increased digital loop and hypothenar loop patterns can also be observed, although analysis for these features is not frequently done in current clinical practice. • Other hand findings (brachydactyly V, brachymesophalangy, and clinodactyly of the 5th digits) can also be seen, but these features rarely lead to clinical issues and are used more as a clue to the diagnosis (see • In a study by • After one year of growth hormone treatment, the average height improved from 2.40 to 1.69 SD below the mean [ • Those who initiated growth hormone therapy at an earlier age received the most benefit in terms of catch-up growth. • After one year of growth hormone therapy, body proportions were not significantly affected. • Failure to recognize and treat HI in a timely fashion can lead to irreversible neurologic damage and exacerbate developmental issues. • It is estimated that about 1% of neonates with HI have a diagnosis of KS [ • In a study of 33 individuals with HI and KS (29 of whom had a confirmed molecular diagnosis) seen in an HI specialty clinic, 25/33 (76%) had hypoglycemia that was identified on the first day of life [ • The median age of diagnosis of HI in this study was 1.8 months, with 20/33 (61%) of affected individuals being diagnosed with KS after their diagnosis of HI. The latest age at which HI was diagnosed in this cohort was 28.3 months. This individual experienced resolution of HI at age 10.5 years. • Diazoxide therapy was trialed in 25/33 of the individuals with HI, with a response rate of 92%. • Treatment for HI was able to be discontinued in 15 individuals at a median age of 2.8 years. • Of the affected individuals with HI and a molecular diagnosis of KS, 24/29 (83%) had a pathogenic variant in • The median age of diagnosis of HI in this study was 1.8 months, with 20/33 (61%) of affected individuals being diagnosed with KS after their diagnosis of HI. The latest age at which HI was diagnosed in this cohort was 28.3 months. This individual experienced resolution of HI at age 10.5 years. • Diazoxide therapy was trialed in 25/33 of the individuals with HI, with a response rate of 92%. • Treatment for HI was able to be discontinued in 15 individuals at a median age of 2.8 years. • Of the affected individuals with HI and a molecular diagnosis of KS, 24/29 (83%) had a pathogenic variant in • The median age of diagnosis of HI in this study was 1.8 months, with 20/33 (61%) of affected individuals being diagnosed with KS after their diagnosis of HI. The latest age at which HI was diagnosed in this cohort was 28.3 months. This individual experienced resolution of HI at age 10.5 years. • Diazoxide therapy was trialed in 25/33 of the individuals with HI, with a response rate of 92%. • Treatment for HI was able to be discontinued in 15 individuals at a median age of 2.8 years. • Of the affected individuals with HI and a molecular diagnosis of KS, 24/29 (83%) had a pathogenic variant in • Adrenal insufficiency • Combined pituitary hormone deficiency • Diabetes insipidus • Frank growth hormone deficiency • Hypothyroidism • Primary ovarian dysfunction • True precocious puberty • Frequent and recurrent infections, such as frequent sinopulmonary infections and recurrent otitis media, are found in a majority of affected individuals [ • Hypogammaglobulinemia and IgA deficiency are common. • Diminished B-cell populations have also been reported [ • Autoimmune conditions such as vitiligo, immune thrombocytopenia (ITP), hemolytic anemia, and even diabetes mellitus have also been described in affected individuals, most commonly in childhood or adolescence [ • Hypotonia may contribute to significant feeding problems in infancy (see • Seizures are seen more frequently in KS (10%-39%) than in the general population and represent a spectrum of findings including infantile spasms [ • Cerebellar and brain stem atrophy • Dandy-walker malformation • Delayed myelination • Mild ventriculomegaly • Average IQ scores in individuals with • Neuropsychiatric testing has identified deficits in both comprehension and production of verbal language, but this may be related, in part, to hearing, neurologic, orofacial, and cognitive deficits [ • No specific language profile has been identified. However, all language subdomains including syntax, morphology, pragmatics, and semantics may be affected. • Dysarthria (reduced rate and stress, distorted pitch, harsh vocal quality, hypernasality, and imprecise consonants) has also been described. • On formal neuropsychiatric testing, individuals with KS tend to score better in the areas of vocabulary comprehension and working memory and score lower in the areas of nonverbal reasoning and processing speed [ • No specific language profile has been identified. However, all language subdomains including syntax, morphology, pragmatics, and semantics may be affected. • Dysarthria (reduced rate and stress, distorted pitch, harsh vocal quality, hypernasality, and imprecise consonants) has also been described. • On formal neuropsychiatric testing, individuals with KS tend to score better in the areas of vocabulary comprehension and working memory and score lower in the areas of nonverbal reasoning and processing speed [ • In terms of adaptive skills, individuals with KS have more difficulties with daily living than with communication. • An educational environment that stresses audio-verbal learning over visual learning may beneficial (see • No specific language profile has been identified. However, all language subdomains including syntax, morphology, pragmatics, and semantics may be affected. • Dysarthria (reduced rate and stress, distorted pitch, harsh vocal quality, hypernasality, and imprecise consonants) has also been described. • On formal neuropsychiatric testing, individuals with KS tend to score better in the areas of vocabulary comprehension and working memory and score lower in the areas of nonverbal reasoning and processing speed [ • Attention-deficit disorder and/or hyperactivity are present in a subset of affected individuals. Other behavioral findings including anxiety disorder, self-harm, and sleep disturbance have been rarely reported [ • Autism continues to be a rare but described finding in affected individuals [ • Those with a • In general, those with a • Hypoglycemia as a result of hyperinsulinism • Note: The overall number of individuals with KS and hyperinsulinism is greater in individuals with a pathogenic variant in • Hypertrichosis • Long halluces • Large central incisors • Individuals with KS caused by a heterozygous pathogenic missense variants in the terminal regions of • Individuals with KS caused by a whole-gene deletion of • Based on small numbers of individuals with • Splice site variants, as compared to nonsense, missense, and small in/dels, are the most common type of single-nucleotide variant in individuals with ## Clinical Description This section summarizes findings in more than 400 individuals with a molecularly confirmed diagnosis of Kabuki syndrome (KS). Individuals with KS typically exhibit normal growth parameters at birth. Infants with KS frequently exhibit failure to thrive for a variety of reasons (see In adolescence and adulthood, more than half of individuals with KS develop obesity [ Without treatment (see Ocular findings occur in more than one third of individuals with Kabuki syndrome and include blue sclerae, strabismus, ptosis, coloboma, Marcus Gunn phenomenon (also referred to as jaw winking), and corneal abnormalities such as Peters anomaly. Rarely, more severe eye anomalies may occur, such as optic nerve hypoplasia, colobomatous microphthalmia, and anophthalmia [ Functional visual problems may include difficulties with motor coordination, visuoperception, and visuomotor integration [ As a result of the everted lower eyelid, children with KS can demonstrate excessive tearing, which is not usually a significant problem. However, nocturnal lagophthalmos, which occurs in many children with KS, can predispose to corneal abrasion and scarring. Most individuals with KS have prominent and cup-shaped ears. Ear pits are also relatively common. From a medical standpoint, chronic otitis media is a major cause of morbidity, including conductive hearing loss. It is not clear, however, whether this finding is related to an underlying susceptibility to infection or to the craniofacial abnormalities, such as palatal insufficiency. Up to 50% of individuals with KS have hearing loss. Although chronic otitis media is the most common cause, sensorineural hearing loss can rarely occur and some individuals have progressive hearing loss. Inner-ear malformations including Mondini dysplasia, vestibular enlargement, aplastic cochlea and semicircular canals, and aqueductal enlargement have been reported. At least one individual with a clinical diagnosis of Kabuki syndrome who had profound progressive sensorineural hearing loss received a cochlear implant with a reported improvement in quality of life [ Cleft lip and/or palate affects approximately one third of individuals with KS. Submucous cleft palate may be underascertained [ The typical facial features (elongated palpebral fissures with eversion of the lateral third of the lower eyelid; arched and broad eyebrows; short columella with depressed nasal tip; and large, prominent, or cupped ears) are considered part of the diagnostic criteria of KS and are therefore present in almost all individuals who have a clinical diagnosis of KS. A majority of individuals with a molecularly confirmed diagnosis of KS are also found to have these characteristic facial features [ A number of different dental anomalies in individuals with KS have been noted [ Approximately 70% of individuals with KS have a congenital heart defect [ Eventration of the diaphragm has been rarely reported [ Laryngeal abnormalities may pose problems with anesthesia (see Management, Feeding difficulties are quite common (~70%) and may be related to hypotonia, poor oromotor coordination, and swallowing difficulties [ Abnormalities involving the gastrointestinal system are not common in KS; however, the following may be seen rarely: Anorectal anomalies including imperforate anus, anovestibular fistula, and anteriorly placed anus [ Congenital diaphragmatic hernia and eventration of the diaphragm Cholestasis from a variety of causes Chronic diarrhea from malabsorption and/or celiac disease Kidney and urinary tract anomalies are seen in more than 25% of affected individuals [ Joint hypermobility is seen in 50%-75% of individuals with KS. Joint dislocations, especially involving the hips, patellae, and shoulders, are not uncommon. As in most conditions with joint laxity, this finding improves with age. Variable degrees of scoliosis and kyphosis are seen and may be associated with vertebral anomalies (hemivertebrae, butterfly vertebrae, sagittal clefts). Persistent fetal fingertip pads are considered one of the five cardinal manifestations of KS and are therefore found in a large proportion of affected individuals [ Absence of digital triradius c and/or d and increased digital loop and hypothenar loop patterns can also be observed, although analysis for these features is not frequently done in current clinical practice. Other hand findings (brachydactyly V, brachymesophalangy, and clinodactyly of the 5th digits) can also be seen, but these features rarely lead to clinical issues and are used more as a clue to the diagnosis (see In a study by After one year of growth hormone treatment, the average height improved from 2.40 to 1.69 SD below the mean [ Those who initiated growth hormone therapy at an earlier age received the most benefit in terms of catch-up growth. After one year of growth hormone therapy, body proportions were not significantly affected. Failure to recognize and treat HI in a timely fashion can lead to irreversible neurologic damage and exacerbate developmental issues. It is estimated that about 1% of neonates with HI have a diagnosis of KS [ In a study of 33 individuals with HI and KS (29 of whom had a confirmed molecular diagnosis) seen in an HI specialty clinic, 25/33 (76%) had hypoglycemia that was identified on the first day of life [ The median age of diagnosis of HI in this study was 1.8 months, with 20/33 (61%) of affected individuals being diagnosed with KS after their diagnosis of HI. The latest age at which HI was diagnosed in this cohort was 28.3 months. This individual experienced resolution of HI at age 10.5 years. Diazoxide therapy was trialed in 25/33 of the individuals with HI, with a response rate of 92%. Treatment for HI was able to be discontinued in 15 individuals at a median age of 2.8 years. Of the affected individuals with HI and a molecular diagnosis of KS, 24/29 (83%) had a pathogenic variant in Adrenal insufficiency Combined pituitary hormone deficiency Diabetes insipidus Frank growth hormone deficiency Hypothyroidism Primary ovarian dysfunction True precocious puberty Immune dysfunction including both humoral immune deficiency and autoimmune disease has been described [ Frequent and recurrent infections, such as frequent sinopulmonary infections and recurrent otitis media, are found in a majority of affected individuals [ Hypogammaglobulinemia and IgA deficiency are common. Diminished B-cell populations have also been reported [ Autoimmune conditions such as vitiligo, immune thrombocytopenia (ITP), hemolytic anemia, and even diabetes mellitus have also been described in affected individuals, most commonly in childhood or adolescence [ Most children with KS are hypotonic and joint laxity may be a contributing factor. Hypotonia may contribute to significant feeding problems in infancy (see Seizures are seen more frequently in KS (10%-39%) than in the general population and represent a spectrum of findings including infantile spasms [ Although most people with Kabuki syndrome undergo brain imaging at some point for indications such as seizures and/or developmental delay, major structural brain anomalies are rare. Reported findings have included the following [ Cerebellar and brain stem atrophy Dandy-walker malformation Delayed myelination Mild ventriculomegaly Note: Prior to the identification of the genetic causes of KS, symptomatic Chiari I malformation was reported in multiple affected individuals [ Intellectual disability, usually in the mild to moderate range, has been reported in a majority of individuals; however, reports of rare individuals with pathogenic variants in either Average IQ scores in individuals with Neuropsychiatric testing has identified deficits in both comprehension and production of verbal language, but this may be related, in part, to hearing, neurologic, orofacial, and cognitive deficits [ No specific language profile has been identified. However, all language subdomains including syntax, morphology, pragmatics, and semantics may be affected. Dysarthria (reduced rate and stress, distorted pitch, harsh vocal quality, hypernasality, and imprecise consonants) has also been described. On formal neuropsychiatric testing, individuals with KS tend to score better in the areas of vocabulary comprehension and working memory and score lower in the areas of nonverbal reasoning and processing speed [ In terms of adaptive skills, individuals with KS have more difficulties with daily living than with communication. An educational environment that stresses audio-verbal learning over visual learning may beneficial (see Individuals with KS tend to be described as pleasant and outgoing. Attention-deficit disorder and/or hyperactivity are present in a subset of affected individuals. Other behavioral findings including anxiety disorder, self-harm, and sleep disturbance have been rarely reported [ Autism continues to be a rare but described finding in affected individuals [ Pilomatricomas, benign tumors of the hair shaft that commonly occur on the head and neck, have been described rarely in those with Kabuki syndrome [ Although pathogenic somatic variants in • Infants with KS frequently exhibit failure to thrive for a variety of reasons (see • In adolescence and adulthood, more than half of individuals with KS develop obesity [ • Without treatment (see • Rarely, more severe eye anomalies may occur, such as optic nerve hypoplasia, colobomatous microphthalmia, and anophthalmia [ • Functional visual problems may include difficulties with motor coordination, visuoperception, and visuomotor integration [ • As a result of the everted lower eyelid, children with KS can demonstrate excessive tearing, which is not usually a significant problem. However, nocturnal lagophthalmos, which occurs in many children with KS, can predispose to corneal abrasion and scarring. • Anorectal anomalies including imperforate anus, anovestibular fistula, and anteriorly placed anus [ • Congenital diaphragmatic hernia and eventration of the diaphragm • Cholestasis from a variety of causes • Chronic diarrhea from malabsorption and/or celiac disease • Variable degrees of scoliosis and kyphosis are seen and may be associated with vertebral anomalies (hemivertebrae, butterfly vertebrae, sagittal clefts). • Persistent fetal fingertip pads are considered one of the five cardinal manifestations of KS and are therefore found in a large proportion of affected individuals [ • Absence of digital triradius c and/or d and increased digital loop and hypothenar loop patterns can also be observed, although analysis for these features is not frequently done in current clinical practice. • Other hand findings (brachydactyly V, brachymesophalangy, and clinodactyly of the 5th digits) can also be seen, but these features rarely lead to clinical issues and are used more as a clue to the diagnosis (see • In a study by • After one year of growth hormone treatment, the average height improved from 2.40 to 1.69 SD below the mean [ • Those who initiated growth hormone therapy at an earlier age received the most benefit in terms of catch-up growth. • After one year of growth hormone therapy, body proportions were not significantly affected. • Failure to recognize and treat HI in a timely fashion can lead to irreversible neurologic damage and exacerbate developmental issues. • It is estimated that about 1% of neonates with HI have a diagnosis of KS [ • In a study of 33 individuals with HI and KS (29 of whom had a confirmed molecular diagnosis) seen in an HI specialty clinic, 25/33 (76%) had hypoglycemia that was identified on the first day of life [ • The median age of diagnosis of HI in this study was 1.8 months, with 20/33 (61%) of affected individuals being diagnosed with KS after their diagnosis of HI. The latest age at which HI was diagnosed in this cohort was 28.3 months. This individual experienced resolution of HI at age 10.5 years. • Diazoxide therapy was trialed in 25/33 of the individuals with HI, with a response rate of 92%. • Treatment for HI was able to be discontinued in 15 individuals at a median age of 2.8 years. • Of the affected individuals with HI and a molecular diagnosis of KS, 24/29 (83%) had a pathogenic variant in • The median age of diagnosis of HI in this study was 1.8 months, with 20/33 (61%) of affected individuals being diagnosed with KS after their diagnosis of HI. The latest age at which HI was diagnosed in this cohort was 28.3 months. This individual experienced resolution of HI at age 10.5 years. • Diazoxide therapy was trialed in 25/33 of the individuals with HI, with a response rate of 92%. • Treatment for HI was able to be discontinued in 15 individuals at a median age of 2.8 years. • Of the affected individuals with HI and a molecular diagnosis of KS, 24/29 (83%) had a pathogenic variant in • The median age of diagnosis of HI in this study was 1.8 months, with 20/33 (61%) of affected individuals being diagnosed with KS after their diagnosis of HI. The latest age at which HI was diagnosed in this cohort was 28.3 months. This individual experienced resolution of HI at age 10.5 years. • Diazoxide therapy was trialed in 25/33 of the individuals with HI, with a response rate of 92%. • Treatment for HI was able to be discontinued in 15 individuals at a median age of 2.8 years. • Of the affected individuals with HI and a molecular diagnosis of KS, 24/29 (83%) had a pathogenic variant in • Adrenal insufficiency • Combined pituitary hormone deficiency • Diabetes insipidus • Frank growth hormone deficiency • Hypothyroidism • Primary ovarian dysfunction • True precocious puberty • Frequent and recurrent infections, such as frequent sinopulmonary infections and recurrent otitis media, are found in a majority of affected individuals [ • Hypogammaglobulinemia and IgA deficiency are common. • Diminished B-cell populations have also been reported [ • Autoimmune conditions such as vitiligo, immune thrombocytopenia (ITP), hemolytic anemia, and even diabetes mellitus have also been described in affected individuals, most commonly in childhood or adolescence [ • Hypotonia may contribute to significant feeding problems in infancy (see • Seizures are seen more frequently in KS (10%-39%) than in the general population and represent a spectrum of findings including infantile spasms [ • Cerebellar and brain stem atrophy • Dandy-walker malformation • Delayed myelination • Mild ventriculomegaly • Average IQ scores in individuals with • Neuropsychiatric testing has identified deficits in both comprehension and production of verbal language, but this may be related, in part, to hearing, neurologic, orofacial, and cognitive deficits [ • No specific language profile has been identified. However, all language subdomains including syntax, morphology, pragmatics, and semantics may be affected. • Dysarthria (reduced rate and stress, distorted pitch, harsh vocal quality, hypernasality, and imprecise consonants) has also been described. • On formal neuropsychiatric testing, individuals with KS tend to score better in the areas of vocabulary comprehension and working memory and score lower in the areas of nonverbal reasoning and processing speed [ • No specific language profile has been identified. However, all language subdomains including syntax, morphology, pragmatics, and semantics may be affected. • Dysarthria (reduced rate and stress, distorted pitch, harsh vocal quality, hypernasality, and imprecise consonants) has also been described. • On formal neuropsychiatric testing, individuals with KS tend to score better in the areas of vocabulary comprehension and working memory and score lower in the areas of nonverbal reasoning and processing speed [ • In terms of adaptive skills, individuals with KS have more difficulties with daily living than with communication. • An educational environment that stresses audio-verbal learning over visual learning may beneficial (see • No specific language profile has been identified. However, all language subdomains including syntax, morphology, pragmatics, and semantics may be affected. • Dysarthria (reduced rate and stress, distorted pitch, harsh vocal quality, hypernasality, and imprecise consonants) has also been described. • On formal neuropsychiatric testing, individuals with KS tend to score better in the areas of vocabulary comprehension and working memory and score lower in the areas of nonverbal reasoning and processing speed [ • Attention-deficit disorder and/or hyperactivity are present in a subset of affected individuals. Other behavioral findings including anxiety disorder, self-harm, and sleep disturbance have been rarely reported [ • Autism continues to be a rare but described finding in affected individuals [ ## Growth Individuals with KS typically exhibit normal growth parameters at birth. Infants with KS frequently exhibit failure to thrive for a variety of reasons (see In adolescence and adulthood, more than half of individuals with KS develop obesity [ Without treatment (see • Infants with KS frequently exhibit failure to thrive for a variety of reasons (see • In adolescence and adulthood, more than half of individuals with KS develop obesity [ • Without treatment (see ## Ophthalmologic Ocular findings occur in more than one third of individuals with Kabuki syndrome and include blue sclerae, strabismus, ptosis, coloboma, Marcus Gunn phenomenon (also referred to as jaw winking), and corneal abnormalities such as Peters anomaly. Rarely, more severe eye anomalies may occur, such as optic nerve hypoplasia, colobomatous microphthalmia, and anophthalmia [ Functional visual problems may include difficulties with motor coordination, visuoperception, and visuomotor integration [ As a result of the everted lower eyelid, children with KS can demonstrate excessive tearing, which is not usually a significant problem. However, nocturnal lagophthalmos, which occurs in many children with KS, can predispose to corneal abrasion and scarring. • Rarely, more severe eye anomalies may occur, such as optic nerve hypoplasia, colobomatous microphthalmia, and anophthalmia [ • Functional visual problems may include difficulties with motor coordination, visuoperception, and visuomotor integration [ • As a result of the everted lower eyelid, children with KS can demonstrate excessive tearing, which is not usually a significant problem. However, nocturnal lagophthalmos, which occurs in many children with KS, can predispose to corneal abrasion and scarring. ## Ears and Hearing Most individuals with KS have prominent and cup-shaped ears. Ear pits are also relatively common. From a medical standpoint, chronic otitis media is a major cause of morbidity, including conductive hearing loss. It is not clear, however, whether this finding is related to an underlying susceptibility to infection or to the craniofacial abnormalities, such as palatal insufficiency. Up to 50% of individuals with KS have hearing loss. Although chronic otitis media is the most common cause, sensorineural hearing loss can rarely occur and some individuals have progressive hearing loss. Inner-ear malformations including Mondini dysplasia, vestibular enlargement, aplastic cochlea and semicircular canals, and aqueductal enlargement have been reported. At least one individual with a clinical diagnosis of Kabuki syndrome who had profound progressive sensorineural hearing loss received a cochlear implant with a reported improvement in quality of life [ ## Craniofacial Cleft lip and/or palate affects approximately one third of individuals with KS. Submucous cleft palate may be underascertained [ The typical facial features (elongated palpebral fissures with eversion of the lateral third of the lower eyelid; arched and broad eyebrows; short columella with depressed nasal tip; and large, prominent, or cupped ears) are considered part of the diagnostic criteria of KS and are therefore present in almost all individuals who have a clinical diagnosis of KS. A majority of individuals with a molecularly confirmed diagnosis of KS are also found to have these characteristic facial features [ ## Dental A number of different dental anomalies in individuals with KS have been noted [ ## Cardiovascular Approximately 70% of individuals with KS have a congenital heart defect [ ## Respiratory Eventration of the diaphragm has been rarely reported [ Laryngeal abnormalities may pose problems with anesthesia (see Management, ## Gastrointestinal Feeding difficulties are quite common (~70%) and may be related to hypotonia, poor oromotor coordination, and swallowing difficulties [ Abnormalities involving the gastrointestinal system are not common in KS; however, the following may be seen rarely: Anorectal anomalies including imperforate anus, anovestibular fistula, and anteriorly placed anus [ Congenital diaphragmatic hernia and eventration of the diaphragm Cholestasis from a variety of causes Chronic diarrhea from malabsorption and/or celiac disease • Anorectal anomalies including imperforate anus, anovestibular fistula, and anteriorly placed anus [ • Congenital diaphragmatic hernia and eventration of the diaphragm • Cholestasis from a variety of causes • Chronic diarrhea from malabsorption and/or celiac disease ## Genitourinary Kidney and urinary tract anomalies are seen in more than 25% of affected individuals [ ## Musculoskeletal Joint hypermobility is seen in 50%-75% of individuals with KS. Joint dislocations, especially involving the hips, patellae, and shoulders, are not uncommon. As in most conditions with joint laxity, this finding improves with age. Variable degrees of scoliosis and kyphosis are seen and may be associated with vertebral anomalies (hemivertebrae, butterfly vertebrae, sagittal clefts). Persistent fetal fingertip pads are considered one of the five cardinal manifestations of KS and are therefore found in a large proportion of affected individuals [ Absence of digital triradius c and/or d and increased digital loop and hypothenar loop patterns can also be observed, although analysis for these features is not frequently done in current clinical practice. Other hand findings (brachydactyly V, brachymesophalangy, and clinodactyly of the 5th digits) can also be seen, but these features rarely lead to clinical issues and are used more as a clue to the diagnosis (see • Variable degrees of scoliosis and kyphosis are seen and may be associated with vertebral anomalies (hemivertebrae, butterfly vertebrae, sagittal clefts). • Persistent fetal fingertip pads are considered one of the five cardinal manifestations of KS and are therefore found in a large proportion of affected individuals [ • Absence of digital triradius c and/or d and increased digital loop and hypothenar loop patterns can also be observed, although analysis for these features is not frequently done in current clinical practice. • Other hand findings (brachydactyly V, brachymesophalangy, and clinodactyly of the 5th digits) can also be seen, but these features rarely lead to clinical issues and are used more as a clue to the diagnosis (see ## Endocrine In a study by After one year of growth hormone treatment, the average height improved from 2.40 to 1.69 SD below the mean [ Those who initiated growth hormone therapy at an earlier age received the most benefit in terms of catch-up growth. After one year of growth hormone therapy, body proportions were not significantly affected. Failure to recognize and treat HI in a timely fashion can lead to irreversible neurologic damage and exacerbate developmental issues. It is estimated that about 1% of neonates with HI have a diagnosis of KS [ In a study of 33 individuals with HI and KS (29 of whom had a confirmed molecular diagnosis) seen in an HI specialty clinic, 25/33 (76%) had hypoglycemia that was identified on the first day of life [ The median age of diagnosis of HI in this study was 1.8 months, with 20/33 (61%) of affected individuals being diagnosed with KS after their diagnosis of HI. The latest age at which HI was diagnosed in this cohort was 28.3 months. This individual experienced resolution of HI at age 10.5 years. Diazoxide therapy was trialed in 25/33 of the individuals with HI, with a response rate of 92%. Treatment for HI was able to be discontinued in 15 individuals at a median age of 2.8 years. Of the affected individuals with HI and a molecular diagnosis of KS, 24/29 (83%) had a pathogenic variant in Adrenal insufficiency Combined pituitary hormone deficiency Diabetes insipidus Frank growth hormone deficiency Hypothyroidism Primary ovarian dysfunction True precocious puberty • In a study by • After one year of growth hormone treatment, the average height improved from 2.40 to 1.69 SD below the mean [ • Those who initiated growth hormone therapy at an earlier age received the most benefit in terms of catch-up growth. • After one year of growth hormone therapy, body proportions were not significantly affected. • Failure to recognize and treat HI in a timely fashion can lead to irreversible neurologic damage and exacerbate developmental issues. • It is estimated that about 1% of neonates with HI have a diagnosis of KS [ • In a study of 33 individuals with HI and KS (29 of whom had a confirmed molecular diagnosis) seen in an HI specialty clinic, 25/33 (76%) had hypoglycemia that was identified on the first day of life [ • The median age of diagnosis of HI in this study was 1.8 months, with 20/33 (61%) of affected individuals being diagnosed with KS after their diagnosis of HI. The latest age at which HI was diagnosed in this cohort was 28.3 months. This individual experienced resolution of HI at age 10.5 years. • Diazoxide therapy was trialed in 25/33 of the individuals with HI, with a response rate of 92%. • Treatment for HI was able to be discontinued in 15 individuals at a median age of 2.8 years. • Of the affected individuals with HI and a molecular diagnosis of KS, 24/29 (83%) had a pathogenic variant in • The median age of diagnosis of HI in this study was 1.8 months, with 20/33 (61%) of affected individuals being diagnosed with KS after their diagnosis of HI. The latest age at which HI was diagnosed in this cohort was 28.3 months. This individual experienced resolution of HI at age 10.5 years. • Diazoxide therapy was trialed in 25/33 of the individuals with HI, with a response rate of 92%. • Treatment for HI was able to be discontinued in 15 individuals at a median age of 2.8 years. • Of the affected individuals with HI and a molecular diagnosis of KS, 24/29 (83%) had a pathogenic variant in • The median age of diagnosis of HI in this study was 1.8 months, with 20/33 (61%) of affected individuals being diagnosed with KS after their diagnosis of HI. The latest age at which HI was diagnosed in this cohort was 28.3 months. This individual experienced resolution of HI at age 10.5 years. • Diazoxide therapy was trialed in 25/33 of the individuals with HI, with a response rate of 92%. • Treatment for HI was able to be discontinued in 15 individuals at a median age of 2.8 years. • Of the affected individuals with HI and a molecular diagnosis of KS, 24/29 (83%) had a pathogenic variant in • Adrenal insufficiency • Combined pituitary hormone deficiency • Diabetes insipidus • Frank growth hormone deficiency • Hypothyroidism • Primary ovarian dysfunction • True precocious puberty ## Immunologic Immune dysfunction including both humoral immune deficiency and autoimmune disease has been described [ Frequent and recurrent infections, such as frequent sinopulmonary infections and recurrent otitis media, are found in a majority of affected individuals [ Hypogammaglobulinemia and IgA deficiency are common. Diminished B-cell populations have also been reported [ Autoimmune conditions such as vitiligo, immune thrombocytopenia (ITP), hemolytic anemia, and even diabetes mellitus have also been described in affected individuals, most commonly in childhood or adolescence [ • Frequent and recurrent infections, such as frequent sinopulmonary infections and recurrent otitis media, are found in a majority of affected individuals [ • Hypogammaglobulinemia and IgA deficiency are common. • Diminished B-cell populations have also been reported [ • Autoimmune conditions such as vitiligo, immune thrombocytopenia (ITP), hemolytic anemia, and even diabetes mellitus have also been described in affected individuals, most commonly in childhood or adolescence [ ## Neurologic Most children with KS are hypotonic and joint laxity may be a contributing factor. Hypotonia may contribute to significant feeding problems in infancy (see Seizures are seen more frequently in KS (10%-39%) than in the general population and represent a spectrum of findings including infantile spasms [ • Hypotonia may contribute to significant feeding problems in infancy (see • Seizures are seen more frequently in KS (10%-39%) than in the general population and represent a spectrum of findings including infantile spasms [ ## Neuroimaging Although most people with Kabuki syndrome undergo brain imaging at some point for indications such as seizures and/or developmental delay, major structural brain anomalies are rare. Reported findings have included the following [ Cerebellar and brain stem atrophy Dandy-walker malformation Delayed myelination Mild ventriculomegaly Note: Prior to the identification of the genetic causes of KS, symptomatic Chiari I malformation was reported in multiple affected individuals [ • Cerebellar and brain stem atrophy • Dandy-walker malformation • Delayed myelination • Mild ventriculomegaly ## Development Intellectual disability, usually in the mild to moderate range, has been reported in a majority of individuals; however, reports of rare individuals with pathogenic variants in either Average IQ scores in individuals with Neuropsychiatric testing has identified deficits in both comprehension and production of verbal language, but this may be related, in part, to hearing, neurologic, orofacial, and cognitive deficits [ No specific language profile has been identified. However, all language subdomains including syntax, morphology, pragmatics, and semantics may be affected. Dysarthria (reduced rate and stress, distorted pitch, harsh vocal quality, hypernasality, and imprecise consonants) has also been described. On formal neuropsychiatric testing, individuals with KS tend to score better in the areas of vocabulary comprehension and working memory and score lower in the areas of nonverbal reasoning and processing speed [ In terms of adaptive skills, individuals with KS have more difficulties with daily living than with communication. An educational environment that stresses audio-verbal learning over visual learning may beneficial (see • Average IQ scores in individuals with • Neuropsychiatric testing has identified deficits in both comprehension and production of verbal language, but this may be related, in part, to hearing, neurologic, orofacial, and cognitive deficits [ • No specific language profile has been identified. However, all language subdomains including syntax, morphology, pragmatics, and semantics may be affected. • Dysarthria (reduced rate and stress, distorted pitch, harsh vocal quality, hypernasality, and imprecise consonants) has also been described. • On formal neuropsychiatric testing, individuals with KS tend to score better in the areas of vocabulary comprehension and working memory and score lower in the areas of nonverbal reasoning and processing speed [ • No specific language profile has been identified. However, all language subdomains including syntax, morphology, pragmatics, and semantics may be affected. • Dysarthria (reduced rate and stress, distorted pitch, harsh vocal quality, hypernasality, and imprecise consonants) has also been described. • On formal neuropsychiatric testing, individuals with KS tend to score better in the areas of vocabulary comprehension and working memory and score lower in the areas of nonverbal reasoning and processing speed [ • In terms of adaptive skills, individuals with KS have more difficulties with daily living than with communication. • An educational environment that stresses audio-verbal learning over visual learning may beneficial (see • No specific language profile has been identified. However, all language subdomains including syntax, morphology, pragmatics, and semantics may be affected. • Dysarthria (reduced rate and stress, distorted pitch, harsh vocal quality, hypernasality, and imprecise consonants) has also been described. • On formal neuropsychiatric testing, individuals with KS tend to score better in the areas of vocabulary comprehension and working memory and score lower in the areas of nonverbal reasoning and processing speed [ ## Behavior Individuals with KS tend to be described as pleasant and outgoing. Attention-deficit disorder and/or hyperactivity are present in a subset of affected individuals. Other behavioral findings including anxiety disorder, self-harm, and sleep disturbance have been rarely reported [ Autism continues to be a rare but described finding in affected individuals [ • Attention-deficit disorder and/or hyperactivity are present in a subset of affected individuals. Other behavioral findings including anxiety disorder, self-harm, and sleep disturbance have been rarely reported [ • Autism continues to be a rare but described finding in affected individuals [ ## Benign Tumors Pilomatricomas, benign tumors of the hair shaft that commonly occur on the head and neck, have been described rarely in those with Kabuki syndrome [ ## Malignancies Although pathogenic somatic variants in ## Phenotype Correlations by Gene Those with a In general, those with a Hypoglycemia as a result of hyperinsulinism Note: The overall number of individuals with KS and hyperinsulinism is greater in individuals with a pathogenic variant in Hypertrichosis Long halluces Large central incisors Affected males are more likely to have moderate-to-severe developmental delay / cognitive impairment than are females, who may have mild-to-moderate intellectual disability. In general, females with a pathogenic variant in • Those with a • In general, those with a • Hypoglycemia as a result of hyperinsulinism • Note: The overall number of individuals with KS and hyperinsulinism is greater in individuals with a pathogenic variant in • Hypertrichosis • Long halluces • Large central incisors ## Genotype-Phenotype Correlations Individuals with KS caused by a heterozygous pathogenic missense variants in the terminal regions of Individuals with KS caused by a whole-gene deletion of Note: Individuals with a heterozygous pathogenic variant involving exons 38 or 39 potentially resulting in a gain of function may have some features similar to KS but otherwise have a phenotype that is noticeably different from KS (see Based on small numbers of individuals with Splice site variants, as compared to nonsense, missense, and small in/dels, are the most common type of single-nucleotide variant in individuals with • Individuals with KS caused by a heterozygous pathogenic missense variants in the terminal regions of • Individuals with KS caused by a whole-gene deletion of • Based on small numbers of individuals with • Splice site variants, as compared to nonsense, missense, and small in/dels, are the most common type of single-nucleotide variant in individuals with ## Penetrance Penetrance for pathogenic variants in ## Prevalence The prevalence of KS in Japan is estimated at 1:32,000 live births [ ## Genetically Related (Allelic) Disorders ## Differential Diagnosis Disorders to Consider in the Differential Diagnosis of Kabuki Syndrome (KS) Cleft palate Congenital heart defects Ocular coloboma Growth restriction Square face Short, wide ear w/little or no earlobe Prominent columella Broad nasal root Cleft palate Congenital heart defects Urinary tract anomalies Short & narrow palpebral fissures w/hooded eyelids Bulbous nasal tip Small, C-shaped ears w/overfolded superior &/or lateral helices Cleft lip & palate Lip pits Pterygia is not expected in KS. Ear pits Cupped ears Hearing loss Kidney anomalies Otherwise normal craniofacies, growth, & development Common kidney anomalies incl renal hypoplasia &/or agenesis (vs in KS: common kidney anomalies incl hydronephrosis & malposition). Branchial cleft cysts may be present (not reported in KS). Significant joint hypermobility (incl congenital hip dislocation & patellar dislocations) Blue sclerae Similar facial features Congenital heart defects Growth restriction Prolonged hyperbilirubinemia Cleft lip & palate AD = autosomal dominant; CHARGE = Deletion of genes within the DiGeorge chromosome region is the only genetic abnormality known to be associated with 22q11.2 deletion syndrome. Although Dependent on anomaly • Cleft palate • Congenital heart defects • Ocular coloboma • Growth restriction • Square face • Short, wide ear w/little or no earlobe • Prominent columella • Broad nasal root • Cleft palate • Congenital heart defects • Urinary tract anomalies • Short & narrow palpebral fissures w/hooded eyelids • Bulbous nasal tip • Small, C-shaped ears w/overfolded superior &/or lateral helices • Cleft lip & palate • Lip pits • Pterygia is not expected in KS. • Ear pits • Cupped ears • Hearing loss • Kidney anomalies • Otherwise normal craniofacies, growth, & development • Common kidney anomalies incl renal hypoplasia &/or agenesis (vs in KS: common kidney anomalies incl hydronephrosis & malposition). • Branchial cleft cysts may be present (not reported in KS). • Significant joint hypermobility (incl congenital hip dislocation & patellar dislocations) • Blue sclerae • Similar facial features • Congenital heart defects • Growth restriction • Prolonged hyperbilirubinemia • Cleft lip & palate ## Management Comprehensive management guidelines for Kabuki syndrome (KS) were developed in 2010 but have not been updated; these guidelines are available To establish the extent of disease and the needs of an individual diagnosed with KS, the following evaluations are recommended if they have not already been completed: Recommended Evaluations Following Initial Diagnosis in Individuals with Kabuki Syndrome Consider plotting growth on Growth restriction & poor weight gain are common sequela of feeding difficulties. Consider assessment by feeding team &/or VFSS for those w/suspected dysphagia. Infants may have FTT; adolescents & adults may have obesity. Levels are abnormal; or Person has history of recurrent infections. Structural brain malformation in those w/seizures Chiari I malformation in those w/suggestive symptoms ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; FTT = failure to thrive; GERD = gastroesophageal reflux disease; KS = Kabuki syndrome; VFSS = videofluoroscopic swallowing study This may include collection of a "critical sample," such as obtaining plasma levels of insulin, free fatty acids, beta-hydroxybutyrate, and glycemic response to glucagon during a period of low plasma glucose [ Thyroid function tests may include free T4 and TSH levels. Assessment for growth hormone deficiency can be challenging and is best directed by an endocrinologist. Tests may include measurement of insulin-like growth factor 1 (IGF-1) and IGF binding protein 3, in addition to consideration of a growth hormone stimulation test using either arginine or clonidine [ Symptoms may include headaches, ocular disturbances, otoneurologic disturbances, lower cranial nerve signs, cerebellar ataxia, spasticity, or seizures. Treatment of Manifestations in Individuals with Kabuki Syndrome Pressure-equalizing tubes for those w/conductive hearing loss; Hearing aids for those w/sensorineural hearing loss. Management through a specialized craniofacial clinic is ideal. The palate may be shorter, which can lead to velopharyngeal insufficiency after typical cleft repair. KS = Kabuki syndrome Cochlear implants can also be considered, as per ENT and audiologist recommendations. 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. Neurodevelopmental therapies should target language and motor abilities to improve daily living skills and behaviors [ In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. In the US: Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility. Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat ADHD, when necessary. Recommended Surveillance for Individuals with Kabuki Syndrome Adolescents and adults may develop obesity. In those with joint laxity, activities that increase the risk of joint damage (e.g., bouncing on a trampoline) should be avoided. See Based on the function of Since ketosis acts as an endogenous HDACi, others have hypothesized that placing individuals with KS on a ketogenic diet could improve their cognitive issues [ Search • Consider plotting growth on • Growth restriction & poor weight gain are common sequela of feeding difficulties. • Consider assessment by feeding team &/or VFSS for those w/suspected dysphagia. • Infants may have FTT; adolescents & adults may have obesity. • Levels are abnormal; or • Person has history of recurrent infections. • Structural brain malformation in those w/seizures • Chiari I malformation in those w/suggestive symptoms • Pressure-equalizing tubes for those w/conductive hearing loss; • Hearing aids for those w/sensorineural hearing loss. • Management through a specialized craniofacial clinic is ideal. • The palate may be shorter, which can lead to velopharyngeal insufficiency after typical cleft repair. • In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. • Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • Physical therapy is recommended to maximize mobility. • Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## Evaluations Following Initial Diagnosis To establish the extent of disease and the needs of an individual diagnosed with KS, the following evaluations are recommended if they have not already been completed: Recommended Evaluations Following Initial Diagnosis in Individuals with Kabuki Syndrome Consider plotting growth on Growth restriction & poor weight gain are common sequela of feeding difficulties. Consider assessment by feeding team &/or VFSS for those w/suspected dysphagia. Infants may have FTT; adolescents & adults may have obesity. Levels are abnormal; or Person has history of recurrent infections. Structural brain malformation in those w/seizures Chiari I malformation in those w/suggestive symptoms ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; FTT = failure to thrive; GERD = gastroesophageal reflux disease; KS = Kabuki syndrome; VFSS = videofluoroscopic swallowing study This may include collection of a "critical sample," such as obtaining plasma levels of insulin, free fatty acids, beta-hydroxybutyrate, and glycemic response to glucagon during a period of low plasma glucose [ Thyroid function tests may include free T4 and TSH levels. Assessment for growth hormone deficiency can be challenging and is best directed by an endocrinologist. Tests may include measurement of insulin-like growth factor 1 (IGF-1) and IGF binding protein 3, in addition to consideration of a growth hormone stimulation test using either arginine or clonidine [ Symptoms may include headaches, ocular disturbances, otoneurologic disturbances, lower cranial nerve signs, cerebellar ataxia, spasticity, or seizures. • Consider plotting growth on • Growth restriction & poor weight gain are common sequela of feeding difficulties. • Consider assessment by feeding team &/or VFSS for those w/suspected dysphagia. • Infants may have FTT; adolescents & adults may have obesity. • Levels are abnormal; or • Person has history of recurrent infections. • Structural brain malformation in those w/seizures • Chiari I malformation in those w/suggestive symptoms ## Treatment of Manifestations Treatment of Manifestations in Individuals with Kabuki Syndrome Pressure-equalizing tubes for those w/conductive hearing loss; Hearing aids for those w/sensorineural hearing loss. Management through a specialized craniofacial clinic is ideal. The palate may be shorter, which can lead to velopharyngeal insufficiency after typical cleft repair. KS = Kabuki syndrome Cochlear implants can also be considered, as per ENT and audiologist recommendations. 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. Neurodevelopmental therapies should target language and motor abilities to improve daily living skills and behaviors [ In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. In the US: Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility. Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat ADHD, when necessary. • Pressure-equalizing tubes for those w/conductive hearing loss; • Hearing aids for those w/sensorineural hearing loss. • Management through a specialized craniofacial clinic is ideal. • The palate may be shorter, which can lead to velopharyngeal insufficiency after typical cleft repair. • In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. • Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • Physical therapy is recommended to maximize mobility. • Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## Developmental Delay / Intellectual Disability Management Issues 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. Neurodevelopmental therapies should target language and motor abilities to improve daily living skills and behaviors [ In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. In the US: Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. • Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. ## Motor Dysfunction Physical therapy is recommended to maximize mobility. Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • Physical therapy is recommended to maximize mobility. • Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## Social/Behavioral Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat ADHD, when necessary. ## Surveillance Recommended Surveillance for Individuals with Kabuki Syndrome Adolescents and adults may develop obesity. ## Agents/Circumstances to Avoid In those with joint laxity, activities that increase the risk of joint damage (e.g., bouncing on a trampoline) should be avoided. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Based on the function of Since ketosis acts as an endogenous HDACi, others have hypothesized that placing individuals with KS on a ketogenic diet could improve their cognitive issues [ Search ## Genetic Counseling A minority of individuals diagnosed with A proband with Recommended evaluations for the parents of a proband include: Molecular genetic testing if the pathogenic variant in the proband has been identified. If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a If the pathogenic variant in the proband is not known, clinical evaluation of the proband's parents, including a thorough physical examination by a clinical geneticist, is indicated to evaluate for any phenotypic features consistent with KS. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed. Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected [ The risk to the sibs of the proband depends on the genetic status of the proband's parents. If a parent of the proband is affected, the risk to the sibs is 50%. If the If both parents are clinically unaffected but have not been tested for the 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 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 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 are carriers. Once the pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for Kabuki syndrome are possible. • A minority of individuals diagnosed with • A proband with • Recommended evaluations for the parents of a proband include: • Molecular genetic testing if the pathogenic variant in the proband has been identified. If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a • If the pathogenic variant in the proband is not known, clinical evaluation of the proband's parents, including a thorough physical examination by a clinical geneticist, is indicated to evaluate for any phenotypic features consistent with KS. • Molecular genetic testing if the pathogenic variant in the proband has been identified. If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a • If the pathogenic variant in the proband is not known, clinical evaluation of the proband's parents, including a thorough physical examination by a clinical geneticist, is indicated to evaluate for any phenotypic features consistent with KS. • Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed. • Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected [ • Molecular genetic testing if the pathogenic variant in the proband has been identified. If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a • If the pathogenic variant in the proband is not known, clinical evaluation of the proband's parents, including a thorough physical examination by a clinical geneticist, is indicated to evaluate for any phenotypic features consistent with KS. • 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 a parent of the proband is affected, the risk to the sibs is 50%. • If the • If both parents are clinically unaffected but have not been tested for the • If a parent of the proband is affected, the risk to the sibs is 50%. • If the • 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 • 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 • 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 are carriers. ## Mode of Inheritance ## Autosomal Dominant Inheritance – Risk to Family Members A minority of individuals diagnosed with A proband with Recommended evaluations for the parents of a proband include: Molecular genetic testing if the pathogenic variant in the proband has been identified. If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a If the pathogenic variant in the proband is not known, clinical evaluation of the proband's parents, including a thorough physical examination by a clinical geneticist, is indicated to evaluate for any phenotypic features consistent with KS. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed. Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected [ The risk to the sibs of the proband depends on the genetic status of the proband's parents. If a parent of the proband is affected, the risk to the sibs is 50%. If the If both parents are clinically unaffected but have not been tested for the • A minority of individuals diagnosed with • A proband with • Recommended evaluations for the parents of a proband include: • Molecular genetic testing if the pathogenic variant in the proband has been identified. If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a • If the pathogenic variant in the proband is not known, clinical evaluation of the proband's parents, including a thorough physical examination by a clinical geneticist, is indicated to evaluate for any phenotypic features consistent with KS. • Molecular genetic testing if the pathogenic variant in the proband has been identified. If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a • If the pathogenic variant in the proband is not known, clinical evaluation of the proband's parents, including a thorough physical examination by a clinical geneticist, is indicated to evaluate for any phenotypic features consistent with KS. • Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed. • Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected [ • Molecular genetic testing if the pathogenic variant in the proband has been identified. If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a • If the pathogenic variant in the proband is not known, clinical evaluation of the proband's parents, including a thorough physical examination by a clinical geneticist, is indicated to evaluate for any phenotypic features consistent with KS. • 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 a parent of the proband is affected, the risk to the sibs is 50%. • If the • If both parents are clinically unaffected but have not been tested for the • If a parent of the proband is affected, the risk to the sibs is 50%. • If the ## X-Linked Inheritance – Risk to Family Members The father of an affected male will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have 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 • 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 • 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 ## Related Genetic Counseling Issues 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 are carriers. • 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 are carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for Kabuki syndrome are possible. ## Resources Northbrook IL 60065 • • • • Northbrook IL 60065 • • • ## Molecular Genetics Kabuki Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Kabuki Syndrome ( Both KDM6A and KMT2D work as part of a complex of proteins termed the ASCOM complex. The function of this complex is to remove repressive epigenetic marks and deposit activating methylation marks on chromatin. This then recruits RNA polymerase II complex, resulting in an activated chromatin state [ ## Molecular Pathogenesis Both KDM6A and KMT2D work as part of a complex of proteins termed the ASCOM complex. The function of this complex is to remove repressive epigenetic marks and deposit activating methylation marks on chromatin. This then recruits RNA polymerase II complex, resulting in an activated chromatin state [ ## Cancer and Benign Tumors ## Chapter Notes Margaret P Adam, MD, MS, FAAP, FACMG (2011-present)Mark Hannibal, MD, PhD (2011-present)Louanne Hudgins, MD; Stanford University (2011-2025) 14 August 2025 (aa) Revision: 13 March 2025 (ma) Revision: added information regarding hyperinsulinism in Kabuki syndrome [ 25 April 2024 (ma) Revision: 15 September 2022 (sw) Revision: epigenetic signature analysis ( 15 July 2021 (ma) Revision: added 21 October 2019 (aa) Revision: X-linked inheritance added to Summary 28 January 2019 (sw) Comprehensive update posted live 1 September 2011 (me) Review posted live 8 July 2011 (ma) Original submission • 14 August 2025 (aa) Revision: • 13 March 2025 (ma) Revision: added information regarding hyperinsulinism in Kabuki syndrome [ • 25 April 2024 (ma) Revision: • 15 September 2022 (sw) Revision: epigenetic signature analysis ( • 15 July 2021 (ma) Revision: added • 21 October 2019 (aa) Revision: X-linked inheritance added to Summary • 28 January 2019 (sw) Comprehensive update posted live • 1 September 2011 (me) Review posted live • 8 July 2011 (ma) Original submission ## Author History Margaret P Adam, MD, MS, FAAP, FACMG (2011-present)Mark Hannibal, MD, PhD (2011-present)Louanne Hudgins, MD; Stanford University (2011-2025) ## Revision History 14 August 2025 (aa) Revision: 13 March 2025 (ma) Revision: added information regarding hyperinsulinism in Kabuki syndrome [ 25 April 2024 (ma) Revision: 15 September 2022 (sw) Revision: epigenetic signature analysis ( 15 July 2021 (ma) Revision: added 21 October 2019 (aa) Revision: X-linked inheritance added to Summary 28 January 2019 (sw) Comprehensive update posted live 1 September 2011 (me) Review posted live 8 July 2011 (ma) Original submission • 14 August 2025 (aa) Revision: • 13 March 2025 (ma) Revision: added information regarding hyperinsulinism in Kabuki syndrome [ • 25 April 2024 (ma) Revision: • 15 September 2022 (sw) Revision: epigenetic signature analysis ( • 15 July 2021 (ma) Revision: added • 21 October 2019 (aa) Revision: X-linked inheritance added to Summary • 28 January 2019 (sw) Comprehensive update posted live • 1 September 2011 (me) Review posted live • 8 July 2011 (ma) Original submission ## References Kabuki Syndrome Guideline Development Group. Management of Kabuki Syndrome – A Clinical Guideline (pdf). Available • Kabuki Syndrome Guideline Development Group. Management of Kabuki Syndrome – A Clinical Guideline (pdf). Available ## Published Guidelines / Consensus Statements Kabuki Syndrome Guideline Development Group. Management of Kabuki Syndrome – A Clinical Guideline (pdf). Available • Kabuki Syndrome Guideline Development Group. Management of Kabuki Syndrome – A Clinical Guideline (pdf). Available ## Literature Cited	[]	1/9/2011	28/2/2019	14/8/2025	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
kagami-ogata	kagami-ogata	[ "KOS14", "KOS14", "Kagami-Ogata Syndrome" ]	Kagami-Ogata Syndrome	Tsutomu Ogata, Masayo Kagami	Summary Kagami-Ogata syndrome is characterized by developmental delay, intellectual disability, feeding difficulty with impaired swallowing, full cheeks, prominent and deep philtrum, small bell-shaped thorax with coat-hanger appearance of the ribs, and abdominal wall defects (omphalocele and diastasis recti). Additional common features include joint contractures, kyphoscoliosis, coxa valga, and laryngomalacia. Cardiac disease and hepatoblastoma have also been reported. The diagnosis of Kagami-Ogata syndrome is established in a proband with suggestive findings and findings on molecular genetic testing that suggest deficient expression of the The recurrence risk of Kagami-Ogata syndrome is dependent on the genetic mechanism underlying deficient expression of the maternal	## Diagnosis No consensus clinical diagnostic criteria for Kagami-Ogata syndrome have been published. Kagami-Ogata syndrome Full cheeks and prominent and deep philtrum (See Small bell-shaped thorax with coat-hanger appearance of the ribs (See Note: Coat-hanger angle is increased from mid-gestation through childhood. Mid-to-widest thorax ratio is decreased from birth through early childhood [ Abdominal wall defects such as omphalocele and diastasis recti Placentomegaly Polyhydramnios Craniofaciocervical features such as frontal bossing, hirsute forehead, blepharophimosis, depressed nasal bridge, anteverted nares, puckered lips, micrognathia, and short, webbed neck Relatively large birth weight Developmental delay (moderate to severe) Feeding difficulty with impaired swallowing Joint contractures Kyphoscoliosis The diagnosis of Kagami-Ogata syndrome Paternal uniparental disomy of chromosome 14 (upd(14)pat) (~50% of affected individuals) Epimutation (hypermethylation) affecting the normally unmethylated Deletion of the maternally inherited 14q32.2 region that includes Deletion of the maternally inherited Translocation (or inversion) disrupting the integrity between the maternally inherited Methylation analysis (methylation-specific PCR, bisulfite sequencing, and pyrosequencing) can detect abnormal methylation pattern at 14q32.2 but cannot distinguish deletion from upd(14)pat and epimutation. High-density SNP array analysis can detect smaller deletions and uniparental isodisomy of 14q32.2 but cannot detect uniparental heterodisomy of 14q32.2. Molecular Genetic Testing Used in Kagami-Ogata Syndrome DMR = differentially methylated region; IG = intergenic; MS-MLPA = methylation-specific multiple ligation-dependent probe amplification; TSS = transcription start site; upd(14)pat = paternal uniparental disomy of chromosome 14 See Identification of hypermethylation of Parent-of-origin analysis is necessary to confirm that the Deletion of A translocation disrupting the integrity between the maternally inherited • Full cheeks and prominent and deep philtrum (See • Small bell-shaped thorax with coat-hanger appearance of the ribs (See • Note: Coat-hanger angle is increased from mid-gestation through childhood. Mid-to-widest thorax ratio is decreased from birth through early childhood [ • Abdominal wall defects such as omphalocele and diastasis recti • Placentomegaly • Polyhydramnios • Craniofaciocervical features such as frontal bossing, hirsute forehead, blepharophimosis, depressed nasal bridge, anteverted nares, puckered lips, micrognathia, and short, webbed neck • Relatively large birth weight • Developmental delay (moderate to severe) • Feeding difficulty with impaired swallowing • Joint contractures • Kyphoscoliosis • Paternal uniparental disomy of chromosome 14 (upd(14)pat) (~50% of affected individuals) • Epimutation (hypermethylation) affecting the normally unmethylated • Deletion of the maternally inherited 14q32.2 region that includes • Deletion of the maternally inherited • Translocation (or inversion) disrupting the integrity between the maternally inherited • Methylation analysis (methylation-specific PCR, bisulfite sequencing, and pyrosequencing) can detect abnormal methylation pattern at 14q32.2 but cannot distinguish deletion from upd(14)pat and epimutation. • High-density SNP array analysis can detect smaller deletions and uniparental isodisomy of 14q32.2 but cannot detect uniparental heterodisomy of 14q32.2. ## Suggestive Findings Kagami-Ogata syndrome Full cheeks and prominent and deep philtrum (See Small bell-shaped thorax with coat-hanger appearance of the ribs (See Note: Coat-hanger angle is increased from mid-gestation through childhood. Mid-to-widest thorax ratio is decreased from birth through early childhood [ Abdominal wall defects such as omphalocele and diastasis recti Placentomegaly Polyhydramnios Craniofaciocervical features such as frontal bossing, hirsute forehead, blepharophimosis, depressed nasal bridge, anteverted nares, puckered lips, micrognathia, and short, webbed neck Relatively large birth weight Developmental delay (moderate to severe) Feeding difficulty with impaired swallowing Joint contractures Kyphoscoliosis • Full cheeks and prominent and deep philtrum (See • Small bell-shaped thorax with coat-hanger appearance of the ribs (See • Note: Coat-hanger angle is increased from mid-gestation through childhood. Mid-to-widest thorax ratio is decreased from birth through early childhood [ • Abdominal wall defects such as omphalocele and diastasis recti • Placentomegaly • Polyhydramnios • Craniofaciocervical features such as frontal bossing, hirsute forehead, blepharophimosis, depressed nasal bridge, anteverted nares, puckered lips, micrognathia, and short, webbed neck • Relatively large birth weight • Developmental delay (moderate to severe) • Feeding difficulty with impaired swallowing • Joint contractures • Kyphoscoliosis ## Establishing the Diagnosis The diagnosis of Kagami-Ogata syndrome Paternal uniparental disomy of chromosome 14 (upd(14)pat) (~50% of affected individuals) Epimutation (hypermethylation) affecting the normally unmethylated Deletion of the maternally inherited 14q32.2 region that includes Deletion of the maternally inherited Translocation (or inversion) disrupting the integrity between the maternally inherited Methylation analysis (methylation-specific PCR, bisulfite sequencing, and pyrosequencing) can detect abnormal methylation pattern at 14q32.2 but cannot distinguish deletion from upd(14)pat and epimutation. High-density SNP array analysis can detect smaller deletions and uniparental isodisomy of 14q32.2 but cannot detect uniparental heterodisomy of 14q32.2. Molecular Genetic Testing Used in Kagami-Ogata Syndrome DMR = differentially methylated region; IG = intergenic; MS-MLPA = methylation-specific multiple ligation-dependent probe amplification; TSS = transcription start site; upd(14)pat = paternal uniparental disomy of chromosome 14 See Identification of hypermethylation of Parent-of-origin analysis is necessary to confirm that the Deletion of A translocation disrupting the integrity between the maternally inherited • Paternal uniparental disomy of chromosome 14 (upd(14)pat) (~50% of affected individuals) • Epimutation (hypermethylation) affecting the normally unmethylated • Deletion of the maternally inherited 14q32.2 region that includes • Deletion of the maternally inherited • Translocation (or inversion) disrupting the integrity between the maternally inherited • Methylation analysis (methylation-specific PCR, bisulfite sequencing, and pyrosequencing) can detect abnormal methylation pattern at 14q32.2 but cannot distinguish deletion from upd(14)pat and epimutation. • High-density SNP array analysis can detect smaller deletions and uniparental isodisomy of 14q32.2 but cannot detect uniparental heterodisomy of 14q32.2. ## First-Tier Testing ## Second-Tier Testing Methylation analysis (methylation-specific PCR, bisulfite sequencing, and pyrosequencing) can detect abnormal methylation pattern at 14q32.2 but cannot distinguish deletion from upd(14)pat and epimutation. High-density SNP array analysis can detect smaller deletions and uniparental isodisomy of 14q32.2 but cannot detect uniparental heterodisomy of 14q32.2. Molecular Genetic Testing Used in Kagami-Ogata Syndrome DMR = differentially methylated region; IG = intergenic; MS-MLPA = methylation-specific multiple ligation-dependent probe amplification; TSS = transcription start site; upd(14)pat = paternal uniparental disomy of chromosome 14 See Identification of hypermethylation of Parent-of-origin analysis is necessary to confirm that the Deletion of A translocation disrupting the integrity between the maternally inherited • Methylation analysis (methylation-specific PCR, bisulfite sequencing, and pyrosequencing) can detect abnormal methylation pattern at 14q32.2 but cannot distinguish deletion from upd(14)pat and epimutation. • High-density SNP array analysis can detect smaller deletions and uniparental isodisomy of 14q32.2 but cannot detect uniparental heterodisomy of 14q32.2. ## Clinical Characteristics Kagami-Ogata syndrome is characterized by developmental delay, intellectual disability, feeding difficulty, full cheeks and prominent and deep philtrum, small bell-shaped thorax with coat-hanger appearance of the ribs, and abdominal wall defects (omphalocele and diastasis recti). Additional common features include joint contractures, kyphoscoliosis, coxa valga, and laryngomalacia. Cardiac disease and hepatoblastoma have also been reported [ Kagami-Ogata Syndrome: Frequency of Select Features SD = standard deviations No abnormal brain MRI findings were delineated in five individuals examined. No clear genotype-phenotype correlations have been identified [ Note: Paternal uniparental disomy of chromosome 14, epimutations, and deletions that do not include Penetrance is complete, and affected individuals invariably show full cheeks, prominent and deep philtrum, and small bell-shaped thorax with coat-hanger appearance of the ribs. However, there could be bias in that molecular studies are performed only when individuals have certain clinical features. In this regard, two individuals with upd(14)pat mosaicism have been reported to date; one individual has a mild phenotype, while the other has a typical Kagami-Ogata syndrome phenotype [ Kagami-Ogata syndrome has also been referred to as upd(14)pat syndrome. However, the term upd(14)pat syndrome may be misleading, as Kagami-Ogata syndrome can be caused by genetic mechanisms other than paternal uniparental disomy of chromosome 14. Thus, "Kagami-Ogata syndrome" has been proposed to describe the unique clinical entity caused by various (epi)genetic aberrations affecting the chromosome 14q32.2 imprinted region. To date, approximately 100 individuals with Kagami-Ogata syndrome have been reported [ ## Clinical Description Kagami-Ogata syndrome is characterized by developmental delay, intellectual disability, feeding difficulty, full cheeks and prominent and deep philtrum, small bell-shaped thorax with coat-hanger appearance of the ribs, and abdominal wall defects (omphalocele and diastasis recti). Additional common features include joint contractures, kyphoscoliosis, coxa valga, and laryngomalacia. Cardiac disease and hepatoblastoma have also been reported [ Kagami-Ogata Syndrome: Frequency of Select Features SD = standard deviations No abnormal brain MRI findings were delineated in five individuals examined. ## Genotype-Phenotype Correlations No clear genotype-phenotype correlations have been identified [ Note: Paternal uniparental disomy of chromosome 14, epimutations, and deletions that do not include ## Penetrance Penetrance is complete, and affected individuals invariably show full cheeks, prominent and deep philtrum, and small bell-shaped thorax with coat-hanger appearance of the ribs. However, there could be bias in that molecular studies are performed only when individuals have certain clinical features. In this regard, two individuals with upd(14)pat mosaicism have been reported to date; one individual has a mild phenotype, while the other has a typical Kagami-Ogata syndrome phenotype [ ## Nomenclature Kagami-Ogata syndrome has also been referred to as upd(14)pat syndrome. However, the term upd(14)pat syndrome may be misleading, as Kagami-Ogata syndrome can be caused by genetic mechanisms other than paternal uniparental disomy of chromosome 14. Thus, "Kagami-Ogata syndrome" has been proposed to describe the unique clinical entity caused by various (epi)genetic aberrations affecting the chromosome 14q32.2 imprinted region. ## Prevalence To date, approximately 100 individuals with Kagami-Ogata syndrome have been reported [ ## Genetically Related (Allelic) Disorders ## Differential Diagnosis Disorders of Interest in the Differential Diagnosis of Kagami-Ogata Syndrome Polyhydramnios Placentomegaly Omphalocele Overgrowth Hepatoblastoma (↑ risk) Characteristic face w/full cheeks & prominent & deep philtrum Small bell-shaped thorax w/coat-hanger appearance of ribs Polyhydramnios Abdominal wall defects Overgrowth Hepatoblastoma (↑ risk) AR = autosomal recessive; CNV = copy number variant; MOI = mode of inheritance; XL = X-linked Reliable recurrence risk assessment requires identification of the genetic mechanism in the proband that underlies the abnormal expression of imprinted genes in the BWS critical region. While the majority of families have a recurrence risk of less than 1%, certain underlying genetic mechanisms may be associated with a recurrence risk as high as 50% (see • Polyhydramnios • Placentomegaly • Omphalocele • Overgrowth • Hepatoblastoma (↑ risk) • Characteristic face w/full cheeks & prominent & deep philtrum • Small bell-shaped thorax w/coat-hanger appearance of ribs • Polyhydramnios • Abdominal wall defects • Overgrowth • Hepatoblastoma (↑ risk) ## Management No clinical practice guidelines for Kagami-Ogata syndrome have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder. To establish the extent of disease and needs in an individual diagnosed with Kagami-Ogata syndrome, the evaluations summarized in Kagami-Ogata Syndrome: Recommended Evaluations Following Initial Diagnosis To incl gross motor & fine motor skills, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Contractures & kyphoscoliosis Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Gastroenterology / nutrition / feeding team eval Assessment of height & weight To incl eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. Community or online Social work involvement for parental support Home nursing referral ADL = activities of daily living; AFP = alpha-fetoprotein; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Kagami-Ogata Syndrome: Treatment of Manifestations Mechanical ventilation & oxygen therapy are almost invariably required immediately after birth. Tracheostomy may be required. Monitor for & treat upper & lower respiratory tract infections. Treatment of kyphoscoliosis per orthopedist; brace or surgery may be indicated. Treatment per rehab medicine specialist for joint contractures Tube feeding is almost invariably required. Gastrostomy tube feeding as needed Feeding training/rehab is recommended. In the absence of knowledge about the detailed clinical course of Kagami-Ogata syndrome, careful follow up appropriate for each affected individual is recommended. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Kagami-Ogata Syndrome: Recommended Surveillance Abdominal ultrasound Serum AFP AFP = alpha-fetoprotein This screening has been recommended for hepatoblastoma in Beckwith-Wiedemann syndrome [ Avoid exposure to respiratory infections; individuals with Kagami-Ogata syndrome may develop respiratory failure with respiratory infections, especially during infancy. See Search • To incl gross motor & fine motor skills, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Contractures & kyphoscoliosis • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Gastroenterology / nutrition / feeding team eval • Assessment of height & weight • To incl eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. • Community or online • Social work involvement for parental support • Home nursing referral • Mechanical ventilation & oxygen therapy are almost invariably required immediately after birth. • Tracheostomy may be required. • Monitor for & treat upper & lower respiratory tract infections. • Treatment of kyphoscoliosis per orthopedist; brace or surgery may be indicated. • Treatment per rehab medicine specialist for joint contractures • Tube feeding is almost invariably required. • Gastrostomy tube feeding as needed • Feeding training/rehab is recommended. • Abdominal ultrasound • Serum AFP ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Kagami-Ogata syndrome, the evaluations summarized in Kagami-Ogata Syndrome: Recommended Evaluations Following Initial Diagnosis To incl gross motor & fine motor skills, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Contractures & kyphoscoliosis Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Gastroenterology / nutrition / feeding team eval Assessment of height & weight To incl eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. Community or online Social work involvement for parental support Home nursing referral ADL = activities of daily living; AFP = alpha-fetoprotein; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse • To incl gross motor & fine motor skills, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Contractures & kyphoscoliosis • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Gastroenterology / nutrition / feeding team eval • Assessment of height & weight • To incl eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. • 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 Kagami-Ogata Syndrome: Treatment of Manifestations Mechanical ventilation & oxygen therapy are almost invariably required immediately after birth. Tracheostomy may be required. Monitor for & treat upper & lower respiratory tract infections. Treatment of kyphoscoliosis per orthopedist; brace or surgery may be indicated. Treatment per rehab medicine specialist for joint contractures Tube feeding is almost invariably required. Gastrostomy tube feeding as needed Feeding training/rehab is recommended. In the absence of knowledge about the detailed clinical course of Kagami-Ogata syndrome, careful follow up appropriate for each affected individual is recommended. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies. • Mechanical ventilation & oxygen therapy are almost invariably required immediately after birth. • Tracheostomy may be required. • Monitor for & treat upper & lower respiratory tract infections. • Treatment of kyphoscoliosis per orthopedist; brace or surgery may be indicated. • Treatment per rehab medicine specialist for joint contractures • Tube feeding is almost invariably required. • Gastrostomy tube feeding as needed • Feeding training/rehab is recommended. ## Developmental Delay / Intellectual Disability Management Issues In the absence of knowledge about the detailed clinical course of Kagami-Ogata syndrome, careful follow up appropriate for each affected individual is recommended. ## Motor Dysfunction ## Neurobehavioral/Psychiatric Concerns Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Kagami-Ogata Syndrome: Recommended Surveillance Abdominal ultrasound Serum AFP AFP = alpha-fetoprotein This screening has been recommended for hepatoblastoma in Beckwith-Wiedemann syndrome [ • Abdominal ultrasound • Serum AFP ## Agents/Circumstances to Avoid Avoid exposure to respiratory infections; individuals with Kagami-Ogata syndrome may develop respiratory failure with respiratory infections, especially during infancy. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling The recurrence risk of Kagami-Ogata syndrome is dependent on the genetic mechanism underlying deficient expression of the maternal Paternal uniparental disomy of chromosome 14 (upd(14)pat) * Epimutation (hypermethylation) of the normally unmethylated Deletion of the 14q32.2 region that includes Translocation (or inversion) disrupting the integrity between the maternally inherited In most affected individuals, the underlying genetic mechanism occurs as a * If the diagnosis of Kagami-Ogata syndrome in the proband has been established by identification of hypermethylation of The parents of a proband with Kagami-Ogata syndrome are not affected with Kagami-Ogata syndrome but may have a predisposing genetic alteration associated with the disorder such the following: Maternal deletion involving the DMRs ( If a proband with Kagami-Ogata syndrome has a maternally inherited deletion, the mother with the same deletion is theoretically predicted to have Kagami-Ogata syndrome when the deletion is derived from her mother, or Temple syndrome when the deletion is derived from her father and involves Transmission of a deletion from a mother with Temple syndrome to a child with Kagami-Ogata syndrome has been reported in several families [ Maternal translocation (or inversion) disrupting the integrity between the Paternal or maternal robertsonian translocation involving chromosome 14 or isochromosome 14q (1(14q)). Evaluation of the parents to clarify recurrence risk is recommended; specific testing recommendations depend on the genetic mechanism underlying Kagami-Ogata syndrome in the proband (see If both parents have normal karyotypes, it is presumed that upd(14)pat occurred in the proband as a If either of the parents has a robertsonian translocation or i(14q), the recurrence risk to sibs is increased. Note: While upd(14)pat mediated by parental robertsonian translocation has been identified in multiple individuals with Kagami-Ogata syndrome [ If the deletion identified in the proband is not identified in maternal leukocyte DNA, it is presumed that the deletion occurred in the proband as a If the mother of the proband has the deletion, the risk to sibs is 50%. Recurrence of Kagami-Ogata syndrome has been reported in sibs with maternally derived deletions [ If the mother of the proband has a normal karyotype, it is presumed that the translocation (or inversion) occurred in the proband as a If the mother of the proband has the same translocation or inversion, the recurrence risk to sibs is increased. If the proband has a deletion involving the 14q32.2 imprinted region, offspring of the proband are at risk for Kagami-Ogata syndrome or Temple syndrome depending on the sex of the proband and the deletion size. If the proband is a female, offspring are predicted to have a 50% risk of Kagami-Ogata syndrome. If the proband is male and the deletion encompasses If the proband has a chromosome alteration predicted to result in uniparental disomy in offspring (e.g., a robertsonian translocation or isochromosome 14q), offspring of the proband are at risk for upd(14)pat-mediated Kagami-Ogata syndrome or upd(14)mat-mediated Temple syndrome, depending on the sex of the proband and the underlying mechanism for the development of uniparental disomy (i.e., trisomy rescue or monosomy rescue). If the mother of the proband is heterozygous for a deletion involving the 14q32.2 imprinted region, the mother's sibs are at risk of having the deletion. If a chromosome alteration involving 14q32.2 (e.g., a translocation) is identified in the mother of the proband, the mother's sibs are at risk of having the chromosome alteration. The optimal time for determination of genetic risk and discussion of the availability of prenatal/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 individuals. If a deletion or translocation involving the chromosome 14q32.2 imprinted region has been identified in the proband, prenatal testing using fetal DNA from samples obtained by chorionic villus sampling or amniocytes and preimplantation genetic testing are possible [ If the proband has Kagami-Ogata syndrome as the result of upd(14)pat (and chromosome analysis of both parents is normal) or an epimutation (hypermethylation), the recurrence risk is presumed to be <1% and prenatal/preimplantation genetic testing is likely unwarranted. Even in the absence of obvious clinical findings of Kagami-Ogata syndrome on prenatal ultrasound investigation, a residual risk for recurrence of Kagami-Ogata syndrome remains given the variability in clinical presentation and the limitation of fetal ultrasound studies. A newborn at risk for Kagami-Ogata syndrome should be monitored for respiratory and feeding conditions. Maternal serum alpha-fetoprotein concentration may be elevated from the second trimester in the presence of omphalocele [ Prenatal testing may be considered when clinical features suggestive of Kagami-Ogata syndrome such as polyhydramnios, characteristic facies, small thorax with coat-hanger appearance of the ribs, and omphalocele are delineated in a fetus not known to be at risk for Kagami-Ogata syndrome. Prenatal testing performed in such conditions has revealed genetic abnormalities consistent with Kagami-Ogata syndrome, including mosaic upd(14)pat [ 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. • Paternal uniparental disomy of chromosome 14 (upd(14)pat) * • Epimutation (hypermethylation) of the normally unmethylated • Deletion of the 14q32.2 region that includes • Translocation (or inversion) disrupting the integrity between the maternally inherited • The parents of a proband with Kagami-Ogata syndrome are not affected with Kagami-Ogata syndrome but may have a predisposing genetic alteration associated with the disorder such the following: • Maternal deletion involving the DMRs ( • If a proband with Kagami-Ogata syndrome has a maternally inherited deletion, the mother with the same deletion is theoretically predicted to have Kagami-Ogata syndrome when the deletion is derived from her mother, or Temple syndrome when the deletion is derived from her father and involves • Transmission of a deletion from a mother with Temple syndrome to a child with Kagami-Ogata syndrome has been reported in several families [ • Maternal translocation (or inversion) disrupting the integrity between the • Paternal or maternal robertsonian translocation involving chromosome 14 or isochromosome 14q (1(14q)). • Maternal deletion involving the DMRs ( • If a proband with Kagami-Ogata syndrome has a maternally inherited deletion, the mother with the same deletion is theoretically predicted to have Kagami-Ogata syndrome when the deletion is derived from her mother, or Temple syndrome when the deletion is derived from her father and involves • Transmission of a deletion from a mother with Temple syndrome to a child with Kagami-Ogata syndrome has been reported in several families [ • Maternal translocation (or inversion) disrupting the integrity between the • Paternal or maternal robertsonian translocation involving chromosome 14 or isochromosome 14q (1(14q)). • Evaluation of the parents to clarify recurrence risk is recommended; specific testing recommendations depend on the genetic mechanism underlying Kagami-Ogata syndrome in the proband (see • Maternal deletion involving the DMRs ( • If a proband with Kagami-Ogata syndrome has a maternally inherited deletion, the mother with the same deletion is theoretically predicted to have Kagami-Ogata syndrome when the deletion is derived from her mother, or Temple syndrome when the deletion is derived from her father and involves • Transmission of a deletion from a mother with Temple syndrome to a child with Kagami-Ogata syndrome has been reported in several families [ • Maternal translocation (or inversion) disrupting the integrity between the • Paternal or maternal robertsonian translocation involving chromosome 14 or isochromosome 14q (1(14q)). • If both parents have normal karyotypes, it is presumed that upd(14)pat occurred in the proband as a • If either of the parents has a robertsonian translocation or i(14q), the recurrence risk to sibs is increased. Note: While upd(14)pat mediated by parental robertsonian translocation has been identified in multiple individuals with Kagami-Ogata syndrome [ • If both parents have normal karyotypes, it is presumed that upd(14)pat occurred in the proband as a • If either of the parents has a robertsonian translocation or i(14q), the recurrence risk to sibs is increased. Note: While upd(14)pat mediated by parental robertsonian translocation has been identified in multiple individuals with Kagami-Ogata syndrome [ • If the deletion identified in the proband is not identified in maternal leukocyte DNA, it is presumed that the deletion occurred in the proband as a • If the mother of the proband has the deletion, the risk to sibs is 50%. Recurrence of Kagami-Ogata syndrome has been reported in sibs with maternally derived deletions [ • If the deletion identified in the proband is not identified in maternal leukocyte DNA, it is presumed that the deletion occurred in the proband as a • If the mother of the proband has the deletion, the risk to sibs is 50%. Recurrence of Kagami-Ogata syndrome has been reported in sibs with maternally derived deletions [ • If the mother of the proband has a normal karyotype, it is presumed that the translocation (or inversion) occurred in the proband as a • If the mother of the proband has the same translocation or inversion, the recurrence risk to sibs is increased. • If the mother of the proband has a normal karyotype, it is presumed that the translocation (or inversion) occurred in the proband as a • If the mother of the proband has the same translocation or inversion, the recurrence risk to sibs is increased. • If both parents have normal karyotypes, it is presumed that upd(14)pat occurred in the proband as a • If either of the parents has a robertsonian translocation or i(14q), the recurrence risk to sibs is increased. Note: While upd(14)pat mediated by parental robertsonian translocation has been identified in multiple individuals with Kagami-Ogata syndrome [ • If the deletion identified in the proband is not identified in maternal leukocyte DNA, it is presumed that the deletion occurred in the proband as a • If the mother of the proband has the deletion, the risk to sibs is 50%. Recurrence of Kagami-Ogata syndrome has been reported in sibs with maternally derived deletions [ • If the mother of the proband has a normal karyotype, it is presumed that the translocation (or inversion) occurred in the proband as a • If the mother of the proband has the same translocation or inversion, the recurrence risk to sibs is increased. • If the proband has a deletion involving the 14q32.2 imprinted region, offspring of the proband are at risk for Kagami-Ogata syndrome or Temple syndrome depending on the sex of the proband and the deletion size. If the proband is a female, offspring are predicted to have a 50% risk of Kagami-Ogata syndrome. If the proband is male and the deletion encompasses • If the proband has a chromosome alteration predicted to result in uniparental disomy in offspring (e.g., a robertsonian translocation or isochromosome 14q), offspring of the proband are at risk for upd(14)pat-mediated Kagami-Ogata syndrome or upd(14)mat-mediated Temple syndrome, depending on the sex of the proband and the underlying mechanism for the development of uniparental disomy (i.e., trisomy rescue or monosomy rescue). • If the mother of the proband is heterozygous for a deletion involving the 14q32.2 imprinted region, the mother's sibs are at risk of having the deletion. • If a chromosome alteration involving 14q32.2 (e.g., a translocation) is identified in the mother of the proband, the mother's sibs are at risk of having the chromosome alteration. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/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 individuals. • If a deletion or translocation involving the chromosome 14q32.2 imprinted region has been identified in the proband, prenatal testing using fetal DNA from samples obtained by chorionic villus sampling or amniocytes and preimplantation genetic testing are possible [ • If the proband has Kagami-Ogata syndrome as the result of upd(14)pat (and chromosome analysis of both parents is normal) or an epimutation (hypermethylation), the recurrence risk is presumed to be <1% and prenatal/preimplantation genetic testing is likely unwarranted. • Even in the absence of obvious clinical findings of Kagami-Ogata syndrome on prenatal ultrasound investigation, a residual risk for recurrence of Kagami-Ogata syndrome remains given the variability in clinical presentation and the limitation of fetal ultrasound studies. A newborn at risk for Kagami-Ogata syndrome should be monitored for respiratory and feeding conditions. • Maternal serum alpha-fetoprotein concentration may be elevated from the second trimester in the presence of omphalocele [ ## Mode of Inheritance The recurrence risk of Kagami-Ogata syndrome is dependent on the genetic mechanism underlying deficient expression of the maternal Paternal uniparental disomy of chromosome 14 (upd(14)pat) * Epimutation (hypermethylation) of the normally unmethylated Deletion of the 14q32.2 region that includes Translocation (or inversion) disrupting the integrity between the maternally inherited In most affected individuals, the underlying genetic mechanism occurs as a * If the diagnosis of Kagami-Ogata syndrome in the proband has been established by identification of hypermethylation of • Paternal uniparental disomy of chromosome 14 (upd(14)pat) * • Epimutation (hypermethylation) of the normally unmethylated • Deletion of the 14q32.2 region that includes • Translocation (or inversion) disrupting the integrity between the maternally inherited ## Risk to Family Members The parents of a proband with Kagami-Ogata syndrome are not affected with Kagami-Ogata syndrome but may have a predisposing genetic alteration associated with the disorder such the following: Maternal deletion involving the DMRs ( If a proband with Kagami-Ogata syndrome has a maternally inherited deletion, the mother with the same deletion is theoretically predicted to have Kagami-Ogata syndrome when the deletion is derived from her mother, or Temple syndrome when the deletion is derived from her father and involves Transmission of a deletion from a mother with Temple syndrome to a child with Kagami-Ogata syndrome has been reported in several families [ Maternal translocation (or inversion) disrupting the integrity between the Paternal or maternal robertsonian translocation involving chromosome 14 or isochromosome 14q (1(14q)). Evaluation of the parents to clarify recurrence risk is recommended; specific testing recommendations depend on the genetic mechanism underlying Kagami-Ogata syndrome in the proband (see If both parents have normal karyotypes, it is presumed that upd(14)pat occurred in the proband as a If either of the parents has a robertsonian translocation or i(14q), the recurrence risk to sibs is increased. Note: While upd(14)pat mediated by parental robertsonian translocation has been identified in multiple individuals with Kagami-Ogata syndrome [ If the deletion identified in the proband is not identified in maternal leukocyte DNA, it is presumed that the deletion occurred in the proband as a If the mother of the proband has the deletion, the risk to sibs is 50%. Recurrence of Kagami-Ogata syndrome has been reported in sibs with maternally derived deletions [ If the mother of the proband has a normal karyotype, it is presumed that the translocation (or inversion) occurred in the proband as a If the mother of the proband has the same translocation or inversion, the recurrence risk to sibs is increased. If the proband has a deletion involving the 14q32.2 imprinted region, offspring of the proband are at risk for Kagami-Ogata syndrome or Temple syndrome depending on the sex of the proband and the deletion size. If the proband is a female, offspring are predicted to have a 50% risk of Kagami-Ogata syndrome. If the proband is male and the deletion encompasses If the proband has a chromosome alteration predicted to result in uniparental disomy in offspring (e.g., a robertsonian translocation or isochromosome 14q), offspring of the proband are at risk for upd(14)pat-mediated Kagami-Ogata syndrome or upd(14)mat-mediated Temple syndrome, depending on the sex of the proband and the underlying mechanism for the development of uniparental disomy (i.e., trisomy rescue or monosomy rescue). If the mother of the proband is heterozygous for a deletion involving the 14q32.2 imprinted region, the mother's sibs are at risk of having the deletion. If a chromosome alteration involving 14q32.2 (e.g., a translocation) is identified in the mother of the proband, the mother's sibs are at risk of having the chromosome alteration. • The parents of a proband with Kagami-Ogata syndrome are not affected with Kagami-Ogata syndrome but may have a predisposing genetic alteration associated with the disorder such the following: • Maternal deletion involving the DMRs ( • If a proband with Kagami-Ogata syndrome has a maternally inherited deletion, the mother with the same deletion is theoretically predicted to have Kagami-Ogata syndrome when the deletion is derived from her mother, or Temple syndrome when the deletion is derived from her father and involves • Transmission of a deletion from a mother with Temple syndrome to a child with Kagami-Ogata syndrome has been reported in several families [ • Maternal translocation (or inversion) disrupting the integrity between the • Paternal or maternal robertsonian translocation involving chromosome 14 or isochromosome 14q (1(14q)). • Maternal deletion involving the DMRs ( • If a proband with Kagami-Ogata syndrome has a maternally inherited deletion, the mother with the same deletion is theoretically predicted to have Kagami-Ogata syndrome when the deletion is derived from her mother, or Temple syndrome when the deletion is derived from her father and involves • Transmission of a deletion from a mother with Temple syndrome to a child with Kagami-Ogata syndrome has been reported in several families [ • Maternal translocation (or inversion) disrupting the integrity between the • Paternal or maternal robertsonian translocation involving chromosome 14 or isochromosome 14q (1(14q)). • Evaluation of the parents to clarify recurrence risk is recommended; specific testing recommendations depend on the genetic mechanism underlying Kagami-Ogata syndrome in the proband (see • Maternal deletion involving the DMRs ( • If a proband with Kagami-Ogata syndrome has a maternally inherited deletion, the mother with the same deletion is theoretically predicted to have Kagami-Ogata syndrome when the deletion is derived from her mother, or Temple syndrome when the deletion is derived from her father and involves • Transmission of a deletion from a mother with Temple syndrome to a child with Kagami-Ogata syndrome has been reported in several families [ • Maternal translocation (or inversion) disrupting the integrity between the • Paternal or maternal robertsonian translocation involving chromosome 14 or isochromosome 14q (1(14q)). • If both parents have normal karyotypes, it is presumed that upd(14)pat occurred in the proband as a • If either of the parents has a robertsonian translocation or i(14q), the recurrence risk to sibs is increased. Note: While upd(14)pat mediated by parental robertsonian translocation has been identified in multiple individuals with Kagami-Ogata syndrome [ • If both parents have normal karyotypes, it is presumed that upd(14)pat occurred in the proband as a • If either of the parents has a robertsonian translocation or i(14q), the recurrence risk to sibs is increased. Note: While upd(14)pat mediated by parental robertsonian translocation has been identified in multiple individuals with Kagami-Ogata syndrome [ • If the deletion identified in the proband is not identified in maternal leukocyte DNA, it is presumed that the deletion occurred in the proband as a • If the mother of the proband has the deletion, the risk to sibs is 50%. Recurrence of Kagami-Ogata syndrome has been reported in sibs with maternally derived deletions [ • If the deletion identified in the proband is not identified in maternal leukocyte DNA, it is presumed that the deletion occurred in the proband as a • If the mother of the proband has the deletion, the risk to sibs is 50%. Recurrence of Kagami-Ogata syndrome has been reported in sibs with maternally derived deletions [ • If the mother of the proband has a normal karyotype, it is presumed that the translocation (or inversion) occurred in the proband as a • If the mother of the proband has the same translocation or inversion, the recurrence risk to sibs is increased. • If the mother of the proband has a normal karyotype, it is presumed that the translocation (or inversion) occurred in the proband as a • If the mother of the proband has the same translocation or inversion, the recurrence risk to sibs is increased. • If both parents have normal karyotypes, it is presumed that upd(14)pat occurred in the proband as a • If either of the parents has a robertsonian translocation or i(14q), the recurrence risk to sibs is increased. Note: While upd(14)pat mediated by parental robertsonian translocation has been identified in multiple individuals with Kagami-Ogata syndrome [ • If the deletion identified in the proband is not identified in maternal leukocyte DNA, it is presumed that the deletion occurred in the proband as a • If the mother of the proband has the deletion, the risk to sibs is 50%. Recurrence of Kagami-Ogata syndrome has been reported in sibs with maternally derived deletions [ • If the mother of the proband has a normal karyotype, it is presumed that the translocation (or inversion) occurred in the proband as a • If the mother of the proband has the same translocation or inversion, the recurrence risk to sibs is increased. • If the proband has a deletion involving the 14q32.2 imprinted region, offspring of the proband are at risk for Kagami-Ogata syndrome or Temple syndrome depending on the sex of the proband and the deletion size. If the proband is a female, offspring are predicted to have a 50% risk of Kagami-Ogata syndrome. If the proband is male and the deletion encompasses • If the proband has a chromosome alteration predicted to result in uniparental disomy in offspring (e.g., a robertsonian translocation or isochromosome 14q), offspring of the proband are at risk for upd(14)pat-mediated Kagami-Ogata syndrome or upd(14)mat-mediated Temple syndrome, depending on the sex of the proband and the underlying mechanism for the development of uniparental disomy (i.e., trisomy rescue or monosomy rescue). • If the mother of the proband is heterozygous for a deletion involving the 14q32.2 imprinted region, the mother's sibs are at risk of having the deletion. • If a chromosome alteration involving 14q32.2 (e.g., a translocation) is identified in the mother of the proband, the mother's sibs are at risk of having the chromosome alteration. ## 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 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 the parents of affected individuals. ## Prenatal Testing and Preimplantation Genetic Testing If a deletion or translocation involving the chromosome 14q32.2 imprinted region has been identified in the proband, prenatal testing using fetal DNA from samples obtained by chorionic villus sampling or amniocytes and preimplantation genetic testing are possible [ If the proband has Kagami-Ogata syndrome as the result of upd(14)pat (and chromosome analysis of both parents is normal) or an epimutation (hypermethylation), the recurrence risk is presumed to be <1% and prenatal/preimplantation genetic testing is likely unwarranted. Even in the absence of obvious clinical findings of Kagami-Ogata syndrome on prenatal ultrasound investigation, a residual risk for recurrence of Kagami-Ogata syndrome remains given the variability in clinical presentation and the limitation of fetal ultrasound studies. A newborn at risk for Kagami-Ogata syndrome should be monitored for respiratory and feeding conditions. Maternal serum alpha-fetoprotein concentration may be elevated from the second trimester in the presence of omphalocele [ Prenatal testing may be considered when clinical features suggestive of Kagami-Ogata syndrome such as polyhydramnios, characteristic facies, small thorax with coat-hanger appearance of the ribs, and omphalocele are delineated in a fetus not known to be at risk for Kagami-Ogata syndrome. Prenatal testing performed in such conditions has revealed genetic abnormalities consistent with Kagami-Ogata syndrome, including mosaic upd(14)pat [ Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • If a deletion or translocation involving the chromosome 14q32.2 imprinted region has been identified in the proband, prenatal testing using fetal DNA from samples obtained by chorionic villus sampling or amniocytes and preimplantation genetic testing are possible [ • If the proband has Kagami-Ogata syndrome as the result of upd(14)pat (and chromosome analysis of both parents is normal) or an epimutation (hypermethylation), the recurrence risk is presumed to be <1% and prenatal/preimplantation genetic testing is likely unwarranted. • Even in the absence of obvious clinical findings of Kagami-Ogata syndrome on prenatal ultrasound investigation, a residual risk for recurrence of Kagami-Ogata syndrome remains given the variability in clinical presentation and the limitation of fetal ultrasound studies. A newborn at risk for Kagami-Ogata syndrome should be monitored for respiratory and feeding conditions. • Maternal serum alpha-fetoprotein concentration may be elevated from the second trimester in the presence of omphalocele [ ## Positive Family History If a deletion or translocation involving the chromosome 14q32.2 imprinted region has been identified in the proband, prenatal testing using fetal DNA from samples obtained by chorionic villus sampling or amniocytes and preimplantation genetic testing are possible [ If the proband has Kagami-Ogata syndrome as the result of upd(14)pat (and chromosome analysis of both parents is normal) or an epimutation (hypermethylation), the recurrence risk is presumed to be <1% and prenatal/preimplantation genetic testing is likely unwarranted. Even in the absence of obvious clinical findings of Kagami-Ogata syndrome on prenatal ultrasound investigation, a residual risk for recurrence of Kagami-Ogata syndrome remains given the variability in clinical presentation and the limitation of fetal ultrasound studies. A newborn at risk for Kagami-Ogata syndrome should be monitored for respiratory and feeding conditions. Maternal serum alpha-fetoprotein concentration may be elevated from the second trimester in the presence of omphalocele [ • If a deletion or translocation involving the chromosome 14q32.2 imprinted region has been identified in the proband, prenatal testing using fetal DNA from samples obtained by chorionic villus sampling or amniocytes and preimplantation genetic testing are possible [ • If the proband has Kagami-Ogata syndrome as the result of upd(14)pat (and chromosome analysis of both parents is normal) or an epimutation (hypermethylation), the recurrence risk is presumed to be <1% and prenatal/preimplantation genetic testing is likely unwarranted. • Even in the absence of obvious clinical findings of Kagami-Ogata syndrome on prenatal ultrasound investigation, a residual risk for recurrence of Kagami-Ogata syndrome remains given the variability in clinical presentation and the limitation of fetal ultrasound studies. A newborn at risk for Kagami-Ogata syndrome should be monitored for respiratory and feeding conditions. • Maternal serum alpha-fetoprotein concentration may be elevated from the second trimester in the presence of omphalocele [ ## Negative Family History Prenatal testing may be considered when clinical features suggestive of Kagami-Ogata syndrome such as polyhydramnios, characteristic facies, small thorax with coat-hanger appearance of the ribs, and omphalocele are delineated in a fetus not known to be at risk for Kagami-Ogata syndrome. Prenatal testing performed in such conditions has revealed genetic abnormalities consistent with Kagami-Ogata syndrome, including mosaic upd(14)pat [ 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 No specific resources for Kagami-Ogata Syndrome have been identified by ## Molecular Genetics OMIM Entries for Kagami-Ogata Syndrome ( The primary underlying factor for the development of Kagami-Ogata syndrome is increased (~2.5 times or ~5 times that of controls) This imprinted region contains the germline-derived Both DMRs are methylated after paternal transmission and unmethylated after maternal transmission in the body; in the placenta, the The unmethylated All the non-coding maternally expressed genes are part of a large transcript expressed by the Mechanisms of disease causation include paternal uniparental disomy of chromosome 14 (upd(14)pat), epimutation (hypermethylation) of Abnormal methylation of The underlying cause of hypermethylation is unknown, and no multilocus imprinting disturbance (MLID) has been identified in individuals with Kagami-Ogata syndrome [ Deletions of Three different deletions involving maternally inherited DMR deletions that include When deletions include This deletion results in loss of • This imprinted region contains the germline-derived • Both DMRs are methylated after paternal transmission and unmethylated after maternal transmission in the body; in the placenta, the • The unmethylated • All the non-coding maternally expressed genes are part of a large transcript expressed by the • Abnormal methylation of • The underlying cause of hypermethylation is unknown, and no multilocus imprinting disturbance (MLID) has been identified in individuals with Kagami-Ogata syndrome [ • Deletions of • Three different deletions involving maternally inherited • DMR deletions that include • When deletions include • This deletion results in loss of ## Molecular Pathogenesis The primary underlying factor for the development of Kagami-Ogata syndrome is increased (~2.5 times or ~5 times that of controls) This imprinted region contains the germline-derived Both DMRs are methylated after paternal transmission and unmethylated after maternal transmission in the body; in the placenta, the The unmethylated All the non-coding maternally expressed genes are part of a large transcript expressed by the Mechanisms of disease causation include paternal uniparental disomy of chromosome 14 (upd(14)pat), epimutation (hypermethylation) of Abnormal methylation of The underlying cause of hypermethylation is unknown, and no multilocus imprinting disturbance (MLID) has been identified in individuals with Kagami-Ogata syndrome [ Deletions of Three different deletions involving maternally inherited DMR deletions that include When deletions include This deletion results in loss of • This imprinted region contains the germline-derived • Both DMRs are methylated after paternal transmission and unmethylated after maternal transmission in the body; in the placenta, the • The unmethylated • All the non-coding maternally expressed genes are part of a large transcript expressed by the • Abnormal methylation of • The underlying cause of hypermethylation is unknown, and no multilocus imprinting disturbance (MLID) has been identified in individuals with Kagami-Ogata syndrome [ • Deletions of • Three different deletions involving maternally inherited • DMR deletions that include • When deletions include • This deletion results in loss of ## Chapter Notes Tsutomu Ogata ( This work was supported by the grant from Japan Agency for Medical Research and Development (AMED) (24ek0109587). 24 October 2024 (sw) Review posted live 29 February 2024 (to) Original submission • 24 October 2024 (sw) Review posted live • 29 February 2024 (to) Original submission ## Author Notes Tsutomu Ogata ( ## Acknowledgments This work was supported by the grant from Japan Agency for Medical Research and Development (AMED) (24ek0109587). ## Revision History 24 October 2024 (sw) Review posted live 29 February 2024 (to) Original submission • 24 October 2024 (sw) Review posted live • 29 February 2024 (to) Original submission ## References ## Literature Cited Female at infancy, age two years, and age eight years with Kagami-Ogata syndrome due to a maternally inherited microdeletion of Adapted from Chest radiograph of a Japanese neonate with Kagami-Ogata syndrome. The coat-hanger angle (CHA) is increased from 30 weeks' gestation through age five years in individuals with Kagami-Ogata syndrome. CHA is the average of the right and left angles between the horizontal axis at the sixth costovertebral junction and the peak point of the sixth posterior rib. Note: If the ribs slope downward, the midpoint of the sixth rib is used for CHA measurement. The mid-to-widest thorax ratio is decreased in infants and young children with Kagami-Ogata syndrome. CHA = coat-hanger angle; GA = gestational age; KOS14 = Kagami-Ogata syndrome; M/W ratio = mid-to-widest thorax ratio Adapted from Testing algorithm to establish the diagnosis and molecular cause of Kagami-Ogata syndrome Chr. = chromosome; DMR = differentially methylated region; KOS14 = Kagami-Ogata syndrome; MS-MLPA = methylation-specific multiple ligation-dependent probe amplification; Chromosome 14q32.2 imprinted region and representative genetic causes leading to Kagami-Ogata syndrome. The black and white circles represent methylated and unmethylated differentially methylated regions (DMRs), respectively. A. Structure and character of the imprinted region B. Expression dosage of imprinted genes in several conditions. Stippled areas denote deleted region, and the cutting mark indicates the translocation breakpoint.	[]	24/10/2024			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
kat6b-dis	kat6b-dis	[ "Say-Barber-Biesecker variant of Ohdo syndrome (SBBYSS)", "Genitopatellar syndrome (GPS)", "Histone acetyltransferase KAT6B", "KAT6B", "KAT6B Disorders" ]		Gabrielle Lemire, Philippe M Campeau, Brendan H Lee	Summary The diagnosis of a	Genitopatellar syndrome (GPS) Say-Barber-Biesecker variant of Ohdo syndrome (SBBYSS) For synonyms and outdated names see For other genetic causes of these phenotypes see • Genitopatellar syndrome (GPS) • Say-Barber-Biesecker variant of Ohdo syndrome (SBBYSS) ## Diagnosis A Features Suggestive of GPS Genital anomalies (females: clitoromegaly &/or hypoplasia of the labia minora or majora; males: cryptorchidism & scrotal hypoplasia) Patellar hypoplasia/agenesis Flexion contractures at the hips & knees (incl clubfoot) Agenesis of the corpus callosum w/microcephaly Hydronephrosis &/or multiple renal cysts Congenital heart defect Dental anomalies (delayed eruption of teeth) Hearing loss Thyroid anomalies Anal anomalies Hypotonia Global developmental delay / intellectual disability Features Suggestive of Ohdo/SBBYS Syndrome (SBBYSS) Long thumbs / great toes Immobile mask-like face Blepharophimosis/ptosis Lacrimal duct anomalies Patellar hypoplasia/agenesis Congenital heart defect Dental anomalies (hypoplastic teeth &/or delayed eruption of teeth) Hearing loss Thyroid anomalies Cleft palate Genital anomalies (males: cryptorchidism) Hypotonia Global developmental delay / intellectual disability The diagnosis of a 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 a For an introduction to multigene panels click When the diagnosis of a If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis. For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and 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 A 5-Mb 10q22.1q22.3 deletion encompassing Interstitial 10q21.3q22.2 deletions encompassing Note: One individual had a "Noonan syndrome-like" phenotype resulting from a translocation interrupting intron 3 of • Genital anomalies (females: clitoromegaly &/or hypoplasia of the labia minora or majora; males: cryptorchidism & scrotal hypoplasia) • Patellar hypoplasia/agenesis • Flexion contractures at the hips & knees (incl clubfoot) • Agenesis of the corpus callosum w/microcephaly • Hydronephrosis &/or multiple renal cysts • Congenital heart defect • Dental anomalies (delayed eruption of teeth) • Hearing loss • Thyroid anomalies • Anal anomalies • Hypotonia • Global developmental delay / intellectual disability • Long thumbs / great toes • Immobile mask-like face • Blepharophimosis/ptosis • Lacrimal duct anomalies • Patellar hypoplasia/agenesis • Congenital heart defect • Dental anomalies (hypoplastic teeth &/or delayed eruption of teeth) • Hearing loss • Thyroid anomalies • Cleft palate • Genital anomalies (males: cryptorchidism) • Hypotonia • Global developmental delay / intellectual disability • For an introduction to multigene panels click ## Suggestive Findings A Features Suggestive of GPS Genital anomalies (females: clitoromegaly &/or hypoplasia of the labia minora or majora; males: cryptorchidism & scrotal hypoplasia) Patellar hypoplasia/agenesis Flexion contractures at the hips & knees (incl clubfoot) Agenesis of the corpus callosum w/microcephaly Hydronephrosis &/or multiple renal cysts Congenital heart defect Dental anomalies (delayed eruption of teeth) Hearing loss Thyroid anomalies Anal anomalies Hypotonia Global developmental delay / intellectual disability Features Suggestive of Ohdo/SBBYS Syndrome (SBBYSS) Long thumbs / great toes Immobile mask-like face Blepharophimosis/ptosis Lacrimal duct anomalies Patellar hypoplasia/agenesis Congenital heart defect Dental anomalies (hypoplastic teeth &/or delayed eruption of teeth) Hearing loss Thyroid anomalies Cleft palate Genital anomalies (males: cryptorchidism) Hypotonia Global developmental delay / intellectual disability • Genital anomalies (females: clitoromegaly &/or hypoplasia of the labia minora or majora; males: cryptorchidism & scrotal hypoplasia) • Patellar hypoplasia/agenesis • Flexion contractures at the hips & knees (incl clubfoot) • Agenesis of the corpus callosum w/microcephaly • Hydronephrosis &/or multiple renal cysts • Congenital heart defect • Dental anomalies (delayed eruption of teeth) • Hearing loss • Thyroid anomalies • Anal anomalies • Hypotonia • Global developmental delay / intellectual disability • Long thumbs / great toes • Immobile mask-like face • Blepharophimosis/ptosis • Lacrimal duct anomalies • Patellar hypoplasia/agenesis • Congenital heart defect • Dental anomalies (hypoplastic teeth &/or delayed eruption of teeth) • Hearing loss • Thyroid anomalies • Cleft palate • Genital anomalies (males: cryptorchidism) • Hypotonia • Global developmental delay / intellectual disability ## Establishing the Diagnosis The diagnosis of a 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 a For an introduction to multigene panels click When the diagnosis of a If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis. For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and 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 A 5-Mb 10q22.1q22.3 deletion encompassing Interstitial 10q21.3q22.2 deletions encompassing Note: One individual had a "Noonan syndrome-like" phenotype resulting from a translocation interrupting intron 3 of • For an introduction to multigene panels click ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of a For an introduction to multigene panels click • For an introduction to multigene panels click ## Option 2 When the diagnosis of a If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis. For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and 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 A 5-Mb 10q22.1q22.3 deletion encompassing Interstitial 10q21.3q22.2 deletions encompassing Note: One individual had a "Noonan syndrome-like" phenotype resulting from a translocation interrupting intron 3 of ## Clinical Characteristics Genitopatellar syndrome (GPS) and Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) are part of a broad phenotypic spectrum, and the variable expressivity of Club feet and flexion contractures of the knees and/or hips are also present in nearly all individuals with GPS and constitute major features of this syndrome. This can significantly hinder mobility, especially since the knees in some cases cannot be extended beyond 90 degrees. Most of the musculoskeletal findings in GPS involve the lower extremities, but contractures of the wrists or elbows have also been observed in two affected individuals [Authors, personal observation]. Other skeletal anomalies are occasionally seen in affected individuals. Spinal anomalies resulting in thoracolumbar kyphoscoliosis have been observed in 11% of individuals reported in the literature. Some have thoracic anomalies such as narrow thorax, pectus excavatum, the presence of small cervical ribs, absence of a pair of ribs, and clavicular exostoses. Pelvic anomalies include hip dislocations and hypoplasia of the iliac bone, ischia, and pubic rami. Rare musculoskeletal findings include osteoporosis, radioulnar synostosis, radial head deformity, brachydactyly, camptodactyly, short stature, joint laxity, undertubulation of long bones, and coxa vara. Nearly all individuals with GPS have agenesis or hypoplasia of the corpus callosum. Seizures, cortical malformations, hydrocephaly, or ventriculomegaly have also been described in some affected individuals. Some have hypotonia at birth, resulting in respiratory and feeding difficulties that can require invasive procedures (see Most have microcephaly, with occipitofrontal circumferences (OFCs) typically 2 SD (and occasionally 3 SD) below the mean. Some neonates have hypotonia, with feeding and respiratory difficulties requiring hospitalization. More than 50% of individuals with Small bowel malrotation has been described in eight affected individuals [ Most affected individuals present with feeding difficulties and pathologic gastroesophageal reflux. Growth restriction, short stature, failure to thrive/poor weight gain and delayed bone age have been reported in 18% of affected individuals. Cleft palate has been reported in one third of affected individuals [ Bilateral hearing loss, both conductive and sensorineural, is often present. Occasional dental anomalies including natal teeth, absent/hypoplastic teeth, retained primary dentition, and delayed eruption of teeth are mostly seen in in individuals with SBBYSS. A minority of individuals have hypothyroidism – some of them having thyroid agenesis or hypoplasia. Polyhydramnios can complicate the pregnancy of fetuses affected with Sagittal craniosynostosis was noted in two individuals with the intermediate phenotype [ Cutaneous manifestations are rarely observed in individuals with Penetrance appears to be complete since all individuals reported to date who carry a Subsequently, the Young-Simpson syndrome was described [ Of note, the disorder described by Ohdo was distinct from the SBBYS variant of Ohdo syndrome because the facial features differed, proteinuria was present, and skeletal anomalies were absent; the mode of inheritance appeared to be autosomal recessive, autosomal dominant with reduced penetrance, or multifactorial. The prevalence of ## Clinical Description Genitopatellar syndrome (GPS) and Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) are part of a broad phenotypic spectrum, and the variable expressivity of Club feet and flexion contractures of the knees and/or hips are also present in nearly all individuals with GPS and constitute major features of this syndrome. This can significantly hinder mobility, especially since the knees in some cases cannot be extended beyond 90 degrees. Most of the musculoskeletal findings in GPS involve the lower extremities, but contractures of the wrists or elbows have also been observed in two affected individuals [Authors, personal observation]. Other skeletal anomalies are occasionally seen in affected individuals. Spinal anomalies resulting in thoracolumbar kyphoscoliosis have been observed in 11% of individuals reported in the literature. Some have thoracic anomalies such as narrow thorax, pectus excavatum, the presence of small cervical ribs, absence of a pair of ribs, and clavicular exostoses. Pelvic anomalies include hip dislocations and hypoplasia of the iliac bone, ischia, and pubic rami. Rare musculoskeletal findings include osteoporosis, radioulnar synostosis, radial head deformity, brachydactyly, camptodactyly, short stature, joint laxity, undertubulation of long bones, and coxa vara. Nearly all individuals with GPS have agenesis or hypoplasia of the corpus callosum. Seizures, cortical malformations, hydrocephaly, or ventriculomegaly have also been described in some affected individuals. Some have hypotonia at birth, resulting in respiratory and feeding difficulties that can require invasive procedures (see Most have microcephaly, with occipitofrontal circumferences (OFCs) typically 2 SD (and occasionally 3 SD) below the mean. Some neonates have hypotonia, with feeding and respiratory difficulties requiring hospitalization. More than 50% of individuals with Small bowel malrotation has been described in eight affected individuals [ Most affected individuals present with feeding difficulties and pathologic gastroesophageal reflux. Growth restriction, short stature, failure to thrive/poor weight gain and delayed bone age have been reported in 18% of affected individuals. Cleft palate has been reported in one third of affected individuals [ Bilateral hearing loss, both conductive and sensorineural, is often present. Occasional dental anomalies including natal teeth, absent/hypoplastic teeth, retained primary dentition, and delayed eruption of teeth are mostly seen in in individuals with SBBYSS. A minority of individuals have hypothyroidism – some of them having thyroid agenesis or hypoplasia. Polyhydramnios can complicate the pregnancy of fetuses affected with Sagittal craniosynostosis was noted in two individuals with the intermediate phenotype [ Cutaneous manifestations are rarely observed in individuals with ## Genitopatellar Syndrome (GPS) Club feet and flexion contractures of the knees and/or hips are also present in nearly all individuals with GPS and constitute major features of this syndrome. This can significantly hinder mobility, especially since the knees in some cases cannot be extended beyond 90 degrees. Most of the musculoskeletal findings in GPS involve the lower extremities, but contractures of the wrists or elbows have also been observed in two affected individuals [Authors, personal observation]. Other skeletal anomalies are occasionally seen in affected individuals. Spinal anomalies resulting in thoracolumbar kyphoscoliosis have been observed in 11% of individuals reported in the literature. Some have thoracic anomalies such as narrow thorax, pectus excavatum, the presence of small cervical ribs, absence of a pair of ribs, and clavicular exostoses. Pelvic anomalies include hip dislocations and hypoplasia of the iliac bone, ischia, and pubic rami. Rare musculoskeletal findings include osteoporosis, radioulnar synostosis, radial head deformity, brachydactyly, camptodactyly, short stature, joint laxity, undertubulation of long bones, and coxa vara. Nearly all individuals with GPS have agenesis or hypoplasia of the corpus callosum. Seizures, cortical malformations, hydrocephaly, or ventriculomegaly have also been described in some affected individuals. Some have hypotonia at birth, resulting in respiratory and feeding difficulties that can require invasive procedures (see Most have microcephaly, with occipitofrontal circumferences (OFCs) typically 2 SD (and occasionally 3 SD) below the mean. ## Say-Barber-Biesecker-Young-SImpson Variant of Ohdo Syndrome (SBBYSS) Some neonates have hypotonia, with feeding and respiratory difficulties requiring hospitalization. ## Other Features Observed in Individuals with Either the GPS or SBBYSS Phenotype More than 50% of individuals with Small bowel malrotation has been described in eight affected individuals [ Most affected individuals present with feeding difficulties and pathologic gastroesophageal reflux. Growth restriction, short stature, failure to thrive/poor weight gain and delayed bone age have been reported in 18% of affected individuals. Cleft palate has been reported in one third of affected individuals [ Bilateral hearing loss, both conductive and sensorineural, is often present. Occasional dental anomalies including natal teeth, absent/hypoplastic teeth, retained primary dentition, and delayed eruption of teeth are mostly seen in in individuals with SBBYSS. A minority of individuals have hypothyroidism – some of them having thyroid agenesis or hypoplasia. Polyhydramnios can complicate the pregnancy of fetuses affected with Sagittal craniosynostosis was noted in two individuals with the intermediate phenotype [ Cutaneous manifestations are rarely observed in individuals with ## Genotype-Phenotype Correlations ## Penetrance Penetrance appears to be complete since all individuals reported to date who carry a ## Nomenclature Subsequently, the Young-Simpson syndrome was described [ Of note, the disorder described by Ohdo was distinct from the SBBYS variant of Ohdo syndrome because the facial features differed, proteinuria was present, and skeletal anomalies were absent; the mode of inheritance appeared to be autosomal recessive, autosomal dominant with reduced penetrance, or multifactorial. ## Prevalence The prevalence of ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Genes of Interest in the Differential Diagnosis of AD = autosomal dominant; AR = autosomal recessive; GI = gastrointestinal; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked Blepharophimosis, ptosis, epicanthus inversus syndrome type II is isolated; type I is associated with premature ovarian insufficiency. Blepharophimosis, ptosis, epicanthus inversus syndrome is usually inherited in an autosomal dominant manner; autosomal recessive inheritance has been reported in one consanguineous family. Mowat-Wilson syndrome is typically the result of a ## Other Disorders to Consider in the Differential Diagnosis ## Management To establish the extent of disease and needs of an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education To incl eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in patients w/dysphagia &/or aspiration risk. Further evidence of utility is required prior to recommending screening of all individuals with Medical problems associated with gastrointestinal, genitourinary, cardiac, palatal, or dental anomalies; abnormal vision or lacrimal duct abnormality; hearing loss; or hypothyroidism associated with Treatment of Manifestations in Individuals with 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. DD = developmental delay; ID = intellectual disability; OT = occupational therapy; PT = physical therapy The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. Individualized education plan (IEP) services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child’s IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child’s access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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 (ADHD), when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. Recommended Periodic Surveillance for Individuals with OT = occupational therapy; PT = physical therapy Annual or as needed See Search • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • To incl eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in patients w/dysphagia &/or aspiration risk. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or Special Olympics. • Individualized education plan (IEP) services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child’s IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child’s access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child’s IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child’s access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child’s IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child’s access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to 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 of an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education To incl eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in patients w/dysphagia &/or aspiration risk. Further evidence of utility is required prior to recommending screening of all individuals with • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • To incl eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in patients w/dysphagia &/or aspiration risk. ## Treatment of Manifestations Medical problems associated with gastrointestinal, genitourinary, cardiac, palatal, or dental anomalies; abnormal vision or lacrimal duct abnormality; hearing loss; or hypothyroidism associated with Treatment of Manifestations in Individuals with 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. DD = developmental delay; ID = intellectual disability; OT = occupational therapy; PT = physical therapy The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. Individualized education plan (IEP) services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child’s IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child’s access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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 (ADHD), 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 multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or Special Olympics. • Individualized education plan (IEP) services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child’s IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child’s access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child’s IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child’s access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child’s IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child’s access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to 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 Disability / 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 (ADHD), when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ## Surveillance Recommended Periodic Surveillance for Individuals with OT = occupational therapy; PT = physical therapy Annual or as needed ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Most individuals diagnosed with a An individual diagnosed with a Transmission of a An inherited pathogenic variant has been found in individuals with mild SBBYSS phenotypes [ A woman with relatively mild SBBYSS had a child with classic SBBYSS [ If a If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include 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 is 50%. If the proband has a known The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to couples who have had a child with 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. • Most individuals diagnosed with a • An individual diagnosed with a • Transmission of a • An inherited pathogenic variant has been found in individuals with mild SBBYSS phenotypes [ • A woman with relatively mild SBBYSS had a child with classic SBBYSS [ • Transmission of a • An inherited pathogenic variant has been found in individuals with mild SBBYSS phenotypes [ • A woman with relatively mild SBBYSS had a child with classic SBBYSS [ • If a • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a • Transmission of a • An inherited pathogenic variant has been found in individuals with mild SBBYSS phenotypes [ • A woman with relatively mild SBBYSS had a child with classic SBBYSS [ • 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 • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to couples who have had a child with a ## Mode of Inheritance ## Risk to Family Members Most individuals diagnosed with a An individual diagnosed with a Transmission of a An inherited pathogenic variant has been found in individuals with mild SBBYSS phenotypes [ A woman with relatively mild SBBYSS had a child with classic SBBYSS [ If a If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include 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 is 50%. If the proband has a known • Most individuals diagnosed with a • An individual diagnosed with a • Transmission of a • An inherited pathogenic variant has been found in individuals with mild SBBYSS phenotypes [ • A woman with relatively mild SBBYSS had a child with classic SBBYSS [ • Transmission of a • An inherited pathogenic variant has been found in individuals with mild SBBYSS phenotypes [ • A woman with relatively mild SBBYSS had a child with classic SBBYSS [ • If a • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a • Transmission of a • An inherited pathogenic variant has been found in individuals with mild SBBYSS phenotypes [ • A woman with relatively mild SBBYSS had a child with classic SBBYSS [ • 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 ## 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 couples who have had a child with a • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to couples who have had a child with 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 • • • • ## Molecular Genetics KAT6B Disorders: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for KAT6B Disorders ( Notable Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis Notable Variants listed in the table have been provided by the authors. ## References ## Literature Cited ## Chapter Notes Dr Brendan Lee's Dr Philippe Campeau's 2 January 2020 (ha) Comprehensive update posted live 10 January 2013 (cd) Revision: sequence analysis and prenatal diagnosis available clinically 13 December 2012 (me) Review posted live 19 June 2012 (pc/bl) Original submission • 2 January 2020 (ha) Comprehensive update posted live • 10 January 2013 (cd) Revision: sequence analysis and prenatal diagnosis available clinically • 13 December 2012 (me) Review posted live • 19 June 2012 (pc/bl) Original submission ## Author Notes Dr Brendan Lee's Dr Philippe Campeau's ## Revision History 2 January 2020 (ha) Comprehensive update posted live 10 January 2013 (cd) Revision: sequence analysis and prenatal diagnosis available clinically 13 December 2012 (me) Review posted live 19 June 2012 (pc/bl) Original submission • 2 January 2020 (ha) Comprehensive update posted live • 10 January 2013 (cd) Revision: sequence analysis and prenatal diagnosis available clinically • 13 December 2012 (me) Review posted live • 19 June 2012 (pc/bl) Original submission Photographs of 11 individuals with a Arrows point to the relative location of an individual's pathogenic variant in the schematic of the last Note: Alphanumeric designations above each photograph identify the institution of the author who described the pathogenic variant and the author's order in the publication originally describing the pathogenic variant. These identifiers are also used in the Reprinted from	[ "RA Bashir, A Dixit, C Goedhart, JS Parboosingh, AM Innes, P Ferreira, PB Au. Lin-Gettig syndrome: Craniosynostosis expands the spectrum of the KAT6B related disorders.. Am J Med Genet A. 2017;173:2596-604", "LG Biesecker. The Ohdo blepharophimosis syndrome: a third case.. J Med Genet. 1991;28:131-4", "PM Campeau, JC Kim, JT Lu, JA Schwartzentruber, OA Abdul-Rahman, S Schlaubitz, DM Murdock, MM Jiang, EJ Lammer, GM Enns, WJ Rhead, J Rowland, SP Robertson, V Cormier-Daire, MN Bainbridge, XJ Yang, MC Gingras, RA Gibbs, DS Rosenblatt, J Majewski, BH Lee. Mutations in KAT6B, encoding a histone acetyltransferase, cause genitopatellar syndrome.. Am J Hum Genet. 2012a;90:282-9", "PM Campeau, JT Lu, BC Dawson, IF Fokkema, SP Robertson, RA Gibbs, BH Lee. The KAT6B-related disorders Genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms.. Hum Mutat. 2012b;33:1520-5", "J Clayton-Smith, J O'Sullivan, S Daly, S Bhaskar, R Day, B Anderson, AK Voss, T Thomas, LG Biesecker, P Smith, A Fryer, KE Chandler, B Kerr, M Tassabehji, SA Lynch, M Krajewska-Walasek, S McKee, J Smith, E Sweeney, S Mansour, S Mohammed, D Donnai, G Black. Whole-exome-sequencing identifies mutations in histone acetyltransferase gene KAT6B in individuals with the Say-Barber-Biesecker variant of Ohdo syndrome.. Am J Hum Genet. 2011;89:675-81", "V Cormier-Daire, ML Chauvet, S Lyonnet, ML Briard, A Munnich, M Le Merrer. Genitopatellar syndrome: a new condition comprising absent patellae, scrotal hypoplasia, renal anomalies, facial dysmorphism, and mental retardation.. J Med Genet. 2000;37:520-4", "Y Doyon, C Cayrou, M Ullah, AJ Landry, V Côté, W Selleck, WS Lane, S Tan, XJ Yang, J Côté. ING tumor suppressor proteins are critical regulators of chromatin acetylation required for genome expression and perpetuation.. Mol Cell. 2006;21:51-64", "T Gannon, R Perveen, H Schlecht, S Ramsden, B Anderson, B Kerr, J Clayton-Smith. Further delineation of the KAT6B molecular and phenotypic spectrum.. Eur J Hum Genet. 2015;23:1165-70", "JC Herriges, SL Dugan, AN Lamb. Clinical and molecular cytogenetic characterization of a novel 10q interstitial deletion: a case report and review of the literature.. Mol Cytogenet. 2019;12:20", "BR Kim, JH Han, JE Shin, MS Park, KI Park, R Namgung, HJ Lee, JS Lee, HS Eun. Genitopatellar syndrome secondary to de novo KAT6B mutation: the first genetically confirmed case in South Korea.. Yonsei Med J. 2019;60:395-8", "YR Kim, JB Park, YJ Lee, MJ Hong, HT Kim, HJ Kim. Identifying the KAT6B mutation via diagnostic exome sequencing to diagnose Say-Barber-Biesecker-Young-Simpson syndrome in three generations of a family.. Ann Rehabil Med. 2017;41:505-10", "S Knight, L VanHouwelingen, D Cervi, MR Clay, M Corkins, S Hines-Dowell, AJ Murphy. Genitopatellar syndrome and neuroblastoma: The multidisciplinary management of a previously unreported association.. Pediatr Blood Cancer. 2018;65", "M Kraft, IC Cirstea, AK Voss, T Thomas, I Goehring, BN Sheikh, L Gordon, H Scott, GK Smyth, MR Ahmadian, U Trautmann, M Zenker, M Tartaglia, A Ekici, A Reis, HG Dörr, A Rauch, CT Thiel. Disruption of the histone acetyltransferase MYST4 leads to a Noonan syndrome-like phenotype and hyperactivated MAPK signaling in humans and mice.. J Clin Invest. 2011;121:3479-91", "F Lonardo, MS Lonardo, F Acquaviva, M Della Monica, F Scarano, G Scarano. Say-Barber-Biesecker-Young-Simpson syndrome and genitopatellar syndrome: lumping or splitting?. Clin Genet. 2019;95:253-61", "FJ Martinez, JH Lee, JE Lee, S Blanco, E Nickerson, S Gabriel, M Frye, L Al-Gazali, JG Gleeson. Whole exome sequencing identifies a splicing mutation in NSUN2 as a cause of a Dubowitz-like syndrome.. J Med Genet. 2012;49:380-5", "AA Mhanni, AJ Dawson, AE Chudley. Vertical transmission of the Ohdo blepharophimosis syndrome.. Am J Med Genet. 1998;77:144-8", "Y Niida, Y Mitani, M Kuroda, A Yokoi, H Nakagawa, A Kato. A Say-Barber-Biesecker-Young-Simpson variant of Ohdo syndrome with a KAT6B 10-base pair palindromic duplication: A recurrent mutation causing a severe phenotype mixed with genitopatellar syndrome.. Congenit Anom (Kyoto) 2017;57:86-8", "S Ohdo, H Madokoro, T Sonoda, K Hayakawa. Mental retardation associated with congenital heart disease, blepharophimosis, blepharoptosis, and hypoplastic teeth.. J Med Genet. 1986;23:242-4", "S Okano, A Miyamoto, I Fukuda, H Tanaka, K Hata, T Kaname, Y. Makita. Genitopatellar syndrome: the first reported case in Japan.. Hum Genome Var. 2018;5:8", "E Preiksaitiene, B Tumiene, Z Maldziene, E Pranckeviciene, A Morkuniene, A Utkus, V Kucinskas. Features of KAT6B-related disorders in a patient with 10q22.1q22.3 deletion.. Ophthalmic Genet. 2017;38:383-6", "J Radvanszky, M Hyblova, D Durovcikova, M Hikkelova, E Fiedler, L Kadasi, T Szemes. Complex phenotypes blur conventional borders between Say-Barber-Biesecker-Young-Simpson syndrome and genitopatellar syndrome.. Clin Genet. 2017;91:339-43", "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", "B Say, N Barber. Mental retardation with blepharophimosis.. J Med Genet. 1987;24:511", "MA Simpson, C Deshpande, D Dafou, LE Vissers, WJ Woollard, SE Holder, G Gillessen-Kaesbach, R Derks, SM White, R Cohen-Snuijf, SG Kant, LH Hoefsloot, W Reardon, HG Brunner, EM Bongers, RC Trembath. De novo mutations of the gene encoding the histone acetyltransferase KAT6B cause Genitopatellar syndrome.. Am J Hum Genet. 2012;90:290-4", "K Szakszon, C Salpietro, N Kakar, AC Knegt, E Olah, B Dallapiccola, G Borck. De novo mutations of the gene encoding the histone acetyltransferase KAT6B in two patients with Say-Barber/Biesecker/Young-Simpson syndrome.. Am J Med Genet A. 2013;161A:884-8", "M Tsukahara, JM Opitz. Dubowitz syndrome: review of 141 cases including 36 previously unreported patients.. Am J Med Genet. 1996;63:277-89", "SM White, LC Adès, D Amor, J Liebelt, A Bankier, E Baker, M Wilson, R Savarirayan. Two further cases of Ohdo syndrome delineate the phenotypic variability of the condition.. Clin Dysmorphol. 2003;12:109-13", "XJ Yang. MOZ and MORF acetyltransferases: Molecular interaction, animal development and human disease.. Biochim Biophys Acta. 2015;1853:1818-26", "TM Yates, CLM Langley, D Grozeva, FL Raymond, DS Johnson. Novel KAT6B proximal familial variant expands genotypic and phenotypic spectrum.. Clin Genet. 2019;95:334-5", "R Yilmaz, A Beleza-Meireles, S Price, R Oliveira, C Kubisch, J Clayton-Smith, G Borck. A recurrent synonymous KAT6B mutation causes Say-Barber-Biesecker/Young-Simpson syndrome by inducing aberrant splicing.. Am J Med Genet A. 2015;167A:3006-10", "ID Young, K Simpson. Unknown syndrome: abnormal facies, congenital heart defects, hypothyroidism, and severe retardation.. J Med Genet. 1987;24:715-6" ]	13/12/2012	2/1/2020	10/1/2013	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
kbgs	kbgs	[ "Ankyrin repeat domain-containing protein 11", "ANKRD11", "KBG Syndrome" ]	KBG Syndrome	Dayna Morel Swols, Mustafa Tekin	Summary KBG syndrome is typically characterized by macrodontia (especially of the upper central incisors), characteristic facial features (triangular face, brachycephaly, synophrys, widely spaced eyes, broad or bushy eyebrows, prominent ears, prominent nasal bridge, bulbous nose, anteverted nares, long philtrum, and thin vermilion of the upper lip), short stature, developmental delay / intellectual disability, and behavioral issues. Affected individuals may have feeding difficulties (particularly in infancy), skeletal anomalies (brachydactyly, large anterior fontanelle with delayed closure, scoliosis), hearing loss (conductive, mixed, and sensorineural), seizure disorder, and brain malformations. There is significant variability in the clinical findings, even between affected members of the same family. The diagnosis of KBG syndrome is confirmed in a proband by detection of either a heterozygous pathogenic variant in Recurrence risk for sibs of a proband with KBG syndrome depends on the genetic alteration: Deletion of 16q24.3 (~75% of reported pathogenic variants are Prenatal testing and preimplantation genetic testing are possible if the causative genetic alteration has been identified in an affected family member.	## Diagnosis While no consensus clinical diagnostic criteria for KBG syndrome have been published, several authors have suggested diagnostic criteria [ KBG syndrome At least two of the findings highlighted by an asterisk (); OR One finding highlighted by an asterisk and at least two additional findings. Conductive hearing loss and/or chronic/recurrent otitis media Palatal abnormalities Hair anomalies (e.g., low hairline, coarse hair) Costovertebral anomalies Postnatal short stature (length and/or height <10th centile) Delayed bone age (>2SD below mean) Brachydactyly Large anterior fontanelle with delayed closure Scoliosis Learning difficulties of variable severity EEG abnormalities with or without seizures * A first-degree relative with KBG syndrome Note: Absence of a family history of KBG syndrome does not preclude the diagnosis. Feeding difficulties Cryptorchidism in males The diagnosis of KBG syndrome Note: Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing may not. Persons with the distinctive features described in When the phenotypic findings suggest the diagnosis of KBG syndrome, genetic testing approaches can include EITHER: For an introduction to multigene panels click When the diagnosis of KBG syndrome has not been considered, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in KBG 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 The percentage represents the proportion of affected individuals who were detected to have a causative Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 single-exon up to whole-gene deletions; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods. Note that one intragenic duplication variant that included Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the 16q24.3 region. Note: The 16q24.3 deletion may not have been detectable by older oligonucleotide or bacterial artificial chromosome (BAC) platforms. • At least two of the findings highlighted by an asterisk (); OR • One finding highlighted by an asterisk and at least two additional findings. • Conductive hearing loss and/or chronic/recurrent otitis media • Palatal abnormalities • Hair anomalies (e.g., low hairline, coarse hair) • Costovertebral anomalies • Postnatal short stature (length and/or height <10th centile) • Delayed bone age (>2SD below mean) • Brachydactyly • Large anterior fontanelle with delayed closure • Scoliosis • Learning difficulties of variable severity • EEG abnormalities with or without seizures • * A first-degree relative with KBG syndrome • Note: Absence of a family history of KBG syndrome does not preclude the diagnosis. • Feeding difficulties • Cryptorchidism in males ## Suggestive Findings KBG syndrome At least two of the findings highlighted by an asterisk (); OR One finding highlighted by an asterisk and at least two additional findings. Conductive hearing loss and/or chronic/recurrent otitis media Palatal abnormalities Hair anomalies (e.g., low hairline, coarse hair) Costovertebral anomalies Postnatal short stature (length and/or height <10th centile) Delayed bone age (>2SD below mean) Brachydactyly Large anterior fontanelle with delayed closure Scoliosis Learning difficulties of variable severity EEG abnormalities with or without seizures * A first-degree relative with KBG syndrome Note: Absence of a family history of KBG syndrome does not preclude the diagnosis. Feeding difficulties Cryptorchidism in males • At least two of the findings highlighted by an asterisk (); OR • One finding highlighted by an asterisk and at least two additional findings. • Conductive hearing loss and/or chronic/recurrent otitis media • Palatal abnormalities • Hair anomalies (e.g., low hairline, coarse hair) • Costovertebral anomalies • Postnatal short stature (length and/or height <10th centile) • Delayed bone age (>2SD below mean) • Brachydactyly • Large anterior fontanelle with delayed closure • Scoliosis • Learning difficulties of variable severity • EEG abnormalities with or without seizures • * A first-degree relative with KBG syndrome • Note: Absence of a family history of KBG syndrome does not preclude the diagnosis. • Feeding difficulties • Cryptorchidism in males ## Establishing the Diagnosis The diagnosis of KBG syndrome Note: Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing may not. Persons with the distinctive features described in When the phenotypic findings suggest the diagnosis of KBG syndrome, genetic testing approaches can include EITHER: For an introduction to multigene panels click When the diagnosis of KBG syndrome has not been considered, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in KBG 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 The percentage represents the proportion of affected individuals who were detected to have a causative Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 single-exon up to whole-gene deletions; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods. Note that one intragenic duplication variant that included Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the 16q24.3 region. Note: The 16q24.3 deletion may not have been detectable by older oligonucleotide or bacterial artificial chromosome (BAC) platforms. ## Option 1 When the phenotypic findings suggest the diagnosis of KBG syndrome, genetic testing approaches can include EITHER: For an introduction to multigene panels click ## Option 2 When the diagnosis of KBG syndrome has not been considered, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in KBG 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 The percentage represents the proportion of affected individuals who were detected to have a causative Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 single-exon up to whole-gene deletions; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods. Note that one intragenic duplication variant that included Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the 16q24.3 region. Note: The 16q24.3 deletion may not have been detectable by older oligonucleotide or bacterial artificial chromosome (BAC) platforms. ## Clinical Characteristics KBG syndrome was first described in 1975. The name KBG is derived from the initials of the first three families in which the condition was characterized [ Macrodontia of the permanent upper incisors is a main finding, making diagnosis prior to the eruption of these teeth more difficult. It is likely this syndrome is underdiagnosed, since many of the features are nonspecific [ Macrodontia of permanent upper central incisors is reported in 85%-95% of affected individuals [ Craniofacial findings have been reported in 62%-80% of affected individuals. The characteristic facial appearance (see Feeding issues, especially during infancy, are reported in 20% of affected individuals and include vomiting, constipation, and gastroesophageal reflux disease [ Short stature (below the 3rd centile) has been observed in 40%-77% of affected individuals [ Variable skeletal anomalies have been reported in 75% of affected individuals [ Attention deficit hyperactivity disorder is diagnosed in 10%-15% of affected individuals [ While behavior issues are common among affected individuals, reports regarding the extent of association between autism spectrum disorder (ASD) and KBG syndrome are conflicting: Previous studies reported an association between ASD and the 16q24.3 deletion [ ASD has not been commonly seen in affected individuals with intragenic Hearing issues are seen in 25%-31% of affected individuals. Recurrent otitis media has been shown to cause hearing loss in some individuals with KBG syndrome. All types of hearing loss (conductive, mixed, and sensorineural) have been reported in association with the condition, with conductive loss being the most common. Undescended testicles have been reported in 25%-35% of males [ Cardiac defects, including ASD and VSD, have been reported [ Various ocular findings, including strabismus, congenital bilateral cataract, high myopia, and megalocornea [ Advanced puberty, sometimes requiring treatment, has been reported in some individuals. Skin and hair abnormalities, such as hyperpigmentation, ichthyosis, hypertrichosis, abnormal hair whorls, and dystrophic nails, have been reported [ There is one report of prenatal diagnosis of KBG syndrome [ The vast majority of pathogenic variants are loss-of-function variants. No specific genotype/phenotype correlations have been reported, with the exception of those who have a larger 16q24.3 deletion. Deletions in the 16q24.3 region are not recurrent; each affected individual or family appears to have a novel deletion. It is likely that other genes deleted in this region have an effect on the phenotype [ Individuals with a 16q24.3 deletion that includes KBG syndrome was initially thought to be quite rare; however, it is likely underdiagnosed because of mild and nonspecific features in some affected individuals especially before eruption of the permanent dentition [ • Attention deficit hyperactivity disorder is diagnosed in 10%-15% of affected individuals [ • While behavior issues are common among affected individuals, reports regarding the extent of association between autism spectrum disorder (ASD) and KBG syndrome are conflicting: • Previous studies reported an association between ASD and the 16q24.3 deletion [ • ASD has not been commonly seen in affected individuals with intragenic • Previous studies reported an association between ASD and the 16q24.3 deletion [ • ASD has not been commonly seen in affected individuals with intragenic • Previous studies reported an association between ASD and the 16q24.3 deletion [ • ASD has not been commonly seen in affected individuals with intragenic • Deletions in the 16q24.3 region are not recurrent; each affected individual or family appears to have a novel deletion. It is likely that other genes deleted in this region have an effect on the phenotype [ • Individuals with a 16q24.3 deletion that includes ## Clinical Description KBG syndrome was first described in 1975. The name KBG is derived from the initials of the first three families in which the condition was characterized [ Macrodontia of the permanent upper incisors is a main finding, making diagnosis prior to the eruption of these teeth more difficult. It is likely this syndrome is underdiagnosed, since many of the features are nonspecific [ Macrodontia of permanent upper central incisors is reported in 85%-95% of affected individuals [ Craniofacial findings have been reported in 62%-80% of affected individuals. The characteristic facial appearance (see Feeding issues, especially during infancy, are reported in 20% of affected individuals and include vomiting, constipation, and gastroesophageal reflux disease [ Short stature (below the 3rd centile) has been observed in 40%-77% of affected individuals [ Variable skeletal anomalies have been reported in 75% of affected individuals [ Attention deficit hyperactivity disorder is diagnosed in 10%-15% of affected individuals [ While behavior issues are common among affected individuals, reports regarding the extent of association between autism spectrum disorder (ASD) and KBG syndrome are conflicting: Previous studies reported an association between ASD and the 16q24.3 deletion [ ASD has not been commonly seen in affected individuals with intragenic Hearing issues are seen in 25%-31% of affected individuals. Recurrent otitis media has been shown to cause hearing loss in some individuals with KBG syndrome. All types of hearing loss (conductive, mixed, and sensorineural) have been reported in association with the condition, with conductive loss being the most common. Undescended testicles have been reported in 25%-35% of males [ Cardiac defects, including ASD and VSD, have been reported [ Various ocular findings, including strabismus, congenital bilateral cataract, high myopia, and megalocornea [ Advanced puberty, sometimes requiring treatment, has been reported in some individuals. Skin and hair abnormalities, such as hyperpigmentation, ichthyosis, hypertrichosis, abnormal hair whorls, and dystrophic nails, have been reported [ There is one report of prenatal diagnosis of KBG syndrome [ • Attention deficit hyperactivity disorder is diagnosed in 10%-15% of affected individuals [ • While behavior issues are common among affected individuals, reports regarding the extent of association between autism spectrum disorder (ASD) and KBG syndrome are conflicting: • Previous studies reported an association between ASD and the 16q24.3 deletion [ • ASD has not been commonly seen in affected individuals with intragenic • Previous studies reported an association between ASD and the 16q24.3 deletion [ • ASD has not been commonly seen in affected individuals with intragenic • Previous studies reported an association between ASD and the 16q24.3 deletion [ • ASD has not been commonly seen in affected individuals with intragenic ## Dental Macrodontia of permanent upper central incisors is reported in 85%-95% of affected individuals [ ## Craniofacial Craniofacial findings have been reported in 62%-80% of affected individuals. The characteristic facial appearance (see ## Feeding Feeding issues, especially during infancy, are reported in 20% of affected individuals and include vomiting, constipation, and gastroesophageal reflux disease [ ## Growth Short stature (below the 3rd centile) has been observed in 40%-77% of affected individuals [ ## Skeletal Variable skeletal anomalies have been reported in 75% of affected individuals [ ## Neurologic Attention deficit hyperactivity disorder is diagnosed in 10%-15% of affected individuals [ While behavior issues are common among affected individuals, reports regarding the extent of association between autism spectrum disorder (ASD) and KBG syndrome are conflicting: Previous studies reported an association between ASD and the 16q24.3 deletion [ ASD has not been commonly seen in affected individuals with intragenic • Attention deficit hyperactivity disorder is diagnosed in 10%-15% of affected individuals [ • While behavior issues are common among affected individuals, reports regarding the extent of association between autism spectrum disorder (ASD) and KBG syndrome are conflicting: • Previous studies reported an association between ASD and the 16q24.3 deletion [ • ASD has not been commonly seen in affected individuals with intragenic • Previous studies reported an association between ASD and the 16q24.3 deletion [ • ASD has not been commonly seen in affected individuals with intragenic • Previous studies reported an association between ASD and the 16q24.3 deletion [ • ASD has not been commonly seen in affected individuals with intragenic ## Hearing Hearing issues are seen in 25%-31% of affected individuals. Recurrent otitis media has been shown to cause hearing loss in some individuals with KBG syndrome. All types of hearing loss (conductive, mixed, and sensorineural) have been reported in association with the condition, with conductive loss being the most common. ## Less Common Findings Undescended testicles have been reported in 25%-35% of males [ Cardiac defects, including ASD and VSD, have been reported [ Various ocular findings, including strabismus, congenital bilateral cataract, high myopia, and megalocornea [ Advanced puberty, sometimes requiring treatment, has been reported in some individuals. Skin and hair abnormalities, such as hyperpigmentation, ichthyosis, hypertrichosis, abnormal hair whorls, and dystrophic nails, have been reported [ ## Prenatal There is one report of prenatal diagnosis of KBG syndrome [ ## Genotype-Phenotype Correlations The vast majority of pathogenic variants are loss-of-function variants. No specific genotype/phenotype correlations have been reported, with the exception of those who have a larger 16q24.3 deletion. Deletions in the 16q24.3 region are not recurrent; each affected individual or family appears to have a novel deletion. It is likely that other genes deleted in this region have an effect on the phenotype [ Individuals with a 16q24.3 deletion that includes • Deletions in the 16q24.3 region are not recurrent; each affected individual or family appears to have a novel deletion. It is likely that other genes deleted in this region have an effect on the phenotype [ • Individuals with a 16q24.3 deletion that includes ## Prevalence KBG syndrome was initially thought to be quite rare; however, it is likely underdiagnosed because of mild and nonspecific features in some affected individuals especially before eruption of the permanent dentition [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this Individuals with larger deletions of the 16q24.3 region that include ## Differential Diagnosis Disorders to Consider in the Differential Diagnosis of KBG Syndrome Facial features DD Growth restriction Hearing loss Cryptorchidism Head circumference small ID more severe Facial features DD Growth restriction Cryptorchidism IUGR Limb/facial asymmetry Short stature Distinctive facial features Macrodontia Brachydactyly Vertebral anomalies Cryptorchidism Cognitive ability normal in most Shawl scrotum in males Prominent central incisors DD Microcephaly Obesity Myopia Choreoretinal dystrophy AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; DiffDx = differential diagnosis; ID = intellectual disability; IUGR = intrauterine growth restriction; MOI = mode of inheritance; XL = X-linked Silver-Russell syndrome has multiple etiologies including: epigenetic changes that modify expression of genes in the imprinted region of chromosome 11p15.5, maternal UPD7, and (infrequently) autosomal dominant or autosomal recessive inheritance. • Facial features • DD • Growth restriction • Hearing loss • Cryptorchidism • Head circumference small • ID more severe • Facial features • DD • Growth restriction • Cryptorchidism • IUGR • Limb/facial asymmetry • Short stature • Distinctive facial features • Macrodontia • Brachydactyly • Vertebral anomalies • Cryptorchidism • Cognitive ability normal in most • Shawl scrotum in males • Prominent central incisors • DD • Microcephaly • Obesity • Myopia • Choreoretinal dystrophy ## Management To establish the extent of disease and needs in an individual diagnosed with KBG syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis of KBG Syndrome Evaluations To Consider Following Initial Diagnosis of KBG Syndrome Treatment of Manifestations in Individuals with KBG Syndrome GERD = gastroesophageal reflux disease 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., scoliosis, hip dislocation). Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications when necessary. Routine monitoring for the following should be considered: Hearing, to assess for hearing loss Vision, if ophthalmologic issues are present Growth and pubertal status, to assess for short stature, growth velocity, and advanced or premature puberty [ Regular developmental assessments to evaluate cognition and learning Because of the risk of hearing loss, ototoxic drugs should be avoided. See There are no universal pregnancy issues in women with KBG syndrome. Pregnancy management should be tailored to the specific features present in the affected woman. For those who have congenital heart defects, management by a cardiologist and maternal fetal medicine physician during pregnancy should be considered. For those who have a seizure disorder that requires medical therapy, management by a neurologist during pregnancy should be considered. 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 • 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., scoliosis, hip dislocation). • Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • Hearing, to assess for hearing loss • Vision, if ophthalmologic issues are present • Growth and pubertal status, to assess for short stature, growth velocity, and advanced or premature puberty [ • Regular developmental assessments to evaluate cognition and learning ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with KBG syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis of KBG Syndrome Evaluations To Consider Following Initial Diagnosis of KBG Syndrome ## Treatment of Manifestations Treatment of Manifestations in Individuals with KBG Syndrome GERD = gastroesophageal reflux disease 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., scoliosis, hip dislocation). Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications when necessary. • 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., scoliosis, hip dislocation). • Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. In the US: Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. • Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. ## Motor Dysfunction Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., scoliosis, hip dislocation). Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., scoliosis, hip dislocation). • Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## Social/Behavioral Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications when necessary. ## Surveillance Routine monitoring for the following should be considered: Hearing, to assess for hearing loss Vision, if ophthalmologic issues are present Growth and pubertal status, to assess for short stature, growth velocity, and advanced or premature puberty [ Regular developmental assessments to evaluate cognition and learning • Hearing, to assess for hearing loss • Vision, if ophthalmologic issues are present • Growth and pubertal status, to assess for short stature, growth velocity, and advanced or premature puberty [ • Regular developmental assessments to evaluate cognition and learning ## Agents/Circumstances to Avoid Because of the risk of hearing loss, ototoxic drugs should be avoided. ## Evaluation of Relatives at Risk See ## Pregnancy Management There are no universal pregnancy issues in women with KBG syndrome. Pregnancy management should be tailored to the specific features present in the affected woman. For those who have congenital heart defects, management by a cardiologist and maternal fetal medicine physician during pregnancy should be considered. For those who have a seizure disorder that requires medical therapy, management by a neurologist during pregnancy should be considered. 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 ## Genetic Counseling KBG syndrome, caused by a non-recurrent deletion of 16q24.3 that includes 25% of probands with KBG syndrome caused by deletion of 16q24.3 have a parent who is mildly affected and/or harbors the deletion in a mosaic fashion. 75% of probands with KBG syndrome caused by deletion 16q24.3 have a Evaluation of the parents by genomic testing that will detect the deletion identified in the proband is recommended. The risk to the sibs of a proband depends on the genetic status of the proband's parents. If the 16q24.3 deletion found in the proband is not identified in one of the parents, the risk to sibs is low (<1%) but greater than that of the general population because of the possibility of parental germline mosaicism [ If one of the parents has the deletion identified in the proband, the risk to each sib of inheriting the deletion is 50%. However, it is not possible to reliably predict clinical severity in sibs who inherit the deletion. Approximately 34% of individuals with KBG syndrome caused by a pathogenic variant within Approximately 66% of individuals with KBG syndrome caused by a pathogenic variant within Molecular genetic testing is recommended for the parents of a proband with an apparent If the 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 [ No cases of mosaicism for the The risk to the sibs of a proband depends on the genetic status of the proband's parents: If a parent of the proband has the If the If the parents have not been tested for the The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having a child with KBG syndrome. Once an intragenic Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • 25% of probands with KBG syndrome caused by deletion of 16q24.3 have a parent who is mildly affected and/or harbors the deletion in a mosaic fashion. • 75% of probands with KBG syndrome caused by deletion 16q24.3 have a • Evaluation of the parents by genomic testing that will detect the deletion identified in the proband is recommended. • The risk to the sibs of a proband depends on the genetic status of the proband's parents. • If the 16q24.3 deletion found in the proband is not identified in one of the parents, the risk to sibs is low (<1%) but greater than that of the general population because of the possibility of parental germline mosaicism [ • If one of the parents has the deletion identified in the proband, the risk to each sib of inheriting the deletion is 50%. However, it is not possible to reliably predict clinical severity in sibs who inherit the deletion. • Approximately 34% of individuals with KBG syndrome caused by a pathogenic variant within • Approximately 66% of individuals with KBG syndrome caused by a pathogenic variant within • Molecular genetic testing is recommended for the parents of a proband with an apparent • If the • 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 [ • No cases of mosaicism for the • 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 [ • No cases of mosaicism for the • 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 [ • No cases of mosaicism for the • The risk to the sibs of a proband depends on the genetic status of the proband's parents: • If a parent of the proband has the • If the • If a parent of the proband has the • If the • If the parents have not been tested for the • If a parent of the proband has the • If the • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having a child with KBG syndrome. ## Mode of Inheritance KBG syndrome, caused by a non-recurrent deletion of 16q24.3 that includes ## Risk to Family Members 25% of probands with KBG syndrome caused by deletion of 16q24.3 have a parent who is mildly affected and/or harbors the deletion in a mosaic fashion. 75% of probands with KBG syndrome caused by deletion 16q24.3 have a Evaluation of the parents by genomic testing that will detect the deletion identified in the proband is recommended. The risk to the sibs of a proband depends on the genetic status of the proband's parents. If the 16q24.3 deletion found in the proband is not identified in one of the parents, the risk to sibs is low (<1%) but greater than that of the general population because of the possibility of parental germline mosaicism [ If one of the parents has the deletion identified in the proband, the risk to each sib of inheriting the deletion is 50%. However, it is not possible to reliably predict clinical severity in sibs who inherit the deletion. Approximately 34% of individuals with KBG syndrome caused by a pathogenic variant within Approximately 66% of individuals with KBG syndrome caused by a pathogenic variant within Molecular genetic testing is recommended for the parents of a proband with an apparent If the 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 [ No cases of mosaicism for the The risk to the sibs of a proband depends on the genetic status of the proband's parents: If a parent of the proband has the If the If the parents have not been tested for the • 25% of probands with KBG syndrome caused by deletion of 16q24.3 have a parent who is mildly affected and/or harbors the deletion in a mosaic fashion. • 75% of probands with KBG syndrome caused by deletion 16q24.3 have a • Evaluation of the parents by genomic testing that will detect the deletion identified in the proband is recommended. • The risk to the sibs of a proband depends on the genetic status of the proband's parents. • If the 16q24.3 deletion found in the proband is not identified in one of the parents, the risk to sibs is low (<1%) but greater than that of the general population because of the possibility of parental germline mosaicism [ • If one of the parents has the deletion identified in the proband, the risk to each sib of inheriting the deletion is 50%. However, it is not possible to reliably predict clinical severity in sibs who inherit the deletion. • Approximately 34% of individuals with KBG syndrome caused by a pathogenic variant within • Approximately 66% of individuals with KBG syndrome caused by a pathogenic variant within • Molecular genetic testing is recommended for the parents of a proband with an apparent • If the • 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 [ • No cases of mosaicism for the • 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 [ • No cases of mosaicism for the • 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 [ • No cases of mosaicism for the • The risk to the sibs of a proband depends on the genetic status of the proband's parents: • If a parent of the proband has the • If the • If a parent of the proband has the • If the • If the parents have not been tested for the • If a parent of the proband has the • If the ## Non-Recurrent Deletion of 16q24.3 Including 25% of probands with KBG syndrome caused by deletion of 16q24.3 have a parent who is mildly affected and/or harbors the deletion in a mosaic fashion. 75% of probands with KBG syndrome caused by deletion 16q24.3 have a Evaluation of the parents by genomic testing that will detect the deletion identified in the proband is recommended. The risk to the sibs of a proband depends on the genetic status of the proband's parents. If the 16q24.3 deletion found in the proband is not identified in one of the parents, the risk to sibs is low (<1%) but greater than that of the general population because of the possibility of parental germline mosaicism [ If one of the parents has the deletion identified in the proband, the risk to each sib of inheriting the deletion is 50%. However, it is not possible to reliably predict clinical severity in sibs who inherit the deletion. • 25% of probands with KBG syndrome caused by deletion of 16q24.3 have a parent who is mildly affected and/or harbors the deletion in a mosaic fashion. • 75% of probands with KBG syndrome caused by deletion 16q24.3 have a • Evaluation of the parents by genomic testing that will detect the deletion identified in the proband is recommended. • The risk to the sibs of a proband depends on the genetic status of the proband's parents. • If the 16q24.3 deletion found in the proband is not identified in one of the parents, the risk to sibs is low (<1%) but greater than that of the general population because of the possibility of parental germline mosaicism [ • If one of the parents has the deletion identified in the proband, the risk to each sib of inheriting the deletion is 50%. However, it is not possible to reliably predict clinical severity in sibs who inherit the deletion. ## Pathogenic Variant Within Approximately 34% of individuals with KBG syndrome caused by a pathogenic variant within Approximately 66% of individuals with KBG syndrome caused by a pathogenic variant within Molecular genetic testing is recommended for the parents of a proband with an apparent If the 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 [ No cases of mosaicism for the The risk to the sibs of a proband depends on the genetic status of the proband's parents: If a parent of the proband has the If the If the parents have not been tested for the • Approximately 34% of individuals with KBG syndrome caused by a pathogenic variant within • Approximately 66% of individuals with KBG syndrome caused by a pathogenic variant within • Molecular genetic testing is recommended for the parents of a proband with an apparent • If the • 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 [ • No cases of mosaicism for the • 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 [ • No cases of mosaicism for the • 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 [ • No cases of mosaicism for the • The risk to the sibs of a proband depends on the genetic status of the proband's parents: • If a parent of the proband has the • If the • If a parent of the proband has the • If the • If the parents have not been tested for the • If a parent of the proband has the • If the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having a child with KBG syndrome. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having a child with KBG syndrome. ## Prenatal Testing and Preimplantation Genetic Testing Once an intragenic Differences in perspective may exist among medical professionals and within families regarding the use 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 KBG Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for KBG 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 We are grateful to Rena Pressman for her critical reading. 22 March 2018 (ma) Review posted live 21 June 2017 (mt) Original submission • 22 March 2018 (ma) Review posted live • 21 June 2017 (mt) Original submission ## Acknowledgments We are grateful to Rena Pressman for her critical reading. ## Revision History 22 March 2018 (ma) Review posted live 21 June 2017 (mt) Original submission • 22 March 2018 (ma) Review posted live • 21 June 2017 (mt) Original submission ## References ## Literature Cited Macrodontia of permanent upper central incisors, dental pits, and prominent mamelons Triangular face, synophrys, prominent nasal bridge, anteverted nares, long philtrum, and thin vermilion of the upper lip in two affected males	[ "F Brancati, MG D'Avanzo, MC Digilio, A Sarkozy, M Biondi, D De Brasi, R Mingarelli, B Dallapiccola. KBG syndrome in a cohort of Italian patients.. Am J Med Genet A. 2004;131:144-9", "M Crippa, D Rusconi, C Castronovo, I Bestetti, S Russo, A Cereda, A Selicorni, L Larizza, P Finelli. Familial intragenic duplication of ANKRD11 underlying three patients of KBG syndrome.. Mol Cytogenet. 2015;8:20", "D Gallagher, A Voronova, MA Zander, GI Cancino, A Bramall, MP Krause, C Abad, M Tekin, PM Neilsen, DF Callen, SW Scherer, GM Keller, DR Kaplan, K Walz, FD Miller. Dev Cell 2015;32:31-42", "A Goldenberg, F Riccardi, A Tessier, R Pfundt, T Busa, P Cacciagli, Y Capri, C Coutton, A Delahaye-Duriez, T Frebourg. Clinical and molecular findings in 39 patients with KBG syndrome caused by deletion or mutation of ANKRD11.. Am J Med Genet A. 2016;170:2847-59", "GR Handrigan, D Chitayat, AC Lionel, M Pinsk, AK Vaags, CR Marshall, S Dyack, LF Escobar, BA Fernandez, JC Stegman, JA Rosenfeld, LG Shaffer, M Goodenberger, JC Hodge, JE Cain, R Babul-Hirji, DJ Stavropoulos, V Yiu, SW Scherer, ND Rosenblum. Deletions in 16q24.2 are associated with autism spectrum disorder, intellectual disability and congenital renal malformation.. J Med Genet. 2013;50:163-73", "J Herrmann, PD Pallister, W Tiddy, JM Opitz. The KBG syndrome-a syndrome of short stature, characteristic facies, mental retardation, macrodontia and skeletal anomalies.. Birth Defects Orig Artic Ser. 1975;11:7-18", "V Hodgetts Morton, E Quinlan-Jones, N Butts, D Williams, S Hamilton, T Marton, K. Morris. The first antenatal diagnosis of KBG syndrome: a microdeletion at chromosome 16q24.2q24.3 containing multiple genes including ANKRD11 associated with the disorder.. Clin Case Rep. 2017;6:189-91", "M Ka, W-Y Kim. ANKRD11 associated with intellectual disability and autism regulates dendrite differentiation via the BDNF/TrkB signaling pathway.. Neurobiol Dis 2018;111:138-52", "M Khalifa, J Stein, L Grau, V Nelson, J Meck, S Aradhya, J Duby. Partial deletion of ANKRD11results in the KBG phenotype distinct from the 16q24.3 microdeletion syndrome.. Am J Med Genet A. 2013;161A:835-40", "H Kumar, N Prabhu, A Cameron. KBG syndrome: review of the literature and findings of 5 affected patients.. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009;108:e72-9", "JH Lim, EJ Seo, YM Kim, HJ Cho, JO Lee, CK Cheon, HW Yoo. A de novo microdeletion of ANKRD11 gene in a Korean patient with KBG syndrome.. Ann Lab Med. 2014;34:390-4", "A Lo-Castro, F Brancati, MC Digilio, FG Garaci, P Bollero, P Alfieri, P Curatolo. Neurobehavioral phenotype observed in KBG syndrome caused by ANKRD11 mutations.. Am J Med Genet B Neuropsychiatr Genet. 2013;162B:17-23", "K Low, T Ashraf, N Canham, J Clayton-Smith, C Deshpande, A Donaldson, R Fisher, F Flinter, N Foulds, A Fryer. Clinical and genetic aspects of KBG syndrome.. Am J Med Genet A. 2016;170:2835-46", "GH Maegawa, JC Leite, TM Félix, HL da Silveira, HE da Silveira. Clinical variability in KBG syndrome: report of three unrelated families.. Am J Med Genet A. 2004;131:150-4", "S Miyatake, A Murakami, N Okamoto, M Sakamoto, N Miyake, H Saitsu, N Matsumoto. A de novo deletion at 16q24.3 involving ANKRD11 in a Japanese patient with KBG syndrome.. Am J Med Genet A. 2013;161A:1073-7", "N Murray, B Burgess, R Hay, A Colley, S Rajagopalan, J McGaughran, C Patel, A Enriquez, L Goodwin, Z Stark, T Tan, M Wilson, T Roscioli, M Tekin, H. Goel. KBG syndrome: an Australian experience.. Am J Med Genet A. 2017;173:1866-77", "F Novara, B Rinaldi, SM Sisodiya, A Coppola, S Giglio, F Stanzial, F Benedicenti, A Donaldson, J Andrieux, R Stapleton, A Weber, P Reho, C van Ravenswaaij-Arts, WS Kerstjens-Frederikse, JR Vermeesch, K Devriendt, CA Bacino, A Delahaye, SM Maas, A Iolascon, O Zuffardi. Haploinsufficiency for ANKRD11-flanking genes makes the difference between KBG and 16q24.3 microdeletion syndromes: 12 new cases.. Eur J Hum Genet. 2017;25:694-701", "CW Ockeloen, MH Willemsen, S de Munnik, BW van Bon, N de Leeuw, A Verrips, SG Kant, EA Jones, HG Brunner, RL van Loon. Further delineation of the KBG syndrome caused by ANKDR11 aberrations.. Eur J Hum Genet. 2015;23:1176-85", "R Oegema, R Schot, MC de Wit, MH Lequin, R Oostenbrink, IF de Coo, GM Mancini. KBG syndrome associated with periventricular nodular heterotopia.. Clin Dysmorphol. 2010;19:164-5", "N Reynaert, CW Ockeloen, L Sävendahl, D Beckers, K Devriendt, T Kleefstra, CE Carels, G Grigelioniene, A Nordgren, I Francois, F de Zegher, K Casteels. Short stature in KBG syndrome: first responses to growth hormone treatment.. Horm Res Paediatr. 2015;83:361-4", "S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24", "S Sacharow, D Li, YS Fan, M Tekin. Familial 16q24.3 microdeletion involving ANKRD11 causes a KBG-like syndrome.. Am J Med Genet A. 2012;158A:547-52", "D Samanta, E. Willis. Electroencephalographic findings in KBG syndrome: a child with novel mutation in ANKRD11 gene.. Acta Neurol Belg 2015;115:779-82", "AK Sarma, N Khandker, L Kurczewski, GM Brophy. Medical management of epileptic seizures: challenges and solutions.. Neuropsychiatr Dis Treat. 2016;12:467-85", "A Sirmaci, M Spiliopoulos, F Brancati, E Powell, D Duman, A Abrams, G Bademci, E Agolini, S Guo, B Konuk, A Kavaz, S Blanton, MC Digilio, B Dallapiccola, J Young, S Zuchner, M Tekin. Mutations in ANKRD11 cause KBG syndrome, characterized by intellectual disability, skeletal malformations, and macrodontia.. Am J Hum Genet. 2011;89:289-94", "KL Skjei, M Martin, A Slavotinek. KBG syndrome: report of twins, neurological characteristics, and delineation of diagnostic criteria.. Am J Med Genet A. 2007;143A:292-300", "LCM van Dongen, E Wingbermühle, W Oomens, AG Bos-Roubus, CW Ockeloen, T Kleefstra, JIM Egger. Intellectual profiles in KBG-syndrome: a Wechsler based case-control study.. Front Behav Neurosci. 2017;11:248", "K Walz, D Cohen, PM Neilsen, J Foster, F Brancati, K Demir, R Fisher, M Moffat, NE Verbeek, K Bjørgo, A Lo Castro, P Curatolo, G Novelli, C Abad, C Lei, L Zhang, O Diaz-Horta, JI Young, DF Callen, M Tekin. Characterization of ANKRD11 mutations in humans and mice related to KBG syndrome.. Hum Genet 2015;134:181-90", "MH Willemsen, BA Fernandez, CA Bacino, E Gerkes, AP de Brouwer, R Pfundt, B Sikkema-Raddatz, SW Scherer, CR Marshall, L Potocki, H van Bokhoven, T Kleefstra. Identification of ANKRD11 and ZNF778 as candidate genes for autism and variable cognitive impairment in the novel 16q24.3 microdeletion syndrome.. Eur J Hum Genet. 2010;18:429-35", "M Zollino, A Battaglia, MG D'Avanzo, MM Della Bruna, R Marini, G Scarano, M Cappa, G Neri. Six additional cases of the KBG syndrome: clinical reports and outline of the diagnostic criteria.. Am J Med Genet. 1994;52:302-7" ]	22/3/2018			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
kcnk9-is	kcnk9-is	[ "Birk-Barel Syndrome", "Birk-Barel Syndrome", "Potassium channel subfamily K member 9", "KCNK9", "KCNK9 Imprinting Syndrome" ]		Neda Zadeh, John M Graham	Summary The diagnosis of the	## Diagnosis Consensus clinical diagnostic criteria for the Congenital central hypotonia and persistent generalized weakness Severe feeding difficulties, often requiring placement of gastrostomy tube. Delayed development / intellectual disability The diagnosis of the Because the phenotype of the 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 Since 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. • Congenital central hypotonia and persistent generalized weakness • Severe feeding difficulties, often requiring placement of gastrostomy tube. • Delayed development / intellectual disability • For an introduction to multigene panels click ## Suggestive Findings Congenital central hypotonia and persistent generalized weakness Severe feeding difficulties, often requiring placement of gastrostomy tube. Delayed development / intellectual disability • Congenital central hypotonia and persistent generalized weakness • Severe feeding difficulties, often requiring placement of gastrostomy tube. • Delayed development / intellectual disability ## Establishing the Diagnosis The diagnosis of the Because the phenotype of the 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 Since Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • For an introduction to multigene panels click ## Clinical Characteristics The phenotype has been severe and consistent in all individuals examined to date. While the hypotonia may improve over time, it is present during childhood and into adulthood. Occasionally weakness of proximal muscles and the supra- and infrascapular and trapezius muscles is observed later in life. Generalized hypotonia at an early age followed by weakness of proximal muscles can lead to contractures and scoliosis. Cleft palate (including full cleft, submucous cleft or velopharyngeal insufficiency) is present in 42% of affected individuals. Occasional neurologic findings include clonus and rarely seizures. Subtle dysmorphic features that can evolve over time include dolichocephaly with a narrow forehead; mild atrophy of the temporalis and masseter muscles; myopathic elongated facies with a tented vermillion of the upper lip and short broad philtrum; reduced facial movement; mild micro/retrognathia with relatively prominent maxillary and premaxillary regions; medially flared, arched eyebrows; and ptosis [ Body habitus is asthenic; a long neck and tapered chest are evident in later childhood. Fingers are tapered; fetal fingertip pads are prominent [ A pilonidal dimple or sinus is evident in most individuals. Rarely, it is associated with a filar cyst (cystic structure in the proximal filum terminale) and lipoma in the sacral region. Some affected individuals have transient neonatal hypoglycemia associated with hyperinsulinism that resolves with diazoxide treatment [ Decreased lacrimation and increased risk for corneal dryness can be observed. Sleep disturbance can be due to both central and obstructive sleep apnea, and usually responds to BiPAP. Normal findings typically include: hearing, ophthalmologic evaluation (including vision), neuroimaging, and muscle biopsy (which may show nonspecific findings such as fiber-size disproportion). X-rays of long bones are normal [ Penetrance for maternally inherited pathogenic variants in ## Clinical Description The phenotype has been severe and consistent in all individuals examined to date. While the hypotonia may improve over time, it is present during childhood and into adulthood. Occasionally weakness of proximal muscles and the supra- and infrascapular and trapezius muscles is observed later in life. Generalized hypotonia at an early age followed by weakness of proximal muscles can lead to contractures and scoliosis. Cleft palate (including full cleft, submucous cleft or velopharyngeal insufficiency) is present in 42% of affected individuals. Occasional neurologic findings include clonus and rarely seizures. Subtle dysmorphic features that can evolve over time include dolichocephaly with a narrow forehead; mild atrophy of the temporalis and masseter muscles; myopathic elongated facies with a tented vermillion of the upper lip and short broad philtrum; reduced facial movement; mild micro/retrognathia with relatively prominent maxillary and premaxillary regions; medially flared, arched eyebrows; and ptosis [ Body habitus is asthenic; a long neck and tapered chest are evident in later childhood. Fingers are tapered; fetal fingertip pads are prominent [ A pilonidal dimple or sinus is evident in most individuals. Rarely, it is associated with a filar cyst (cystic structure in the proximal filum terminale) and lipoma in the sacral region. Some affected individuals have transient neonatal hypoglycemia associated with hyperinsulinism that resolves with diazoxide treatment [ Decreased lacrimation and increased risk for corneal dryness can be observed. Sleep disturbance can be due to both central and obstructive sleep apnea, and usually responds to BiPAP. Normal findings typically include: hearing, ophthalmologic evaluation (including vision), neuroimaging, and muscle biopsy (which may show nonspecific findings such as fiber-size disproportion). X-rays of long bones are normal [ ## Penetrance Penetrance for maternally inherited pathogenic variants in ## Prevalence ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis A number of disorders can mimic some aspects of the Disorders to Consider in the Differential Diagnosis of Hypotonia & severe generalized weakness at birth Intellectual disability Usually no cleft palate Severe hypotonia & feeding difficulties in early infancy Delayed motor milestones & language development; some degree of cognitive impairment in all persons Hypotonia & feeding problems resolve more quickly. Usually no cleft palate Palatal abnormalities Characteristic facial features Learning difficulties Immune deficiency Hypocalcemia w/significant feeding & swallowing problems Initial hypotonia less severe Presence of heart defects AD = autosomal dominant; MOI = mode of inheritance PWS is caused by lack of expression of the paternally derived PWS/AS region of chromosome 15q11.2-q13 by one of several genetic mechanisms. • Hypotonia & severe generalized weakness at birth • Intellectual disability • Usually no cleft palate • Severe hypotonia & feeding difficulties in early infancy • Delayed motor milestones & language development; some degree of cognitive impairment in all persons • Hypotonia & feeding problems resolve more quickly. • Usually no cleft palate • Palatal abnormalities • Characteristic facial features • Learning difficulties • Immune deficiency • Hypocalcemia w/significant feeding & swallowing problems • Initial hypotonia less severe • Presence of heart defects ## Management To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis of Assess strength & motor skills. EEG if seizures are suspected Spinal ultrasound of a pilonidal dimple or sinus to assess for filar cyst & lipoma in sacral region Developmental assessment Consultation w/clinical geneticist &/or genetic counselor No specific management guidelines have been developed. Management is mostly supportive. A multidisciplinary team of specialists in clinical genetics, plastic surgery, ophthalmology, pulmonology, gastroenterology, feeding, endocrinology, and neurology is recommended depending on the affected individual’s manifestations. Treatment of Manifestations in Individuals with OT = occupational therapy; PT = physical therapy Recommended Surveillance for Individuals with See Three members of the nonsteroidal anti-inflammatory fenamic acid class of drugs – flufenamic acid (FFA), niflumic acid (NFA) and mefanamic acid (MFA) – have been shown to stimulate two pore-domain potassium channels [ Two affected individuals to date have been treated with oral MFA starting at age 14 months, with noted increased energy while on the medication and no adverse reactions. Clinical features are still present, and long-term studies are necessary to predict the outcome of individuals treated with MFA [ Search • Assess strength & motor skills. • EEG if seizures are suspected • Spinal ultrasound of a pilonidal dimple or sinus to assess for filar cyst & lipoma in sacral region • Developmental assessment • Consultation w/clinical geneticist &/or genetic counselor ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis of Assess strength & motor skills. EEG if seizures are suspected Spinal ultrasound of a pilonidal dimple or sinus to assess for filar cyst & lipoma in sacral region Developmental assessment Consultation w/clinical geneticist &/or genetic counselor • Assess strength & motor skills. • EEG if seizures are suspected • Spinal ultrasound of a pilonidal dimple or sinus to assess for filar cyst & lipoma in sacral region • Developmental assessment • Consultation w/clinical geneticist &/or genetic counselor ## Treatment of Manifestations No specific management guidelines have been developed. Management is mostly supportive. A multidisciplinary team of specialists in clinical genetics, plastic surgery, ophthalmology, pulmonology, gastroenterology, feeding, endocrinology, and neurology is recommended depending on the affected individual’s manifestations. Treatment of Manifestations in Individuals with OT = occupational therapy; PT = physical therapy ## Surveillance Recommended Surveillance for Individuals with ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Three members of the nonsteroidal anti-inflammatory fenamic acid class of drugs – flufenamic acid (FFA), niflumic acid (NFA) and mefanamic acid (MFA) – have been shown to stimulate two pore-domain potassium channels [ Two affected individuals to date have been treated with oral MFA starting at age 14 months, with noted increased energy while on the medication and no adverse reactions. Clinical features are still present, and long-term studies are necessary to predict the outcome of individuals treated with MFA [ Search ## Genetic Counseling Approximately 80% of affected individuals reported to date inherited the p.Gly236Arg Approximately 20% of individuals diagnosed with Recommendations for the evaluation of the mother of a proband include The father of an affected individual will not be affected with The risk to the sibs of the proband depends on the genetic status of the proband’s mother. If the mother of the proband is heterozygous for the If the The risk to other family members depends on the genetic status of the proband's mother. If the proband’s mother is heterozygous for a Offspring of heterozygous females would be at risk for Offspring of heterozygous males would not be at risk for The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young females heterozygous for a paternally inherited 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 affected individuals reported to date inherited the p.Gly236Arg • Approximately 20% of individuals diagnosed with • Recommendations for the evaluation of the mother of a proband include • The father of an affected individual will not be affected with • The risk to the sibs of the proband depends on the genetic status of the proband’s mother. • If the mother of the proband is heterozygous for the • If the • The risk to other family members depends on the genetic status of the proband's mother. • If the proband’s mother is heterozygous for a • Offspring of heterozygous females would be at risk for • Offspring of heterozygous males would not be at risk for • Offspring of heterozygous females would be at risk for • Offspring of heterozygous males would not be at risk for • Offspring of heterozygous females would be at risk for • Offspring of heterozygous males would not be at risk for • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young females heterozygous for a paternally inherited ## Mode of Inheritance ## Risk to Family Members Approximately 80% of affected individuals reported to date inherited the p.Gly236Arg Approximately 20% of individuals diagnosed with Recommendations for the evaluation of the mother of a proband include The father of an affected individual will not be affected with The risk to the sibs of the proband depends on the genetic status of the proband’s mother. If the mother of the proband is heterozygous for the If the The risk to other family members depends on the genetic status of the proband's mother. If the proband’s mother is heterozygous for a Offspring of heterozygous females would be at risk for Offspring of heterozygous males would not be at risk for • Approximately 80% of affected individuals reported to date inherited the p.Gly236Arg • Approximately 20% of individuals diagnosed with • Recommendations for the evaluation of the mother of a proband include • The father of an affected individual will not be affected with • The risk to the sibs of the proband depends on the genetic status of the proband’s mother. • If the mother of the proband is heterozygous for the • If the • The risk to other family members depends on the genetic status of the proband's mother. • If the proband’s mother is heterozygous for a • Offspring of heterozygous females would be at risk for • Offspring of heterozygous males would not be at risk for • Offspring of heterozygous females would be at risk for • Offspring of heterozygous males would not be at risk for • Offspring of heterozygous females would be at risk for • Offspring of heterozygous males would not be at risk for ## 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 females heterozygous for a paternally inherited • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young females heterozygous for a paternally inherited ## 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 KCNK9 Imprinting Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for KCNK9 Imprinting Syndrome ( Variants listed in the table have been provided by the authors. Because TASK3 channels are found throughout the body, especially in the brain where they may play a role in the migration of cortical pyramidal neurons by regulating membrane potential and in action potential repolarization [ ## References ## Literature Cited ## Chapter Notes Melissa Kelley 23 March 2017 (bp) Review posted live 14 July 2016 (jmg) Original submission • 23 March 2017 (bp) Review posted live • 14 July 2016 (jmg) Original submission ## Author Notes ## Acknowledgments Melissa Kelley ## Revision History 23 March 2017 (bp) Review posted live 14 July 2016 (jmg) Original submission • 23 March 2017 (bp) Review posted live • 14 July 2016 (jmg) Original submission	[ "Y Bando, T Hirano, Y. Tagawa. Dysfunction of KCNK potassium channels impairs neuronal migration in the developing mouse cerebral cortex.. Cereb Cortex. 2014;24:1017-29", "O Barel, SA Shalev, R Ofir, A Chone, J Zlotogora, Z Shorer, G Mazor, G Finer, S Khateeb, N Zilberberg, OS Birk. Maternally inherited Birk Barel mental retardation dysmorphism syndrome caused by a mutation in the genomically imprinted potassium channel KCNK9.. Am J Hum Genet. 2008;83:193-199", "SG Brickley, MI Aller, C Sandu, EL Veale, FG Alder, H Sambi, A Mathie, W Wisden. TASK-3 two-pore domain potassium channels enable sustained high-frequency firing in cerebellar granule neurons.. J Neurosci. 2007;27:9329-40", "JM Graham, N Zadeh, M Kelley, ES Tan, W Liew, V Tan, MA Deardorff, GN Wilson, L Sagi-Dain, SA Shalev. KCNK9 imprinting syndrome-further delineation of a possible treatable disorder.. Am J Med Genet A. 2016;170:2632-7", "JB Redman, RG Fenwick, YH Fu, A Pizzuti, CT Caskey. Relationship between parental trinucleotide GCT repeat length and severity of myotonic dystrophy in offspring.. JAMA 1993;269:1960-5", "M Takahira, M Sakurai, N Sakurada, K Sugiyama. Fenamates and diltiazem modulate lipid-sensitive mechano-gated 2P domain K(+) channels.. Pflugers Arch. 2005;451:474-8", "EL Veale, M Hassan, Y Walsh, E Al-Moubarak, A Mathie. Recovery of current through mutated. Mol Pharmacol. 2014;85:397-407" ]	23/3/2017			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
kcnq3-dis	kcnq3-dis	[ "KCNQ3-Related Self-Limited Familial Infantile Epilepsy (SLFIE)", "KCNQ3-Related Self-Limited Familial Neonatal Epilepsy (SLFNE)", "KCNQ3-Related Neurodevelopmental Disorder With or Without Seizures", "Potassium voltage-gated channel subfamily KQT member 3", "KCNQ3", "KCNQ3-Related Disorders" ]		Francesco Miceli, Maria Virginia Soldovieri, Sarah Weckhuysen, Edward C Cooper, Maurizio Taglialatela	Summary In In In The diagnosis of a Once the	For synonyms and outdated names see For other genetic causes of these phenotypes see ## Diagnosis Seizures in an otherwise healthy infant with age of onset between two and eight days of life, spontaneously disappearing within the first year of life. The occurrence of a seizure-free interval between birth and the onset of seizures is a relevant diagnostic and prognostic element. Wide spectrum of seizure types, including tonic or apneic episodes, focal tonic or clonic episodes, or autonomic changes. Motor activity may be confined to one body part, migrate to other body regions, or generalize. Seizures are usually brief, lasting one to two minutes. Normal physical examination and laboratory tests prior to the onset of seizures, between seizure episodes, and following cessation of seizures. No specific EEG findings. Ictal EEG may show focal onset with possible secondary generalization. Interictal EEG and EEG background are usually normal. Brief, repeated, focal, and secondarily generalized seizures in an otherwise healthy infant; seizures occur within the first year of life after the neonatal period. Seizures spontaneously disappear after age one to two years without neurologic sequelae in adulthood. Developmental delays or intellectual disability without epilepsy, with or without autism spectrum disorder Developmental delays or intellectual disability with epilepsy and cortical visual impairment, with or without autism spectrum disorder Developmental and epileptic encephalopathy (DEE), in which aggressive epileptogenic activity during brain maturation accompanies cognitive and neuropsychological stagnation or regression The diagnosis of a Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of a Note: Single gene testing can be used for individuals who present with the SLFNE or SLFIE phenotype and have previously tested negative for pathogenic variants in Note: For individuals who have had no previous molecular genetic testing, the authors recommend using a multigene panel or more comprehensive genomic testing whenever possible, given the lack of distinguishing features between the different genetic-related forms of SLFNE and SLFIE. For an individual with NDD, there are no features to distinguish For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by epilepsy, 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. • • Seizures in an otherwise healthy infant with age of onset between two and eight days of life, spontaneously disappearing within the first year of life. The occurrence of a seizure-free interval between birth and the onset of seizures is a relevant diagnostic and prognostic element. • Wide spectrum of seizure types, including tonic or apneic episodes, focal tonic or clonic episodes, or autonomic changes. Motor activity may be confined to one body part, migrate to other body regions, or generalize. Seizures are usually brief, lasting one to two minutes. • Normal physical examination and laboratory tests prior to the onset of seizures, between seizure episodes, and following cessation of seizures. • No specific EEG findings. Ictal EEG may show focal onset with possible secondary generalization. Interictal EEG and EEG background are usually normal. • Seizures in an otherwise healthy infant with age of onset between two and eight days of life, spontaneously disappearing within the first year of life. The occurrence of a seizure-free interval between birth and the onset of seizures is a relevant diagnostic and prognostic element. • Wide spectrum of seizure types, including tonic or apneic episodes, focal tonic or clonic episodes, or autonomic changes. Motor activity may be confined to one body part, migrate to other body regions, or generalize. Seizures are usually brief, lasting one to two minutes. • Normal physical examination and laboratory tests prior to the onset of seizures, between seizure episodes, and following cessation of seizures. • No specific EEG findings. Ictal EEG may show focal onset with possible secondary generalization. Interictal EEG and EEG background are usually normal. • Seizures in an otherwise healthy infant with age of onset between two and eight days of life, spontaneously disappearing within the first year of life. The occurrence of a seizure-free interval between birth and the onset of seizures is a relevant diagnostic and prognostic element. • Wide spectrum of seizure types, including tonic or apneic episodes, focal tonic or clonic episodes, or autonomic changes. Motor activity may be confined to one body part, migrate to other body regions, or generalize. Seizures are usually brief, lasting one to two minutes. • Normal physical examination and laboratory tests prior to the onset of seizures, between seizure episodes, and following cessation of seizures. • No specific EEG findings. Ictal EEG may show focal onset with possible secondary generalization. Interictal EEG and EEG background are usually normal. • • Brief, repeated, focal, and secondarily generalized seizures in an otherwise healthy infant; seizures occur within the first year of life after the neonatal period. • Seizures spontaneously disappear after age one to two years without neurologic sequelae in adulthood. • Brief, repeated, focal, and secondarily generalized seizures in an otherwise healthy infant; seizures occur within the first year of life after the neonatal period. • Seizures spontaneously disappear after age one to two years without neurologic sequelae in adulthood. • Brief, repeated, focal, and secondarily generalized seizures in an otherwise healthy infant; seizures occur within the first year of life after the neonatal period. • Seizures spontaneously disappear after age one to two years without neurologic sequelae in adulthood. • Developmental delays or intellectual disability without epilepsy, with or without autism spectrum disorder • Developmental delays or intellectual disability with epilepsy and cortical visual impairment, with or without autism spectrum disorder • Developmental and epileptic encephalopathy (DEE), in which aggressive epileptogenic activity during brain maturation accompanies cognitive and neuropsychological stagnation or regression • Note: Single gene testing can be used for individuals who present with the SLFNE or SLFIE phenotype and have previously tested negative for pathogenic variants in • Note: For individuals who have had no previous molecular genetic testing, the authors recommend using a multigene panel or more comprehensive genomic testing whenever possible, given the lack of distinguishing features between the different genetic-related forms of SLFNE and SLFIE. For an individual with NDD, there are no features to distinguish • For an introduction to multigene panels click ## Suggestive Findings Seizures in an otherwise healthy infant with age of onset between two and eight days of life, spontaneously disappearing within the first year of life. The occurrence of a seizure-free interval between birth and the onset of seizures is a relevant diagnostic and prognostic element. Wide spectrum of seizure types, including tonic or apneic episodes, focal tonic or clonic episodes, or autonomic changes. Motor activity may be confined to one body part, migrate to other body regions, or generalize. Seizures are usually brief, lasting one to two minutes. Normal physical examination and laboratory tests prior to the onset of seizures, between seizure episodes, and following cessation of seizures. No specific EEG findings. Ictal EEG may show focal onset with possible secondary generalization. Interictal EEG and EEG background are usually normal. Brief, repeated, focal, and secondarily generalized seizures in an otherwise healthy infant; seizures occur within the first year of life after the neonatal period. Seizures spontaneously disappear after age one to two years without neurologic sequelae in adulthood. Developmental delays or intellectual disability without epilepsy, with or without autism spectrum disorder Developmental delays or intellectual disability with epilepsy and cortical visual impairment, with or without autism spectrum disorder Developmental and epileptic encephalopathy (DEE), in which aggressive epileptogenic activity during brain maturation accompanies cognitive and neuropsychological stagnation or regression • • Seizures in an otherwise healthy infant with age of onset between two and eight days of life, spontaneously disappearing within the first year of life. The occurrence of a seizure-free interval between birth and the onset of seizures is a relevant diagnostic and prognostic element. • Wide spectrum of seizure types, including tonic or apneic episodes, focal tonic or clonic episodes, or autonomic changes. Motor activity may be confined to one body part, migrate to other body regions, or generalize. Seizures are usually brief, lasting one to two minutes. • Normal physical examination and laboratory tests prior to the onset of seizures, between seizure episodes, and following cessation of seizures. • No specific EEG findings. Ictal EEG may show focal onset with possible secondary generalization. Interictal EEG and EEG background are usually normal. • Seizures in an otherwise healthy infant with age of onset between two and eight days of life, spontaneously disappearing within the first year of life. The occurrence of a seizure-free interval between birth and the onset of seizures is a relevant diagnostic and prognostic element. • Wide spectrum of seizure types, including tonic or apneic episodes, focal tonic or clonic episodes, or autonomic changes. Motor activity may be confined to one body part, migrate to other body regions, or generalize. Seizures are usually brief, lasting one to two minutes. • Normal physical examination and laboratory tests prior to the onset of seizures, between seizure episodes, and following cessation of seizures. • No specific EEG findings. Ictal EEG may show focal onset with possible secondary generalization. Interictal EEG and EEG background are usually normal. • Seizures in an otherwise healthy infant with age of onset between two and eight days of life, spontaneously disappearing within the first year of life. The occurrence of a seizure-free interval between birth and the onset of seizures is a relevant diagnostic and prognostic element. • Wide spectrum of seizure types, including tonic or apneic episodes, focal tonic or clonic episodes, or autonomic changes. Motor activity may be confined to one body part, migrate to other body regions, or generalize. Seizures are usually brief, lasting one to two minutes. • Normal physical examination and laboratory tests prior to the onset of seizures, between seizure episodes, and following cessation of seizures. • No specific EEG findings. Ictal EEG may show focal onset with possible secondary generalization. Interictal EEG and EEG background are usually normal. • • Brief, repeated, focal, and secondarily generalized seizures in an otherwise healthy infant; seizures occur within the first year of life after the neonatal period. • Seizures spontaneously disappear after age one to two years without neurologic sequelae in adulthood. • Brief, repeated, focal, and secondarily generalized seizures in an otherwise healthy infant; seizures occur within the first year of life after the neonatal period. • Seizures spontaneously disappear after age one to two years without neurologic sequelae in adulthood. • Brief, repeated, focal, and secondarily generalized seizures in an otherwise healthy infant; seizures occur within the first year of life after the neonatal period. • Seizures spontaneously disappear after age one to two years without neurologic sequelae in adulthood. • Developmental delays or intellectual disability without epilepsy, with or without autism spectrum disorder • Developmental delays or intellectual disability with epilepsy and cortical visual impairment, with or without autism spectrum disorder • Developmental and epileptic encephalopathy (DEE), in which aggressive epileptogenic activity during brain maturation accompanies cognitive and neuropsychological stagnation or regression ## Establishing the Diagnosis The diagnosis of a Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of a Note: Single gene testing can be used for individuals who present with the SLFNE or SLFIE phenotype and have previously tested negative for pathogenic variants in Note: For individuals who have had no previous molecular genetic testing, the authors recommend using a multigene panel or more comprehensive genomic testing whenever possible, given the lack of distinguishing features between the different genetic-related forms of SLFNE and SLFIE. For an individual with NDD, there are no features to distinguish For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by epilepsy, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. • Note: Single gene testing can be used for individuals who present with the SLFNE or SLFIE phenotype and have previously tested negative for pathogenic variants in • Note: For individuals who have had no previous molecular genetic testing, the authors recommend using a multigene panel or more comprehensive genomic testing whenever possible, given the lack of distinguishing features between the different genetic-related forms of SLFNE and SLFIE. For an individual with NDD, there are no features to distinguish • For an introduction to multigene panels click ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of a Note: Single gene testing can be used for individuals who present with the SLFNE or SLFIE phenotype and have previously tested negative for pathogenic variants in Note: For individuals who have had no previous molecular genetic testing, the authors recommend using a multigene panel or more comprehensive genomic testing whenever possible, given the lack of distinguishing features between the different genetic-related forms of SLFNE and SLFIE. For an individual with NDD, there are no features to distinguish For an introduction to multigene panels click • Note: Single gene testing can be used for individuals who present with the SLFNE or SLFIE phenotype and have previously tested negative for pathogenic variants in • Note: For individuals who have had no previous molecular genetic testing, the authors recommend using a multigene panel or more comprehensive genomic testing whenever possible, given the lack of distinguishing features between the different genetic-related forms of SLFNE and SLFIE. For an individual with NDD, there are no features to distinguish • For an introduction to multigene panels click ## Option 2 When the phenotype is indistinguishable from many other inherited disorders characterized by epilepsy, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. ## Clinical Characteristics To date, about 140 individuals have been identified with a pathogenic variant in Age of onset of seizures is between 2-8 days of life; spontaneously disappear between age 1-12 mos in otherwise healthy infant. Seizures are generally brief, lasting 1-2 minutes. Seizure types incl tonic or apneic episodes, focal clonic activity, & autonomic changes. Age of onset of seizures is w/in 1st yr of life, beyond neonatal period, & seizures disappear in 1-2 years. Seizures are generally brief, lasting ~2 minutes; they are usually focal but can be also generalized. ASD = autism spectrum disorder; DD = developmental delay; ID = intellectual delay; NDD = neurodevelopmental disorder; SLFIE = self-limited familial infantile epilepsy; SLFNE = self-limited familial neonatal epilepsy Percentages are based on nearly 140 reported symptomatic individuals with heterozygous pathogenic variants only and do not include individuals with biallelic pathogenic variants in Psychomotor development is usually normal. However, two individuals within a family with Infants are typically well between seizures and psychomotor development is usually normal. Pathogenic variants in In Incomplete penetrance in Penetrance in In the most recent International League Against Epilepsy (ILAE) classification, the term "benign" is replaced by "self-limited" as a descriptor for epilepsy, referring to the likely resolution of the seizures during early infancy as well as good developmental outcome [ About 20 families (72 individuals) with SLFNE with a heterozygous Only four families (8 individuals) with SLFIE and a heterozygous The prevalence of • Age of onset of seizures is between 2-8 days of life; spontaneously disappear between age 1-12 mos in otherwise healthy infant. • Seizures are generally brief, lasting 1-2 minutes. • Seizure types incl tonic or apneic episodes, focal clonic activity, & autonomic changes. • Age of onset of seizures is w/in 1st yr of life, beyond neonatal period, & seizures disappear in 1-2 years. • Seizures are generally brief, lasting ~2 minutes; they are usually focal but can be also generalized. ## Clinical Description To date, about 140 individuals have been identified with a pathogenic variant in Age of onset of seizures is between 2-8 days of life; spontaneously disappear between age 1-12 mos in otherwise healthy infant. Seizures are generally brief, lasting 1-2 minutes. Seizure types incl tonic or apneic episodes, focal clonic activity, & autonomic changes. Age of onset of seizures is w/in 1st yr of life, beyond neonatal period, & seizures disappear in 1-2 years. Seizures are generally brief, lasting ~2 minutes; they are usually focal but can be also generalized. ASD = autism spectrum disorder; DD = developmental delay; ID = intellectual delay; NDD = neurodevelopmental disorder; SLFIE = self-limited familial infantile epilepsy; SLFNE = self-limited familial neonatal epilepsy Percentages are based on nearly 140 reported symptomatic individuals with heterozygous pathogenic variants only and do not include individuals with biallelic pathogenic variants in Psychomotor development is usually normal. However, two individuals within a family with Infants are typically well between seizures and psychomotor development is usually normal. • Age of onset of seizures is between 2-8 days of life; spontaneously disappear between age 1-12 mos in otherwise healthy infant. • Seizures are generally brief, lasting 1-2 minutes. • Seizure types incl tonic or apneic episodes, focal clonic activity, & autonomic changes. • Age of onset of seizures is w/in 1st yr of life, beyond neonatal period, & seizures disappear in 1-2 years. • Seizures are generally brief, lasting ~2 minutes; they are usually focal but can be also generalized. ## Genotype-Phenotype Correlations Pathogenic variants in ## Penetrance In Incomplete penetrance in Penetrance in ## Nomenclature In the most recent International League Against Epilepsy (ILAE) classification, the term "benign" is replaced by "self-limited" as a descriptor for epilepsy, referring to the likely resolution of the seizures during early infancy as well as good developmental outcome [ ## Prevalence About 20 families (72 individuals) with SLFNE with a heterozygous Only four families (8 individuals) with SLFIE and a heterozygous The prevalence of ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The genetic differential diagnosis of Self-limited familial neonatal epilepsy (SLFNE); Self-limited familial infantile epilepsy (SLFIE); and Self-limited familial neonatal-infantile epilepsy (SLFNIE). Of note, laboratory tests and imaging studies are important to exclude other possible causes for seizures including non-genetic etiologies. It is important not to miss a diagnosis of a treatable meningoencephalitis in the early stages or of intracranial hemorrhage – as neonates may not exhibit the typical findings observed in older infants and children, and seizures may be the only early manifestation. Selected Genes to Consider in the Differential Diagnosis of AD = autosomal dominant; MOI = mode of inheritance • Self-limited familial neonatal epilepsy (SLFNE); • Self-limited familial infantile epilepsy (SLFIE); and • Self-limited familial neonatal-infantile epilepsy (SLFNIE). • • • • ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with a To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Gross motor & fine motor skills Contractures, clubfoot, & kyphoscoliosis Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) To incl eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. 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; OT = occupational therapy; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse Epilepsy in Seizures are generally well-controlled using standard ASM. Due to the limited nature of the epilepsy, most ASMs are discontinued between age 3-6 mos in Neonates w/more severe or intractable seizures may benefit from other ASM (e.g., levetiracetam & topiramate) despite limited data & off-label use. One study has shown that early initiation of CBZ or OXC in SLFNE was assoc w/shorter hospitalization. No side effects of CBZ were reported, suggesting that CBZ is safe & rapidly effective in neonates w/SLFNE, even in status epilepticus, & that CBZ should be the drug of choice in SLFNE. Education of parents/caregivers Seizures are generally well-controlled using standard ASM. Due to the limited nature of the epilepsy, most ASMs are discontinued between age 1-3 yrs w/no relapses. Phenobarbital, carbamazepine, or valproate have been shown to control seizures. Consultation w/neurodevelopmental specialist may be considered. It is currently unclear whether behavior or cognition are improved by suppressing the abundant EEG abnormalities seen in some children during sleep. ABA = applied behavioral therapy; ASM = anti-seizure medication; CBZ = carbamazepine; OT = occupational therapy; OXC = oxcarbazepine; 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 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. No specific primary prevention measure is available before symptom appearance. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in EEG at onset & age 3, 12, & 24 mos is recommended. EEG at 24 mos should be normal. EEG at onset & age 12, 24, & 36 mos is recommended. The EEG at 36 mos should be normal. In individuals with known gain-of-function pathogenic variants in The management of a pregnant woman with a No medication is indicated if (1) the woman has been seizure free and is not taking medications or (2) the woman has no history of seizures. Treatment with anti-seizure medication (ASM) may be continued for active epilepsy during pregnancy. 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 ASM during pregnancy reduces this risk. However, exposure to ASM may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from ASM exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of ASM to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [ See Search • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Gross motor & fine motor skills • Contractures, clubfoot, & kyphoscoliosis • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • To incl eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. • Community or • Social work involvement for parental support. • Seizures are generally well-controlled using standard ASM. Due to the limited nature of the epilepsy, most ASMs are discontinued between age 3-6 mos in • Neonates w/more severe or intractable seizures may benefit from other ASM (e.g., levetiracetam & topiramate) despite limited data & off-label use. • One study has shown that early initiation of CBZ or OXC in SLFNE was assoc w/shorter hospitalization. No side effects of CBZ were reported, suggesting that CBZ is safe & rapidly effective in neonates w/SLFNE, even in status epilepticus, & that CBZ should be the drug of choice in SLFNE. • Education of parents/caregivers • Seizures are generally well-controlled using standard ASM. Due to the limited nature of the epilepsy, most ASMs are discontinued between age 1-3 yrs w/no relapses. • Phenobarbital, carbamazepine, or valproate have been shown to control seizures. • Consultation w/neurodevelopmental specialist may be considered. • It is currently unclear whether behavior or cognition are improved by suppressing the abundant EEG abnormalities seen in some children during sleep. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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. • EEG at onset & age 3, 12, & 24 mos is recommended. • EEG at 24 mos should be normal. • EEG at onset & age 12, 24, & 36 mos is recommended. • The EEG at 36 mos should be normal. • No medication is indicated if (1) the woman has been seizure free and is not taking medications or (2) the woman has no history of seizures. • Treatment with anti-seizure medication (ASM) may be continued for active epilepsy during pregnancy. • 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 ASM during pregnancy reduces this risk. However, exposure to ASM may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from ASM exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of ASM to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [ ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with a To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Gross motor & fine motor skills Contractures, clubfoot, & kyphoscoliosis Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) To incl eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. 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; 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 • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • To incl eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. • Community or • Social work involvement for parental support. ## Treatment of Manifestations Epilepsy in Seizures are generally well-controlled using standard ASM. Due to the limited nature of the epilepsy, most ASMs are discontinued between age 3-6 mos in Neonates w/more severe or intractable seizures may benefit from other ASM (e.g., levetiracetam & topiramate) despite limited data & off-label use. One study has shown that early initiation of CBZ or OXC in SLFNE was assoc w/shorter hospitalization. No side effects of CBZ were reported, suggesting that CBZ is safe & rapidly effective in neonates w/SLFNE, even in status epilepticus, & that CBZ should be the drug of choice in SLFNE. Education of parents/caregivers Seizures are generally well-controlled using standard ASM. Due to the limited nature of the epilepsy, most ASMs are discontinued between age 1-3 yrs w/no relapses. Phenobarbital, carbamazepine, or valproate have been shown to control seizures. Consultation w/neurodevelopmental specialist may be considered. It is currently unclear whether behavior or cognition are improved by suppressing the abundant EEG abnormalities seen in some children during sleep. ABA = applied behavioral therapy; ASM = anti-seizure medication; CBZ = carbamazepine; OT = occupational therapy; OXC = oxcarbazepine; 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 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. • Seizures are generally well-controlled using standard ASM. Due to the limited nature of the epilepsy, most ASMs are discontinued between age 3-6 mos in • Neonates w/more severe or intractable seizures may benefit from other ASM (e.g., levetiracetam & topiramate) despite limited data & off-label use. • One study has shown that early initiation of CBZ or OXC in SLFNE was assoc w/shorter hospitalization. No side effects of CBZ were reported, suggesting that CBZ is safe & rapidly effective in neonates w/SLFNE, even in status epilepticus, & that CBZ should be the drug of choice in SLFNE. • Education of parents/caregivers • Seizures are generally well-controlled using standard ASM. Due to the limited nature of the epilepsy, most ASMs are discontinued between age 1-3 yrs w/no relapses. • Phenobarbital, carbamazepine, or valproate have been shown to control seizures. • Consultation w/neurodevelopmental specialist may be considered. • It is currently unclear whether behavior or cognition are improved by suppressing the abundant EEG abnormalities seen in some children during sleep. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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. ## Prevention of Primary Manifestations No specific primary prevention measure is available before symptom appearance. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in EEG at onset & age 3, 12, & 24 mos is recommended. EEG at 24 mos should be normal. EEG at onset & age 12, 24, & 36 mos is recommended. The EEG at 36 mos should be normal. • EEG at onset & age 3, 12, & 24 mos is recommended. • EEG at 24 mos should be normal. • EEG at onset & age 12, 24, & 36 mos is recommended. • The EEG at 36 mos should be normal. ## Agents/Circumstances to Avoid In individuals with known gain-of-function pathogenic variants in ## Pregnancy Management The management of a pregnant woman with a No medication is indicated if (1) the woman has been seizure free and is not taking medications or (2) the woman has no history of seizures. Treatment with anti-seizure medication (ASM) may be continued for active epilepsy during pregnancy. 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 ASM during pregnancy reduces this risk. However, exposure to ASM may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from ASM exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of ASM to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [ See • No medication is indicated if (1) the woman has been seizure free and is not taking medications or (2) the woman has no history of seizures. • Treatment with anti-seizure medication (ASM) may be continued for active epilepsy during pregnancy. • 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 ASM during pregnancy reduces this risk. However, exposure to ASM may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from ASM exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of ASM to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [ ## Therapies Under Investigation Search ## Genetic Counseling In most individuals reported to date, Most individuals diagnosed with In contrast, most individuals with autosomal dominant Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. The family history of some individuals diagnosed with If a parent of the proband is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Given the rarity of If the Note: While parental mosaicism has not been reported in autosomal dominant If the parents have not been tested for the The parents of a child with autosomal recessive 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. The heterozygous parents of a child with autosomal recessive If both parents are known to be heterozygous for a The heterozygous sibs of a proband with autosomal recessive The offspring of an individual with autosomal recessive To date, individuals 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 known to have, or to be at risk of having, a It is appropriate to offer Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • Most individuals diagnosed with • In contrast, most individuals with autosomal dominant • Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The family history of some individuals diagnosed with • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If a parent of the proband is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. • Given the rarity of • If the • Note: While parental mosaicism has not been reported in autosomal dominant • If the parents have not been tested for the • The parents of a child with autosomal recessive • 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. • The heterozygous parents of a child with autosomal recessive • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • The heterozygous sibs of a proband with autosomal recessive • The offspring of an individual with autosomal recessive • To date, individuals 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 known to have, or to be at risk of having, a • It is appropriate to offer ## Mode of Inheritance In most individuals reported to date, ## Autosomal Dominant Inheritance – Risk to Family Members Most individuals diagnosed with In contrast, most individuals with autosomal dominant Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. The family history of some individuals diagnosed with If a parent of the proband is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Given the rarity of If the Note: While parental mosaicism has not been reported in autosomal dominant If the parents have not been tested for the • Most individuals diagnosed with • In contrast, most individuals with autosomal dominant • Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The family history of some individuals diagnosed with • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If a parent of the proband is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. • Given the rarity of • If the • Note: While parental mosaicism has not been reported in autosomal dominant • If the parents have not been tested for the ## Autosomal Recessive Inheritance – Risk to Family Members The parents of a child with autosomal recessive 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. The heterozygous parents of a child with autosomal recessive If both parents are known to be heterozygous for a The heterozygous sibs of a proband with autosomal recessive The offspring of an individual with autosomal recessive To date, individuals with autosomal recessive • The parents of a child with autosomal recessive • 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. • The heterozygous parents of a child with autosomal recessive • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • The heterozygous sibs of a proband with autosomal recessive • The offspring of an individual with autosomal recessive • To date, individuals with autosomal recessive ## 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 known to have, or to be at risk of having, a It is appropriate to offer • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are known to have, or to be at risk of having, a • It is appropriate to offer ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources Canada 60187 • • • • Canada • • • • • • • • • 60187 • • • ## Molecular Genetics KCNQ3-Related Disorders: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for KCNQ3-Related Disorders ( The KCNQ subunits, like other voltage-gated potassium channel subunits, include six transmembrane domains, with cytoplasmic N- and C-terminal regions. In neurons, KCNQ2, KCNQ3, KCNQ4, and KCNQ5 subunits (either as homomultimers or heteromultimers) represent the molecular basis of the M-current (I Most In addition to ASD = autism spectrum disorder; DD = developmental delay Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis The KCNQ subunits, like other voltage-gated potassium channel subunits, include six transmembrane domains, with cytoplasmic N- and C-terminal regions. In neurons, KCNQ2, KCNQ3, KCNQ4, and KCNQ5 subunits (either as homomultimers or heteromultimers) represent the molecular basis of the M-current (I Most In addition to ASD = autism spectrum disorder; DD = developmental delay Variants listed in the table have been provided by the authors. ## Chapter Notes Sarah Weckhuysen ( The authors acknowledge funding from the following agencies for supporting their studies: the Italian Ministry for University and Research (MUR) (PRIN 2017ALCR7C), #NEXTGENERATIONEU (NGEU), National Recovery and Resilience Plan (NRRP), Project MNESYS (PE0000006 – A Multiscale Integrated Approach to the Study of the Nervous System in Health and Disease), the Italian Ministry of Health (Project GR-2016-02363337 and RF-2019-12370491), the European Commission H2020 (UNICOM – 875299), FWO (1861419N and G041821N), KCNQ2e.v., and the European Joint Programme on Rare Disease JTC 2020 (TreatKCNQ). Giulia Bellini, PhD; Second University of Naples (2014-2017)Edward C Cooper, MD, PhD (2017-present)Giangennaro Coppola, MD; University of Salerno (2014-2017)Nishtha Joshi, BDS, MPH (2017-present)Francesco Miceli, PhD (2014-present)Emanuele Miraglia del Giudice, MD; Second University of Naples (2014-2017)Maria Virginia Soldovieri, PhD (2014-present)Maurizio Taglialatela, MD, PhD (2014-present)Sarah Weckhuysen, MD, PhD (2017-present) 28 September 2023 (gm) Comprehensive update posted live 7 September 2017 (ha) Comprehensive update posted live 22 May 2014 (me) Review posted live 26 September 2013 (mt) Original submission • 28 September 2023 (gm) Comprehensive update posted live • 7 September 2017 (ha) Comprehensive update posted live • 22 May 2014 (me) Review posted live • 26 September 2013 (mt) Original submission ## Author Notes Sarah Weckhuysen ( ## Acknowledgments The authors acknowledge funding from the following agencies for supporting their studies: the Italian Ministry for University and Research (MUR) (PRIN 2017ALCR7C), #NEXTGENERATIONEU (NGEU), National Recovery and Resilience Plan (NRRP), Project MNESYS (PE0000006 – A Multiscale Integrated Approach to the Study of the Nervous System in Health and Disease), the Italian Ministry of Health (Project GR-2016-02363337 and RF-2019-12370491), the European Commission H2020 (UNICOM – 875299), FWO (1861419N and G041821N), KCNQ2e.v., and the European Joint Programme on Rare Disease JTC 2020 (TreatKCNQ). ## Author History Giulia Bellini, PhD; Second University of Naples (2014-2017)Edward C Cooper, MD, PhD (2017-present)Giangennaro Coppola, MD; University of Salerno (2014-2017)Nishtha Joshi, BDS, MPH (2017-present)Francesco Miceli, PhD (2014-present)Emanuele Miraglia del Giudice, MD; Second University of Naples (2014-2017)Maria Virginia Soldovieri, PhD (2014-present)Maurizio Taglialatela, MD, PhD (2014-present)Sarah Weckhuysen, MD, PhD (2017-present) ## Revision History 28 September 2023 (gm) Comprehensive update posted live 7 September 2017 (ha) Comprehensive update posted live 22 May 2014 (me) Review posted live 26 September 2013 (mt) Original submission • 28 September 2023 (gm) Comprehensive update posted live • 7 September 2017 (ha) Comprehensive update posted live • 22 May 2014 (me) Review posted live • 26 September 2013 (mt) Original submission ## References ## Literature Cited	[]	22/5/2014	28/9/2023		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
kcnt1-epilepsy	kcnt1-epilepsy	[ "Potassium channel subfamily T member 1", "KCNT1", "KCNT1-Related Epilepsy" ]		Tracy Gertler, David Bearden, Arin Bhattacharjee, Gemma Carvill	Summary EIMFS is characterized by seizures, typically focal and asynchronous, beginning in the first six months of life with associated developmental plateau or regression. Autonomic manifestations (e.g., perioral cyanosis, flushing, apnea) are common. Seizures are intractable to multiple anticonvulsants and progress to become nearly continuous by age six to nine months. ADNFLE is characterized by clusters of nocturnal motor seizures that vary from simple arousals to hyperkinetic events with tonic or dystonic features. Individuals with Less common seizure phenotypes in individuals with The diagnosis of	## Diagnosis No formal diagnostic criteria for Normal prenatal course and birth without history, clinical features, or imaging suggestive of traumatic, anoxic, vascular, or infectious injury Sporadic, asynchronous focal seizures arising independently from either hemisphere with patterns of intracortical "migration" occurring by age six months, with subsequent escalation of seizure frequency Developmental plateau or regression following the onset of seizures Intractability to anticonvulsant medication Frequent brief, nocturnal seizures Mild-to-moderate intellectual disability Psychiatric disease (e.g., depression, anxiety, suicidality, attention-deficit/hyperactivity disorder) Family history of ADNFLE or EIMFS West syndrome Ohtahara syndrome (early-infantile epileptic encephalopathy) Early myoclonic encephalopathy Leukodystrophy/leukoencephalopathy Focal epilepsy Multifocal epilepsy The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Because the phenotype of Note: (1) 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. • Normal prenatal course and birth without history, clinical features, or imaging suggestive of traumatic, anoxic, vascular, or infectious injury • Sporadic, asynchronous focal seizures arising independently from either hemisphere with patterns of intracortical "migration" occurring by age six months, with subsequent escalation of seizure frequency • Developmental plateau or regression following the onset of seizures • Intractability to anticonvulsant medication • Frequent brief, nocturnal seizures • Mild-to-moderate intellectual disability • Psychiatric disease (e.g., depression, anxiety, suicidality, attention-deficit/hyperactivity disorder) • Family history of ADNFLE or EIMFS • West syndrome • Ohtahara syndrome (early-infantile epileptic encephalopathy) • Early myoclonic encephalopathy • Leukodystrophy/leukoencephalopathy • Focal epilepsy • Multifocal epilepsy ## Suggestive Findings Normal prenatal course and birth without history, clinical features, or imaging suggestive of traumatic, anoxic, vascular, or infectious injury Sporadic, asynchronous focal seizures arising independently from either hemisphere with patterns of intracortical "migration" occurring by age six months, with subsequent escalation of seizure frequency Developmental plateau or regression following the onset of seizures Intractability to anticonvulsant medication Frequent brief, nocturnal seizures Mild-to-moderate intellectual disability Psychiatric disease (e.g., depression, anxiety, suicidality, attention-deficit/hyperactivity disorder) Family history of ADNFLE or EIMFS West syndrome Ohtahara syndrome (early-infantile epileptic encephalopathy) Early myoclonic encephalopathy Leukodystrophy/leukoencephalopathy Focal epilepsy Multifocal epilepsy • Normal prenatal course and birth without history, clinical features, or imaging suggestive of traumatic, anoxic, vascular, or infectious injury • Sporadic, asynchronous focal seizures arising independently from either hemisphere with patterns of intracortical "migration" occurring by age six months, with subsequent escalation of seizure frequency • Developmental plateau or regression following the onset of seizures • Intractability to anticonvulsant medication • Frequent brief, nocturnal seizures • Mild-to-moderate intellectual disability • Psychiatric disease (e.g., depression, anxiety, suicidality, attention-deficit/hyperactivity disorder) • Family history of ADNFLE or EIMFS • West syndrome • Ohtahara syndrome (early-infantile epileptic encephalopathy) • Early myoclonic encephalopathy • Leukodystrophy/leukoencephalopathy • Focal epilepsy • Multifocal epilepsy ## Establishing the Diagnosis The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Because the phenotype of Note: (1) 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. ## Clinical Characteristics Additional neurologic features reported in individuals with Prognosis for individuals with West syndrome Ohtahara syndrome (early-infantile epileptic encephalopathy) Early myoclonic encephalopathy Leukodystrophy/leukoencephalopathy Focal or multifocal epilepsy Three individuals with Brugada syndrome was reported in one individual with a There is some evidence for a genotype-phenotype correlation. However, disparate phenotypes (e.g., ADNFLE, EIMFS) have been identified in family members with the same pathogenic variant. Specific correlations between genetic variant and seizure burden, developmental impairment, or medication responsiveness have not yet been elucidated. Penetrance is reported to be 100% for In the initial description of EIMFS, The prevalence of • West syndrome • Ohtahara syndrome (early-infantile epileptic encephalopathy) • Early myoclonic encephalopathy • Leukodystrophy/leukoencephalopathy • Focal or multifocal epilepsy ## Clinical Description Additional neurologic features reported in individuals with Prognosis for individuals with West syndrome Ohtahara syndrome (early-infantile epileptic encephalopathy) Early myoclonic encephalopathy Leukodystrophy/leukoencephalopathy Focal or multifocal epilepsy Three individuals with Brugada syndrome was reported in one individual with a • West syndrome • Ohtahara syndrome (early-infantile epileptic encephalopathy) • Early myoclonic encephalopathy • Leukodystrophy/leukoencephalopathy • Focal or multifocal epilepsy ## Epilepsy Phenotype Additional neurologic features reported in individuals with Prognosis for individuals with West syndrome Ohtahara syndrome (early-infantile epileptic encephalopathy) Early myoclonic encephalopathy Leukodystrophy/leukoencephalopathy Focal or multifocal epilepsy • West syndrome • Ohtahara syndrome (early-infantile epileptic encephalopathy) • Early myoclonic encephalopathy • Leukodystrophy/leukoencephalopathy • Focal or multifocal epilepsy ## Pulmonary Hemorrhage Three individuals with ## Cardiac Arrhythmia Brugada syndrome was reported in one individual with a ## Genotype-Phenotype Correlations There is some evidence for a genotype-phenotype correlation. However, disparate phenotypes (e.g., ADNFLE, EIMFS) have been identified in family members with the same pathogenic variant. Specific correlations between genetic variant and seizure burden, developmental impairment, or medication responsiveness have not yet been elucidated. ## Penetrance Penetrance is reported to be 100% for ## Nomenclature In the initial description of EIMFS, ## Prevalence The prevalence of ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Phenotypic and EEG features associated with Note: At seizure onset, it is most important to distinguish Treatable Disorders Associated with Early Infantile-Onset Epileptic Encephalopathy ↑ plasma & urine alpha-aminoadipic semialdehyde ↑ plasma & CSF pipecolic acid Lactic acidemia Hypoglycemia Deficient biotinidase enzyme activity in serum or plasma Ketolactic acidosis, organic aciduria, hyperammonemia Skin rash, alopecia, recurrent viral or fungal infections ↓ CSF glucose concentration Absence seizures beginning age <3 Cerebral creatine deficiency on brain MR spectroscopy Suggestive ratio of guanidinoacetate, creatine, &/or creatinine in plasma & urine Ketolactic acidosis, organic aciduria, hyperammonemia Skin rash, alopecia Congenital or acquired microcephaly, congenital cataracts ↓ plasma & CSF serine MRI brain lesions (subependymal nodules, subependymal giant cell astrocytomas, tubers, focal cortical dysplasias) Cardiac rhabdomyoma, skin lesions, retinal lesions, renal lesions AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; NA = not applicable; XL = X-linked • ↑ plasma & urine alpha-aminoadipic semialdehyde • ↑ plasma & CSF pipecolic acid • Lactic acidemia • Hypoglycemia • Deficient biotinidase enzyme activity in serum or plasma • Ketolactic acidosis, organic aciduria, hyperammonemia • Skin rash, alopecia, recurrent viral or fungal infections • ↓ CSF glucose concentration • Absence seizures beginning age <3 • Cerebral creatine deficiency on brain MR spectroscopy • Suggestive ratio of guanidinoacetate, creatine, &/or creatinine in plasma & urine • Ketolactic acidosis, organic aciduria, hyperammonemia • Skin rash, alopecia • Congenital or acquired microcephaly, congenital cataracts • ↓ plasma & CSF serine • MRI brain lesions (subependymal nodules, subependymal giant cell astrocytomas, tubers, focal cortical dysplasias) • Cardiac rhabdomyoma, skin lesions, retinal lesions, renal lesions ## Management To establish the extent of disease and needs in an individual diagnosed with Prolonged video EEG monitoring to evaluate electroclinical and electrographic seizure burden in consultation with a pediatric epileptologist Evaluation by a movement disorder specialist if dictated by clinical presentation Consideration of echocardiogram to evaluate for pulmonary collaterals Electrocardiogram (EKG) to evaluate for cardiac rhythm abnormalities Cognitive and behavioral assessment Physical, occupational, and speech therapy evaluation Consultation with a clinical geneticist and/or genetic counselor Vagal nerve stimulator (VNS) has not been shown to be effective [ The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. In the US: Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility. Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications (e.g., to treat attention-deficit/hyperactivity disorder) when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. EEG is recommended at intervals determined by seizure frequency and progression, for evaluation of new involuntary movements or unexplained, paroxysmal changes in vital signs, or following adjustments to an anticonvulsant regimen. Developmental evaluation and initiation of therapies is recommended at time of diagnosis if not already begun. Following initial EKG and echocardiogram, there is no indication to repeat cardiac monitoring or cardiopulmonary imaging unless clinically indicated or following initiation of quinidine therapy. No anticonvulsants have been noted to exacerbate For individuals with ADNFLE, activities in which a sudden loss of consciousness could lead to injury or death should be avoided (e.g., bathing, swimming, driving, or working/playing at heights). It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives of an affected individual by molecular genetic testing for the See In general, women with epilepsy or a seizure disorder from any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of anti-seizure medication during pregnancy reduces this risk. However, exposure to anti-seizure medication (e.g., valproate, phenobarbital, topiramate) 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 medication during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [ See Search • Prolonged video EEG monitoring to evaluate electroclinical and electrographic seizure burden in consultation with a pediatric epileptologist • Evaluation by a movement disorder specialist if dictated by clinical presentation • Consideration of echocardiogram to evaluate for pulmonary collaterals • Electrocardiogram (EKG) to evaluate for cardiac rhythm abnormalities • Cognitive and behavioral assessment • Physical, occupational, and speech therapy evaluation • Consultation with a clinical geneticist and/or genetic counselor • Vagal nerve stimulator (VNS) has not been shown to be effective [ • In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. • Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • Physical therapy is recommended to maximize mobility. • Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Prolonged video EEG monitoring to evaluate electroclinical and electrographic seizure burden in consultation with a pediatric epileptologist Evaluation by a movement disorder specialist if dictated by clinical presentation Consideration of echocardiogram to evaluate for pulmonary collaterals Electrocardiogram (EKG) to evaluate for cardiac rhythm abnormalities Cognitive and behavioral assessment Physical, occupational, and speech therapy evaluation Consultation with a clinical geneticist and/or genetic counselor • Prolonged video EEG monitoring to evaluate electroclinical and electrographic seizure burden in consultation with a pediatric epileptologist • Evaluation by a movement disorder specialist if dictated by clinical presentation • Consideration of echocardiogram to evaluate for pulmonary collaterals • Electrocardiogram (EKG) to evaluate for cardiac rhythm abnormalities • Cognitive and behavioral assessment • Physical, occupational, and speech therapy evaluation • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations Vagal nerve stimulator (VNS) has not been shown to be effective [ The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. In the US: Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility. Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications (e.g., to treat attention-deficit/hyperactivity disorder) when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. • Vagal nerve stimulator (VNS) has not been shown to be effective [ • In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. • Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • Physical therapy is recommended to maximize mobility. • Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. In the US: Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. • Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. ## Motor Dysfunction Physical therapy is recommended to maximize mobility. Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • Physical therapy is recommended to maximize mobility. • Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## Social/Behavioral Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications (e.g., to treat attention-deficit/hyperactivity disorder) when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ## Surveillance EEG is recommended at intervals determined by seizure frequency and progression, for evaluation of new involuntary movements or unexplained, paroxysmal changes in vital signs, or following adjustments to an anticonvulsant regimen. Developmental evaluation and initiation of therapies is recommended at time of diagnosis if not already begun. Following initial EKG and echocardiogram, there is no indication to repeat cardiac monitoring or cardiopulmonary imaging unless clinically indicated or following initiation of quinidine therapy. ## Agents/Circumstances to Avoid No anticonvulsants have been noted to exacerbate For individuals with ADNFLE, activities in which a sudden loss of consciousness could lead to injury or death should be avoided (e.g., bathing, swimming, driving, or working/playing at heights). ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives of an affected individual by molecular genetic testing for the See ## Pregnancy Management In general, women with epilepsy or a seizure disorder from any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of anti-seizure medication during pregnancy reduces this risk. However, exposure to anti-seizure medication (e.g., valproate, phenobarbital, topiramate) 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 medication during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [ See ## Therapies Under Investigation Search ## Genetic Counseling Most individuals diagnosed with All 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 The family history of some individuals diagnosed with Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. If a parent of the proband is known to be affected and/or is heterozygous for 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. • Most individuals diagnosed with • All individuals diagnosed with • Some individuals diagnosed with • All 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 • The family history of some individuals diagnosed with • Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. • All individuals diagnosed with • Some individuals diagnosed with • If a parent of the proband is known to be affected and/or is heterozygous for the • If the • If the parents have not been tested for the • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance ## Risk to Family Members Most individuals diagnosed with All 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 The family history of some individuals diagnosed with Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. If a parent of the proband is known to be affected and/or is heterozygous for the If the If the parents have not been tested for the • Most individuals diagnosed with • All individuals diagnosed with • Some individuals diagnosed with • All 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 • The family history of some individuals diagnosed with • Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. • All individuals diagnosed with • Some individuals diagnosed with • If a parent of the proband is known to be affected and/or is heterozygous for 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 Canada • • • • Canada • • • • • ## Molecular Genetics KCNT1-Related Epilepsy: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for KCNT1-Related Epilepsy ( The majority of ADNFLE-associated variants have also been observed in individuals with an EIMFS phenotype, consistent with variable expressivity [ Variants listed in the table have been provided by the authors. While KNa1.1 possesses six transmembrane domains and a pore domain between the S5 and S6 transmembrane domains, similar to other voltage-gated potassium channels, its C-terminus is disproportionately large. The C-terminus comprises: Two regulators of conductance of K+ (RCK) domains that form a ring on the cytoplasmic face of the channel, which, in the presence of sodium, undergoes a conformational shift to expose the electrostatic channel pore [ An NAD+ binding domain in the C-terminus, which, in the presence of increased NAD+ concentrations, reduces the sodium requirement of the channel [ The C-terminus regulates channel opening by interaction with fragile X mental retardation protein (FMRP) [ Although the majority of variants associated with Several mechanisms of channel dysfunction have been described. Some variants cause a shift in time spent in subconductance states, either secondary to loss of PKC-dependent regulation [ • Two regulators of conductance of K+ (RCK) domains that form a ring on the cytoplasmic face of the channel, which, in the presence of sodium, undergoes a conformational shift to expose the electrostatic channel pore [ • An NAD+ binding domain in the C-terminus, which, in the presence of increased NAD+ concentrations, reduces the sodium requirement of the channel [ ## Chapter Notes The 20 September 2018 (tg) Review posted live 28 February 2018 (jlr) Original submission • 20 September 2018 (tg) Review posted live • 28 February 2018 (jlr) Original submission ## Author Notes The ## Revision History 20 September 2018 (tg) Review posted live 28 February 2018 (jlr) Original submission • 20 September 2018 (tg) Review posted live • 28 February 2018 (jlr) Original submission ## References ## Literature Cited Pathogenic variants identified in Generated from an image drawn using Protter open-source software [	[]	20/9/2018			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
kennedy	kennedy	[ "Kennedy's Disease", "SBMA", "X-Linked Spinal and Bulbar Muscular Atrophy", "Kennedy's Disease", "SBMA", "X-Linked Spinal and Bulbar Muscular Atrophy", "Androgen receptor", "AR", "Spinal and Bulbar Muscular Atrophy" ]	Spinal and Bulbar Muscular Atrophy	Albert La Spada	Summary Spinal and bulbar muscular atrophy (SBMA) is a gradually progressive neuromuscular disorder in which degeneration of lower motor neurons results in muscle weakness, muscle atrophy, and fasciculations in affected males. Affected individuals often show gynecomastia, testicular atrophy, and reduced fertility as a result of mild androgen insensitivity. The diagnosis of SBMA is established in a male proband by the identification of a hemizygous expansion of a CAG trinucleotide repeat (>35 CAGs) in SBMA is inherited in an X-linked manner. Affected males who are fertile pass the expanded CAG repeat to each daughter. Carrier females have a 50% chance of transmitting the CAG trinucleotide expansion to each child; males who inherit it will be affected; females who inherit it will be carriers and will usually not be affected. Carrier testing for at-risk female relatives and prenatal testing for a pregnancy at increased risk are possible if the expanded CAG repeat has been identified in an affected family member.	## Diagnosis Spinal and bulbar muscular atrophy (SBMA) Adolescent-onset signs of androgen insensitivity (e.g., gynecomastia) Post-adolescent onset of: Spinal lower motor neuron disease with muscle weakness of the limbs or muscle cramps Bulbar lower motor neuron disease with fasciculations of the tongue, lips, or perioral region; dysarthria and difficulty swallowing No signs of upper motor neuron disease (e.g., hyperreflexia, spasticity) The diagnosis of SBMA Molecular genetic testing approaches include Molecular Genetic Testing Used in Spinal and Bulbar Muscular Atrophy See See CAG repeat number can be determined by fragment length analysis of amplicons from polymerase chain reaction (PCR) amplification of the CAG repeat region within AR. • Adolescent-onset signs of androgen insensitivity (e.g., gynecomastia) • Post-adolescent onset of: • Spinal lower motor neuron disease with muscle weakness of the limbs or muscle cramps • Bulbar lower motor neuron disease with fasciculations of the tongue, lips, or perioral region; dysarthria and difficulty swallowing • Spinal lower motor neuron disease with muscle weakness of the limbs or muscle cramps • Bulbar lower motor neuron disease with fasciculations of the tongue, lips, or perioral region; dysarthria and difficulty swallowing • No signs of upper motor neuron disease (e.g., hyperreflexia, spasticity) • Spinal lower motor neuron disease with muscle weakness of the limbs or muscle cramps • Bulbar lower motor neuron disease with fasciculations of the tongue, lips, or perioral region; dysarthria and difficulty swallowing ## Suggestive Findings Spinal and bulbar muscular atrophy (SBMA) Adolescent-onset signs of androgen insensitivity (e.g., gynecomastia) Post-adolescent onset of: Spinal lower motor neuron disease with muscle weakness of the limbs or muscle cramps Bulbar lower motor neuron disease with fasciculations of the tongue, lips, or perioral region; dysarthria and difficulty swallowing No signs of upper motor neuron disease (e.g., hyperreflexia, spasticity) • Adolescent-onset signs of androgen insensitivity (e.g., gynecomastia) • Post-adolescent onset of: • Spinal lower motor neuron disease with muscle weakness of the limbs or muscle cramps • Bulbar lower motor neuron disease with fasciculations of the tongue, lips, or perioral region; dysarthria and difficulty swallowing • Spinal lower motor neuron disease with muscle weakness of the limbs or muscle cramps • Bulbar lower motor neuron disease with fasciculations of the tongue, lips, or perioral region; dysarthria and difficulty swallowing • No signs of upper motor neuron disease (e.g., hyperreflexia, spasticity) • Spinal lower motor neuron disease with muscle weakness of the limbs or muscle cramps • Bulbar lower motor neuron disease with fasciculations of the tongue, lips, or perioral region; dysarthria and difficulty swallowing ## Establishing the Diagnosis The diagnosis of SBMA Molecular genetic testing approaches include Molecular Genetic Testing Used in Spinal and Bulbar Muscular Atrophy See See CAG repeat number can be determined by fragment length analysis of amplicons from polymerase chain reaction (PCR) amplification of the CAG repeat region within AR. ## Clinical Characteristics Spinal and bulbar muscular atrophy (SBMA) is a disorder of slowly progressive muscle weakness associated with mild androgen insensitivity. Early signs are difficulty with walking and a tendency to fall. Many individuals have muscle cramps, while others report an action tremor [ After one to two decades of symptoms, most affected individuals have difficulty climbing stairs. With time, atrophy of the proximal and distal musculature becomes evident. About one third of affected individuals require a wheelchair 20 years after the onset of symptoms. Most individuals eventually show involvement of the bulbar muscles and have difficulty with speech articulation and swallowing. Severely affected individuals (many of whom are non-ambulatory) are at risk for aspiration pneumonia and ventilatory failure because of weakness of the bulbar and respiratory musculature [ Affected males may also have degeneration of the dorsal root ganglia, leading to mild-to-moderate abnormalities in sensory function in the distal extremities [ The androgen insensitivity can be of greater concern to affected individuals than the motor neuron disease, especially early in the course of the disorder [ Studies of the number of CAG repeats in The genotype-phenotype correlation between allelic CAG repeat number and disease severity can only account for about 60% of the variability observed in clinical findings, indicating that other factors in addition to CAG repeat number determine age of disease onset and rate of disease progression. Indeed, relatives with SBMA with an identical CAG repeat number may have considerably different disease courses. SBMA has been called Kennedy's disease, named for the neurologist who published an early clinical description. In the past, SBMA has also been called X-linked spinal muscular atrophy. SBMA has an estimated prevalence of 1:300,000 males. To date, SBMA has only been reported in individuals of European or Asian ethnic background; it has yet to be reported in individuals of African or Aboriginal racial background. European populations in which SBMA has been observed include English, Belgian, French, Italian, German, Polish, Spanish, Swiss, Moroccan, and Turkish [ Asian populations in which SBMA has been observed include Chinese, Japanese, Korean, and Vietnamese. SBMA is much more common in the Japanese population than in other population groups because of a founder effect [ ## Clinical Description Spinal and bulbar muscular atrophy (SBMA) is a disorder of slowly progressive muscle weakness associated with mild androgen insensitivity. Early signs are difficulty with walking and a tendency to fall. Many individuals have muscle cramps, while others report an action tremor [ After one to two decades of symptoms, most affected individuals have difficulty climbing stairs. With time, atrophy of the proximal and distal musculature becomes evident. About one third of affected individuals require a wheelchair 20 years after the onset of symptoms. Most individuals eventually show involvement of the bulbar muscles and have difficulty with speech articulation and swallowing. Severely affected individuals (many of whom are non-ambulatory) are at risk for aspiration pneumonia and ventilatory failure because of weakness of the bulbar and respiratory musculature [ Affected males may also have degeneration of the dorsal root ganglia, leading to mild-to-moderate abnormalities in sensory function in the distal extremities [ The androgen insensitivity can be of greater concern to affected individuals than the motor neuron disease, especially early in the course of the disorder [ ## Affected Males Early signs are difficulty with walking and a tendency to fall. Many individuals have muscle cramps, while others report an action tremor [ After one to two decades of symptoms, most affected individuals have difficulty climbing stairs. With time, atrophy of the proximal and distal musculature becomes evident. About one third of affected individuals require a wheelchair 20 years after the onset of symptoms. Most individuals eventually show involvement of the bulbar muscles and have difficulty with speech articulation and swallowing. Severely affected individuals (many of whom are non-ambulatory) are at risk for aspiration pneumonia and ventilatory failure because of weakness of the bulbar and respiratory musculature [ Affected males may also have degeneration of the dorsal root ganglia, leading to mild-to-moderate abnormalities in sensory function in the distal extremities [ The androgen insensitivity can be of greater concern to affected individuals than the motor neuron disease, especially early in the course of the disorder [ ## Heterozygous Females ## Genotype-Phenotype Correlations Studies of the number of CAG repeats in The genotype-phenotype correlation between allelic CAG repeat number and disease severity can only account for about 60% of the variability observed in clinical findings, indicating that other factors in addition to CAG repeat number determine age of disease onset and rate of disease progression. Indeed, relatives with SBMA with an identical CAG repeat number may have considerably different disease courses. ## Nomenclature SBMA has been called Kennedy's disease, named for the neurologist who published an early clinical description. In the past, SBMA has also been called X-linked spinal muscular atrophy. ## Prevalence SBMA has an estimated prevalence of 1:300,000 males. To date, SBMA has only been reported in individuals of European or Asian ethnic background; it has yet to be reported in individuals of African or Aboriginal racial background. European populations in which SBMA has been observed include English, Belgian, French, Italian, German, Polish, Spanish, Swiss, Moroccan, and Turkish [ Asian populations in which SBMA has been observed include Chinese, Japanese, Korean, and Vietnamese. SBMA is much more common in the Japanese population than in other population groups because of a founder effect [ ## Genetically Related (Allelic) Disorders Germline single-nucleotide variants in ## Differential Diagnosis A number of hereditary and acquired neuromuscular disorders can produce gradually progressive muscle weakness. The disorder with which spinal and bulbar muscular atrophy (SBMA) is most often confused is Genes of Interest in the Differential Diagnosis of Spinal and Bulbar Muscular Atrophy AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; SBMA = spinal and bulbar muscular atrophy; XL = X-linked It is estimated that 10% of individuals with ALS have at least one family member with ALS. The identified ALS-related genes may account for at least half of ALS that occurs in families with a history of more than one affected individual. Thirty genes have been implicated in ALS; of these, SMA IV is the least common form of SMA and affects fewer than 5% of individuals with SMA. Muscle atrophy and muscle weakness from loss of motor neurons in the spinal cord are seen in other inherited neurodegenerative disorders including ## Management To establish the extent of disease and needs of an individual diagnosed with spinal and bulbar muscular atrophy (SBMA), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Spinal and Bulbar Muscular Atrophy UMN involvement: spasticity, Babinski signs, hyperreflexia; LMN involvement: weakness, amyotrophy, fasciculations, EMG. Muscle tone, joint range of motion, posture, mobility, strength, coordination & endurance, pain, bedsores Need for adaptive devices Footwear needs PT needs Need for assistive walking devices (e.g., canes, walker, walker w/wheels, walker w/seat, wheelchairs) Fine motor function (e.g., hands, feet, face, fingers, toes); Home adaptations for ADL & safety. Androgen responsiveness: male-pattern hair growth, testicular size, & fertility Assess for gynecomastia. ADL = activities of daily living; EMG = electromyography; LMN = lower motor neuron; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; SBMA = spinal and bulbar muscular atrophy; UMN = upper motor neuron Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Treatment of Manifestations in Individuals with Spinal and Bulbar Muscular Atrophy Safe swallowing techniques, diet modifications, education re cutting food into small pieces for eating & avoiding items that may be difficult to chew & swallow Gastrostomy tube as needed ADL = activities of daily living; LMN = lower motor neuron; OT = occupational therapy; PT = physical therapy; UMN = upper motor neuron 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 Spinal and Bulbar Muscular Atrophy Strength assessment Physical medicine & rehab / PT & OT assessments Cholesterol & triglycerides Hepatic function testing in those w/↑ cholesterol &/or triglycerides Any additional assessment of cardiac health per cardiologist ADL = activities of daily living; OT = occupational therapy; PT = physical therapy Individuals with a tendency to fall should avoid slippery or rough walking surfaces. See Anti-androgen therapy shows promise based on studies in A larger subsequent study in Japan with swallow function as the primary outcome measure also did not show an overall benefit, except in post hoc analysis of subjects in whom disease duration was less than ten years [ In another anti-androgen therapy study [ Hence, the utility of anti-androgen therapy as a treatment for SBMA remains controversial. Furthermore, it is possible that anti-androgen therapies, even if effective, would need to be administered prior to disease onset or early on in the neurodegenerative process. More importantly, the side effects of anti-androgen therapies would probably far outweigh the therapeutic benefit for most individuals, and likely should be reserved for people with SBMA who are wheelchair bound or exhibit pronounced bulbar weakness. Other interventions shown to have benefit in mouse models of SBMA include the HSP-90 inhibitors 17-AAG and 17-DMAG, the synthetic curcumin derivative ASC-J9, and insulin-like growth factor 1 (reviewed in Another study sought to ameliorate toxicity in mouse models of SBMA by suppressing polyQ-AR expression using antisense oligonucleotides (ASOs) [ Search Administration of male hormones (testosterone and its analogs) is not effective in overcoming the androgen insensitivity. • UMN involvement: spasticity, Babinski signs, hyperreflexia; • LMN involvement: weakness, amyotrophy, fasciculations, EMG. • Muscle tone, joint range of motion, posture, mobility, strength, coordination & endurance, pain, bedsores • Need for adaptive devices • Footwear needs • PT needs • Need for assistive walking devices (e.g., canes, walker, walker w/wheels, walker w/seat, wheelchairs) • Fine motor function (e.g., hands, feet, face, fingers, toes); • Home adaptations for ADL & safety. • Androgen responsiveness: male-pattern hair growth, testicular size, & fertility • Assess for gynecomastia. • Safe swallowing techniques, diet modifications, education re cutting food into small pieces for eating & avoiding items that may be difficult to chew & swallow • Gastrostomy tube as needed • Strength assessment • Physical medicine & rehab / PT & OT assessments • Cholesterol & triglycerides • Hepatic function testing in those w/↑ cholesterol &/or triglycerides • Any additional assessment of cardiac health per cardiologist • Anti-androgen therapy shows promise based on studies in • A larger subsequent study in Japan with swallow function as the primary outcome measure also did not show an overall benefit, except in post hoc analysis of subjects in whom disease duration was less than ten years [ • In another anti-androgen therapy study [ • Other interventions shown to have benefit in mouse models of SBMA include the HSP-90 inhibitors 17-AAG and 17-DMAG, the synthetic curcumin derivative ASC-J9, and insulin-like growth factor 1 (reviewed in • Another study sought to ameliorate toxicity in mouse models of SBMA by suppressing polyQ-AR expression using antisense oligonucleotides (ASOs) [ ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with spinal and bulbar muscular atrophy (SBMA), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Spinal and Bulbar Muscular Atrophy UMN involvement: spasticity, Babinski signs, hyperreflexia; LMN involvement: weakness, amyotrophy, fasciculations, EMG. Muscle tone, joint range of motion, posture, mobility, strength, coordination & endurance, pain, bedsores Need for adaptive devices Footwear needs PT needs Need for assistive walking devices (e.g., canes, walker, walker w/wheels, walker w/seat, wheelchairs) Fine motor function (e.g., hands, feet, face, fingers, toes); Home adaptations for ADL & safety. Androgen responsiveness: male-pattern hair growth, testicular size, & fertility Assess for gynecomastia. ADL = activities of daily living; EMG = electromyography; LMN = lower motor neuron; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; SBMA = spinal and bulbar muscular atrophy; UMN = upper motor neuron Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • UMN involvement: spasticity, Babinski signs, hyperreflexia; • LMN involvement: weakness, amyotrophy, fasciculations, EMG. • Muscle tone, joint range of motion, posture, mobility, strength, coordination & endurance, pain, bedsores • Need for adaptive devices • Footwear needs • PT needs • Need for assistive walking devices (e.g., canes, walker, walker w/wheels, walker w/seat, wheelchairs) • Fine motor function (e.g., hands, feet, face, fingers, toes); • Home adaptations for ADL & safety. • Androgen responsiveness: male-pattern hair growth, testicular size, & fertility • Assess for gynecomastia. ## Treatment of Manifestations Treatment of Manifestations in Individuals with Spinal and Bulbar Muscular Atrophy Safe swallowing techniques, diet modifications, education re cutting food into small pieces for eating & avoiding items that may be difficult to chew & swallow Gastrostomy tube as needed ADL = activities of daily living; LMN = lower motor neuron; OT = occupational therapy; PT = physical therapy; UMN = upper motor neuron • Safe swallowing techniques, diet modifications, education re cutting food into small pieces for eating & avoiding items that may be difficult to chew & swallow • Gastrostomy tube as needed ## 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 Spinal and Bulbar Muscular Atrophy Strength assessment Physical medicine & rehab / PT & OT assessments Cholesterol & triglycerides Hepatic function testing in those w/↑ cholesterol &/or triglycerides Any additional assessment of cardiac health per cardiologist ADL = activities of daily living; OT = occupational therapy; PT = physical therapy • Strength assessment • Physical medicine & rehab / PT & OT assessments • Cholesterol & triglycerides • Hepatic function testing in those w/↑ cholesterol &/or triglycerides • Any additional assessment of cardiac health per cardiologist ## Agents/Circumstances to Avoid Individuals with a tendency to fall should avoid slippery or rough walking surfaces. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Anti-androgen therapy shows promise based on studies in A larger subsequent study in Japan with swallow function as the primary outcome measure also did not show an overall benefit, except in post hoc analysis of subjects in whom disease duration was less than ten years [ In another anti-androgen therapy study [ Hence, the utility of anti-androgen therapy as a treatment for SBMA remains controversial. Furthermore, it is possible that anti-androgen therapies, even if effective, would need to be administered prior to disease onset or early on in the neurodegenerative process. More importantly, the side effects of anti-androgen therapies would probably far outweigh the therapeutic benefit for most individuals, and likely should be reserved for people with SBMA who are wheelchair bound or exhibit pronounced bulbar weakness. Other interventions shown to have benefit in mouse models of SBMA include the HSP-90 inhibitors 17-AAG and 17-DMAG, the synthetic curcumin derivative ASC-J9, and insulin-like growth factor 1 (reviewed in Another study sought to ameliorate toxicity in mouse models of SBMA by suppressing polyQ-AR expression using antisense oligonucleotides (ASOs) [ Search • Anti-androgen therapy shows promise based on studies in • A larger subsequent study in Japan with swallow function as the primary outcome measure also did not show an overall benefit, except in post hoc analysis of subjects in whom disease duration was less than ten years [ • In another anti-androgen therapy study [ • Other interventions shown to have benefit in mouse models of SBMA include the HSP-90 inhibitors 17-AAG and 17-DMAG, the synthetic curcumin derivative ASC-J9, and insulin-like growth factor 1 (reviewed in • Another study sought to ameliorate toxicity in mouse models of SBMA by suppressing polyQ-AR expression using antisense oligonucleotides (ASOs) [ ## Other Administration of male hormones (testosterone and its analogs) is not effective in overcoming the androgen insensitivity. ## Genetic Counseling Spinal and bulbar muscular atrophy (SBMA) is inherited in an X-linked manner. The father of an affected male will not have the disorder, nor will he be hemizygous for a CAG trinucleotide repeat expansion in To date, all mothers of affected males who have undergone molecular genetic testing have been shown to be heterozygous for a CAG trinucleotide repeat expansion. 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 CAG trinucleotide repeat expansion 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, theoretically, the affected male may have a The true incidence of Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. (Note: Because SBMA is a late-onset disorder, mothers may not always be available for testing.) If the mother of the proband has a CAG trinucleotide repeat expansion, the chance of transmitting it in each pregnancy is 50%. Males who inherit: An expansion of 38 or more CAG trinucleotide repeats will be affected; A CAG trinucleotide repeat expansion in the reduced-penetrance range are at risk for SBMA. (The clinical significance of alleles with 36-37 CAG repeats should be interpreted within the context of family history and genotype-phenotype correlations in other family members; see Intrafamilial clinical variability is observed in SBMA; affected male family members with identical CAG repeat numbers may have considerably different disease courses (see Females who inherit a full-penetrance allele of 38 or more CAG repeats are usually asymptomatic or may have mild symptoms (see Clinical Description, Affected males who are fertile transmit the CAG trinucleotide repeat expansion to all of their daughters (who will be heterozygotes and will usually not be affected) and none of their sons. Repeat instability with male transmission of a CAG trinucleotide repeat expansion has been described (see Identification of female heterozygotes requires prior identification of the Note: Females who are heterozygous (carriers) for this X-linked disorder will usually not be affected. Predictive testing for at-risk relatives is possible once the Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. In a family with an established diagnosis of SBMA, it is appropriate to consider testing of symptomatic individuals regardless of age. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once an Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The father of an affected male will not have the disorder, nor will he be hemizygous for a CAG trinucleotide repeat expansion in • To date, all mothers of affected males who have undergone molecular genetic testing have been shown to be heterozygous for a CAG trinucleotide repeat expansion. • 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 CAG trinucleotide repeat expansion 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, theoretically, the affected male may have a • The true incidence of • Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. (Note: Because SBMA is a late-onset disorder, mothers may not always be available for testing.) • If the mother of the proband has a CAG trinucleotide repeat expansion, the chance of transmitting it in each pregnancy is 50%. • Males who inherit: • An expansion of 38 or more CAG trinucleotide repeats will be affected; • A CAG trinucleotide repeat expansion in the reduced-penetrance range are at risk for SBMA. (The clinical significance of alleles with 36-37 CAG repeats should be interpreted within the context of family history and genotype-phenotype correlations in other family members; see • An expansion of 38 or more CAG trinucleotide repeats will be affected; • A CAG trinucleotide repeat expansion in the reduced-penetrance range are at risk for SBMA. (The clinical significance of alleles with 36-37 CAG repeats should be interpreted within the context of family history and genotype-phenotype correlations in other family members; see • Intrafamilial clinical variability is observed in SBMA; affected male family members with identical CAG repeat numbers may have considerably different disease courses (see • Females who inherit a full-penetrance allele of 38 or more CAG repeats are usually asymptomatic or may have mild symptoms (see Clinical Description, • An expansion of 38 or more CAG trinucleotide repeats will be affected; • A CAG trinucleotide repeat expansion in the reduced-penetrance range are at risk for SBMA. (The clinical significance of alleles with 36-37 CAG repeats should be interpreted within the context of family history and genotype-phenotype correlations in other family members; see • Affected males who are fertile transmit the CAG trinucleotide repeat expansion to all of their daughters (who will be heterozygotes and will usually not be affected) and none of their sons. • Repeat instability with male transmission of a CAG trinucleotide repeat expansion has been described (see • Predictive testing for at-risk relatives is possible once the • Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance Spinal and bulbar muscular atrophy (SBMA) 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 a CAG trinucleotide repeat expansion in To date, all mothers of affected males who have undergone molecular genetic testing have been shown to be heterozygous for a CAG trinucleotide repeat expansion. 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 CAG trinucleotide repeat expansion 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, theoretically, the affected male may have a The true incidence of Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. (Note: Because SBMA is a late-onset disorder, mothers may not always be available for testing.) If the mother of the proband has a CAG trinucleotide repeat expansion, the chance of transmitting it in each pregnancy is 50%. Males who inherit: An expansion of 38 or more CAG trinucleotide repeats will be affected; A CAG trinucleotide repeat expansion in the reduced-penetrance range are at risk for SBMA. (The clinical significance of alleles with 36-37 CAG repeats should be interpreted within the context of family history and genotype-phenotype correlations in other family members; see Intrafamilial clinical variability is observed in SBMA; affected male family members with identical CAG repeat numbers may have considerably different disease courses (see Females who inherit a full-penetrance allele of 38 or more CAG repeats are usually asymptomatic or may have mild symptoms (see Clinical Description, Affected males who are fertile transmit the CAG trinucleotide repeat expansion to all of their daughters (who will be heterozygotes and will usually not be affected) and none of their sons. Repeat instability with male transmission of a CAG trinucleotide repeat expansion has been described (see • The father of an affected male will not have the disorder, nor will he be hemizygous for a CAG trinucleotide repeat expansion in • To date, all mothers of affected males who have undergone molecular genetic testing have been shown to be heterozygous for a CAG trinucleotide repeat expansion. • 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 CAG trinucleotide repeat expansion 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, theoretically, the affected male may have a • The true incidence of • Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. (Note: Because SBMA is a late-onset disorder, mothers may not always be available for testing.) • If the mother of the proband has a CAG trinucleotide repeat expansion, the chance of transmitting it in each pregnancy is 50%. • Males who inherit: • An expansion of 38 or more CAG trinucleotide repeats will be affected; • A CAG trinucleotide repeat expansion in the reduced-penetrance range are at risk for SBMA. (The clinical significance of alleles with 36-37 CAG repeats should be interpreted within the context of family history and genotype-phenotype correlations in other family members; see • An expansion of 38 or more CAG trinucleotide repeats will be affected; • A CAG trinucleotide repeat expansion in the reduced-penetrance range are at risk for SBMA. (The clinical significance of alleles with 36-37 CAG repeats should be interpreted within the context of family history and genotype-phenotype correlations in other family members; see • Intrafamilial clinical variability is observed in SBMA; affected male family members with identical CAG repeat numbers may have considerably different disease courses (see • Females who inherit a full-penetrance allele of 38 or more CAG repeats are usually asymptomatic or may have mild symptoms (see Clinical Description, • An expansion of 38 or more CAG trinucleotide repeats will be affected; • A CAG trinucleotide repeat expansion in the reduced-penetrance range are at risk for SBMA. (The clinical significance of alleles with 36-37 CAG repeats should be interpreted within the context of family history and genotype-phenotype correlations in other family members; see • Affected males who are fertile transmit the CAG trinucleotide repeat expansion to all of their daughters (who will be heterozygotes and will usually not be affected) and none of their sons. • Repeat instability with male transmission of a CAG trinucleotide repeat expansion has been described (see ## Heterozygote (Carrier) Detection Identification of female heterozygotes requires prior identification of the Note: Females who are heterozygous (carriers) for this X-linked disorder will usually not be affected. ## 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. In a family with an established diagnosis of SBMA, it is appropriate to consider testing of symptomatic individuals regardless of age. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • Predictive testing for at-risk relatives is possible once the • Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once an 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 Spinal and Bulbar Muscular Atrophy: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Spinal and Bulbar Muscular Atrophy ( In addition to gain-of-function polyglutamine proteotoxicity, recent research work has focused on the role of altered normal function in dictating cell type specificity in SBMA, and this work suggests that altered protein complex interactions between the AR protein and its coactivators and corepressors may underlie disease pathogenesis [ Genetic testing of sperm of an affected male showed that 20% of the sperm had a CAG repeat number equal to that in the DNA from somatic cells, whereas 56% had further expansion of the CAG repeat number, and 24% had contraction of the CAG repeat number. Most of the allelic expansions and contractions were between one and three CAG repeats. Similar studies on oocytes have not been possible. Notable Variants listed in the table have been provided by the author. Each CAG repeat results in the addition of a glutamine residue to the polymorphic polyglutamine repeat. ## Molecular Pathogenesis In addition to gain-of-function polyglutamine proteotoxicity, recent research work has focused on the role of altered normal function in dictating cell type specificity in SBMA, and this work suggests that altered protein complex interactions between the AR protein and its coactivators and corepressors may underlie disease pathogenesis [ Genetic testing of sperm of an affected male showed that 20% of the sperm had a CAG repeat number equal to that in the DNA from somatic cells, whereas 56% had further expansion of the CAG repeat number, and 24% had contraction of the CAG repeat number. Most of the allelic expansions and contractions were between one and three CAG repeats. Similar studies on oocytes have not been possible. Notable Variants listed in the table have been provided by the author. Each CAG repeat results in the addition of a glutamine residue to the polymorphic polyglutamine repeat. ## Chapter Notes Dr La Spada is a Distinguished Professor at UC Irvine , where he maintains a research program focused on neurodegenerative proteinopathies. Spinal and bulbar muscular atrophy (SBMA) remains a major focus of his research efforts. Dr La Spada's SBMA research is supported by a R35 award (NS122140) from the NINDS at the National Institutes of Health. 15 December 2022 (sw) Comprehensive update posted live 26 January 2017 (ma) Comprehensive update posted live 3 July 2014 (me) Comprehensive update posted live 13 October 2011 (me) Comprehensive update posted live 28 December 2006 (me) Comprehensive update posted live 1 July 2004 (me) Comprehensive update posted live 29 August 2002 (me) Comprehensive update posted live 26 February 1999 (pb) Review posted live 15 December 1998 (als) Original submission • 15 December 2022 (sw) Comprehensive update posted live • 26 January 2017 (ma) Comprehensive update posted live • 3 July 2014 (me) Comprehensive update posted live • 13 October 2011 (me) Comprehensive update posted live • 28 December 2006 (me) Comprehensive update posted live • 1 July 2004 (me) Comprehensive update posted live • 29 August 2002 (me) Comprehensive update posted live • 26 February 1999 (pb) Review posted live • 15 December 1998 (als) Original submission ## Author Notes Dr La Spada is a Distinguished Professor at UC Irvine , where he maintains a research program focused on neurodegenerative proteinopathies. Spinal and bulbar muscular atrophy (SBMA) remains a major focus of his research efforts. ## Acknowledgments Dr La Spada's SBMA research is supported by a R35 award (NS122140) from the NINDS at the National Institutes of Health. ## Revision History 15 December 2022 (sw) Comprehensive update posted live 26 January 2017 (ma) Comprehensive update posted live 3 July 2014 (me) Comprehensive update posted live 13 October 2011 (me) Comprehensive update posted live 28 December 2006 (me) Comprehensive update posted live 1 July 2004 (me) Comprehensive update posted live 29 August 2002 (me) Comprehensive update posted live 26 February 1999 (pb) Review posted live 15 December 1998 (als) Original submission • 15 December 2022 (sw) Comprehensive update posted live • 26 January 2017 (ma) Comprehensive update posted live • 3 July 2014 (me) Comprehensive update posted live • 13 October 2011 (me) Comprehensive update posted live • 28 December 2006 (me) Comprehensive update posted live • 1 July 2004 (me) Comprehensive update posted live • 29 August 2002 (me) Comprehensive update posted live • 26 February 1999 (pb) Review posted live • 15 December 1998 (als) Original submission ## References ## Literature Cited	[]	26/2/1999	15/12/2022		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
kindler	kindler	[ "Congenital Bullous Poikiloderma", "Congenital Bullous Poikiloderma", "Fermitin family homolog 1", "FERMT1", "Kindler Syndrome" ]	Kindler Syndrome	Leila Youssefian, Hassan Vahidnezhad, Jouni Uitto	Summary Kindler syndrome (KS), a rare subtype of inherited epidermolysis bullosa, is characterized by skin fragility and acral blister formation beginning at birth, diffuse cutaneous atrophy, photosensitivity (most prominent during childhood and usually decreasing after adolescence), poikiloderma, diffuse palmoplantar hyperkeratosis, and pseudosyndactyly. Mucosal manifestations are also common and include hemorrhagic mucositis and gingivitis, periodontal disease, premature loss of teeth, and labial leukokeratosis. Other mucosal findings can include ectropion, urethral stenosis, and severe phimosis. Severe long-term complications of KS include periodontitis, mucosal strictures, and aggressive squamous cell carcinomas. Manifestations can range from mild to severe. The diagnosis of KS is established in a proband with suggestive clinical findings and biallelic pathogenic variants in KS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an	## Diagnosis No consensus clinical diagnostic criteria for Kindler syndrome (KS) have been published. KS The diagnosis of KS 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 KS may be indistinguishable from many other inherited disorders with cutaneous fragility, recommended molecular genetic testing approaches include use of a A For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Kindler 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. • A • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings KS ## Establishing the Diagnosis The diagnosis of KS 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 KS may be indistinguishable from many other inherited disorders with cutaneous fragility, recommended molecular genetic testing approaches include use of a A For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Kindler 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. • A • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics Kindler syndrome (KS), a rare subtype of epidermolysis bullosa, is characterized by skin fragility and acral blister formation beginning at birth or in early infancy, diffuse cutaneous atrophy, photosensitivity (most prominent during childhood and usually decreasing after adolescence), poikiloderma, palmoplantar hyperkeratosis, and pseudosyndactyly. Mucosal manifestations are also common and include hemorrhagic mucositis and gingivitis, periodontal disease, premature loss of teeth, and labial leukokeratosis. Other mucosal findings include ectropion, urethral stenosis, and severe phimosis. Severe long-term complications of KS include periodontitis, mucosal strictures, and aggressive squamous cell carcinomas. To date, about 400 individuals have been identified with biallelic pathogenic variants in Kindler Syndrome: Frequency of Select Features Blisters result from trauma and/or exposure to sunlight. The number of blisters decreases by age ten to 12 years [ Pyogenic skin infections can be a complication of blistering. Axillary freckling may be observed in some ( Constricting bands of the pseudoainhum type have also been reported ( Vaginal stenosis and labial synechiae Urethral meatal stenosis and urethral strictures, phimosis Squamous cell carcinomas in acral skin and the mouth (lip and hard palate) [ Transitional cell carcinomas of the bladder [ Xerosis, eczema, and dermatitis Variable hypermobility of the thumb, fingers, knees, and elbows without skin hyperextensibility [ Nail dystrophy ( No genotype-phenotype correlations have been identified. Most KS was first described by Theresa Kindler [ In May 2007, 18 leading authorities on epidermolysis bullosa (EB) revised the EB classification to include KS based on its biologic and clinical findings [ Since the first description of KS in 1954 [ Persons of any geographic origin can be affected and there is no sex predilection [ • Blisters result from trauma and/or exposure to sunlight. • The number of blisters decreases by age ten to 12 years [ • Pyogenic skin infections can be a complication of blistering. • • Vaginal stenosis and labial synechiae • Urethral meatal stenosis and urethral strictures, phimosis • Vaginal stenosis and labial synechiae • Urethral meatal stenosis and urethral strictures, phimosis • Vaginal stenosis and labial synechiae • Urethral meatal stenosis and urethral strictures, phimosis • Squamous cell carcinomas in acral skin and the mouth (lip and hard palate) [ • Transitional cell carcinomas of the bladder [ • Xerosis, eczema, and dermatitis • Variable hypermobility of the thumb, fingers, knees, and elbows without skin hyperextensibility [ • Nail dystrophy ( ## Clinical Description Kindler syndrome (KS), a rare subtype of epidermolysis bullosa, is characterized by skin fragility and acral blister formation beginning at birth or in early infancy, diffuse cutaneous atrophy, photosensitivity (most prominent during childhood and usually decreasing after adolescence), poikiloderma, palmoplantar hyperkeratosis, and pseudosyndactyly. Mucosal manifestations are also common and include hemorrhagic mucositis and gingivitis, periodontal disease, premature loss of teeth, and labial leukokeratosis. Other mucosal findings include ectropion, urethral stenosis, and severe phimosis. Severe long-term complications of KS include periodontitis, mucosal strictures, and aggressive squamous cell carcinomas. To date, about 400 individuals have been identified with biallelic pathogenic variants in Kindler Syndrome: Frequency of Select Features Blisters result from trauma and/or exposure to sunlight. The number of blisters decreases by age ten to 12 years [ Pyogenic skin infections can be a complication of blistering. Axillary freckling may be observed in some ( Constricting bands of the pseudoainhum type have also been reported ( Vaginal stenosis and labial synechiae Urethral meatal stenosis and urethral strictures, phimosis Squamous cell carcinomas in acral skin and the mouth (lip and hard palate) [ Transitional cell carcinomas of the bladder [ Xerosis, eczema, and dermatitis Variable hypermobility of the thumb, fingers, knees, and elbows without skin hyperextensibility [ Nail dystrophy ( • Blisters result from trauma and/or exposure to sunlight. • The number of blisters decreases by age ten to 12 years [ • Pyogenic skin infections can be a complication of blistering. • • Vaginal stenosis and labial synechiae • Urethral meatal stenosis and urethral strictures, phimosis • Vaginal stenosis and labial synechiae • Urethral meatal stenosis and urethral strictures, phimosis • Vaginal stenosis and labial synechiae • Urethral meatal stenosis and urethral strictures, phimosis • Squamous cell carcinomas in acral skin and the mouth (lip and hard palate) [ • Transitional cell carcinomas of the bladder [ • Xerosis, eczema, and dermatitis • Variable hypermobility of the thumb, fingers, knees, and elbows without skin hyperextensibility [ • Nail dystrophy ( ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been identified. Most ## Nomenclature KS was first described by Theresa Kindler [ In May 2007, 18 leading authorities on epidermolysis bullosa (EB) revised the EB classification to include KS based on its biologic and clinical findings [ ## Prevalence Since the first description of KS in 1954 [ Persons of any geographic origin can be affected and there is no sex predilection [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Before the onset of the photosensitivity and poikiloderma in the first few years of life, Kindler syndrome (KS) is frequently confused with other variants of epidermolysis bullosa (e.g., Disorders of known genetic cause that can exhibit features of poikiloderma but are distinguishable by other clinical features are summarized Disorders with Features of Poikiloderma in the Differential Diagnosis of Kindler Syndrome AD = autosomal dominant; AR = autosomal recessive; KS = Kindler syndrome; MOI = mode of inheritance; XL = X-linked The designation • The designation ## Management No clinical practice guidelines for Kindler syndrome (KS) have been published. To establish the extent of disease and needs in an individual diagnosed with KS, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Kindler Syndrome Gastroenterology eval for strictures affecting GI tract Incl eval of nutritional status, diet, & oral intake Males: urology consult for urethra or foreskin stricture/stenosis Females: gynecology eval for vaginal or labial stricture/stenosis Community or Social work involvement for parental support; Home nursing referral. GI = gastrointestinal; KS = Kindler syndrome; MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse No established treatment for KS exists. The goals of care are to treat manifestations and prevent complications. When possible, children with KS should be managed in a center experienced in caring for children with skin fragility by a multidisciplinary team that includes a dermatologist, pediatrician, ophthalmologist, dentist, gastroenterologist, urologist, nurse specialist, and dietitian. Treatment of Manifestations in Individuals with Kindler Syndrome If blister is not painful, it should be kept intact. Otherwise alleviate blister-related pain by draining fluid using a sterile needle, leaving overlying skin in place. Apply ointment to blister & cover w/nonstick gauze bandage. Antibiotics may be used to treat infected blister. Lubrication of cornea by artificial tears & eye drops Prevention of infections by use of local antibiotics Surgical correction of corneal scarring by ophthalmologist as needed Esophageal dilation may be indicated for those w/dysphagia. Esophageal strictures & stenosis may require fluoroscopically guided balloon dilations [ Temporary parenteral nutrition may be necessary when esophageal dysfunction is severe. Anal stenosis & bleeding requires regular laxatives. Severe colitis may require surgical bowel resection in some cases. Urethral meatal stenosis may require dilation. Strictures may require stenting &/or surgical intervention. Most males require circumcision for phimosis. Vaginal or labial stricture/stenosis may require surgical intervention. In case of pregnancy, delivery should be considered by an elective cesarean section. GI = gastrointestinal Recommended Surveillance for Individuals with Kindler Syndrome Avoid sun exposure by using sunscreen (SFP >30) and sun-protective clothing. See Although the cutaneous manifestations of KS are not exacerbated by pregnancy, vaginal stenosis and labial synechiae have been reported; thus, obstetric planning, such as consideration of delivery by elective cesarean section, warrants consideration [ Breastfeeding is not advised because of the risk of blistering the breasts [ Search • Gastroenterology eval for strictures affecting GI tract • Incl eval of nutritional status, diet, & oral intake • Males: urology consult for urethra or foreskin stricture/stenosis • Females: gynecology eval for vaginal or labial stricture/stenosis • Community or • Social work involvement for parental support; • Home nursing referral. • If blister is not painful, it should be kept intact. • Otherwise alleviate blister-related pain by draining fluid using a sterile needle, leaving overlying skin in place. • Apply ointment to blister & cover w/nonstick gauze bandage. • Antibiotics may be used to treat infected blister. • Lubrication of cornea by artificial tears & eye drops • Prevention of infections by use of local antibiotics • Surgical correction of corneal scarring by ophthalmologist as needed • Esophageal dilation may be indicated for those w/dysphagia. • Esophageal strictures & stenosis may require fluoroscopically guided balloon dilations [ • Temporary parenteral nutrition may be necessary when esophageal dysfunction is severe. • Anal stenosis & bleeding requires regular laxatives. • Severe colitis may require surgical bowel resection in some cases. • Urethral meatal stenosis may require dilation. Strictures may require stenting &/or surgical intervention. • Most males require circumcision for phimosis. • Vaginal or labial stricture/stenosis may require surgical intervention. In case of pregnancy, delivery should be considered by an elective cesarean section. ## Evaluation Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with KS, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Kindler Syndrome Gastroenterology eval for strictures affecting GI tract Incl eval of nutritional status, diet, & oral intake Males: urology consult for urethra or foreskin stricture/stenosis Females: gynecology eval for vaginal or labial stricture/stenosis Community or Social work involvement for parental support; Home nursing referral. GI = gastrointestinal; KS = Kindler syndrome; MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Gastroenterology eval for strictures affecting GI tract • Incl eval of nutritional status, diet, & oral intake • Males: urology consult for urethra or foreskin stricture/stenosis • Females: gynecology eval for vaginal or labial stricture/stenosis • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations No established treatment for KS exists. The goals of care are to treat manifestations and prevent complications. When possible, children with KS should be managed in a center experienced in caring for children with skin fragility by a multidisciplinary team that includes a dermatologist, pediatrician, ophthalmologist, dentist, gastroenterologist, urologist, nurse specialist, and dietitian. Treatment of Manifestations in Individuals with Kindler Syndrome If blister is not painful, it should be kept intact. Otherwise alleviate blister-related pain by draining fluid using a sterile needle, leaving overlying skin in place. Apply ointment to blister & cover w/nonstick gauze bandage. Antibiotics may be used to treat infected blister. Lubrication of cornea by artificial tears & eye drops Prevention of infections by use of local antibiotics Surgical correction of corneal scarring by ophthalmologist as needed Esophageal dilation may be indicated for those w/dysphagia. Esophageal strictures & stenosis may require fluoroscopically guided balloon dilations [ Temporary parenteral nutrition may be necessary when esophageal dysfunction is severe. Anal stenosis & bleeding requires regular laxatives. Severe colitis may require surgical bowel resection in some cases. Urethral meatal stenosis may require dilation. Strictures may require stenting &/or surgical intervention. Most males require circumcision for phimosis. Vaginal or labial stricture/stenosis may require surgical intervention. In case of pregnancy, delivery should be considered by an elective cesarean section. GI = gastrointestinal • If blister is not painful, it should be kept intact. • Otherwise alleviate blister-related pain by draining fluid using a sterile needle, leaving overlying skin in place. • Apply ointment to blister & cover w/nonstick gauze bandage. • Antibiotics may be used to treat infected blister. • Lubrication of cornea by artificial tears & eye drops • Prevention of infections by use of local antibiotics • Surgical correction of corneal scarring by ophthalmologist as needed • Esophageal dilation may be indicated for those w/dysphagia. • Esophageal strictures & stenosis may require fluoroscopically guided balloon dilations [ • Temporary parenteral nutrition may be necessary when esophageal dysfunction is severe. • Anal stenosis & bleeding requires regular laxatives. • Severe colitis may require surgical bowel resection in some cases. • Urethral meatal stenosis may require dilation. Strictures may require stenting &/or surgical intervention. • Most males require circumcision for phimosis. • Vaginal or labial stricture/stenosis may require surgical intervention. In case of pregnancy, delivery should be considered by an elective cesarean section. ## Surveillance Recommended Surveillance for Individuals with Kindler Syndrome ## Agents/Circumstances to Avoid Avoid sun exposure by using sunscreen (SFP >30) and sun-protective clothing. ## Evaluation of Relatives at Risk See ## Pregnancy Management Although the cutaneous manifestations of KS are not exacerbated by pregnancy, vaginal stenosis and labial synechiae have been reported; thus, obstetric planning, such as consideration of delivery by elective cesarean section, warrants consideration [ Breastfeeding is not advised because of the risk of blistering the breasts [ ## Therapies Under Investigation Search ## Genetic Counseling Kindler syndrome (KS) is inherited in an autosomal recessive manner. The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of the 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. Unless an individual with KS has children with an affected individual or a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in KS is reported more frequently in populations with high rates of consanguinity [ The offspring of a proband and an individual heterozygous for an Carrier testing for at-risk relatives requires prior identification of the The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of the 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. • Unless an individual with KS has children with an affected individual or a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in • KS is reported more frequently in populations with high rates of consanguinity [ • The offspring of a proband and an individual heterozygous for an • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance Kindler syndrome (KS) is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of the 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. Unless an individual with KS has children with an affected individual or a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in KS is reported more frequently in populations with high rates of consanguinity [ The offspring of a proband and an individual heterozygous for an • 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 the 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. • Unless an individual with KS has children with an affected individual or a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in • KS is reported more frequently in populations with high rates of consanguinity [ • The offspring of a proband and an individual heterozygous for an ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom • • • • • • United Kingdom • • • • • ## Molecular Genetics Kindler Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Kindler Syndrome ( To date, a total of 91 loss-of-function pathogenic variants have been reported in Notable Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis To date, a total of 91 loss-of-function pathogenic variants have been reported in Notable Variants listed in the table have been provided by the authors. ## Chapter Notes Leila Youssefian and Hassan Vahidnezhad contributed equally to this work. Department of Dermatology and Cutaneous BiologyThomas Jefferson University233 South 10th StreetBluemle Life Sciences Building, Suite 431Philadelphia, PA, USA 19107 Individuals with Kindler syndrome, Kindler epidermolysis bullosa, or Kindler-like syndrome interested in receiving information and free genetic testing can contact Leila Youssefian (email: [email protected] or phone: 610-999-9402). Carol Kelly assisted in manuscript preparation. 6 January 2022 (ha) Comprehensive update posted live 1 December 2016 (aa) Revision: addition to 3 March 2016 (bp) Review posted live 3 August 2015 (ly) Original submission • 6 January 2022 (ha) Comprehensive update posted live • 1 December 2016 (aa) Revision: addition to • 3 March 2016 (bp) Review posted live • 3 August 2015 (ly) Original submission ## Author Notes Leila Youssefian and Hassan Vahidnezhad contributed equally to this work. Department of Dermatology and Cutaneous BiologyThomas Jefferson University233 South 10th StreetBluemle Life Sciences Building, Suite 431Philadelphia, PA, USA 19107 Individuals with Kindler syndrome, Kindler epidermolysis bullosa, or Kindler-like syndrome interested in receiving information and free genetic testing can contact Leila Youssefian (email: [email protected] or phone: 610-999-9402). ## Acknowledgments Carol Kelly assisted in manuscript preparation. ## Revision History 6 January 2022 (ha) Comprehensive update posted live 1 December 2016 (aa) Revision: addition to 3 March 2016 (bp) Review posted live 3 August 2015 (ly) Original submission • 6 January 2022 (ha) Comprehensive update posted live • 1 December 2016 (aa) Revision: addition to • 3 March 2016 (bp) Review posted live • 3 August 2015 (ly) Original submission ## References ## Literature Cited Characteristic clinical features of Kindler syndrome a. Child age nine years: atrophy of skin on the dorsum of the hands and poikiloderma on the neck and axillary area b. Poikiloderma of the neck c. Urethral stenosis d. Gingival fragility and enamel hypoplasia (arrows) e. Individual age 35 years: atrophy of the skin on the dorsum of the feet, nail dystrophy, and bilateral pseudoainhum (acquired constricting ring around a digit) of fifth toes (arrow heads) f. Cutaneous atrophy with calcinosis cutis of the dorsum of the hands and pseudosyndactyly g. Pseudoainhum in the fifth finger (arrow head)	[ "JC Alper, HP Baden, LA Goldsmith. Kindler's syndrome.. Arch Dermatol. 1978;114:457", "GH Ashton, WH McLean, AP South, N Oyama, FJ Smith, R Al-Suwaid, A Al-Ismaily, DJ Atherton, CA Harwood, IM Leigh, C Moss, B Didona, G Zambruno, A Patrizi, RA Eady, JA McGrath. Recurrent mutations in kindlin-1, a novel keratinocyte focal contact protein, in the autosomal recessive skin fragility and photosensitivity disorder, Kindler syndrome.. J Invest Dermatol. 2004;122:78-83", "M Barzegar, Z Asadi-Kani, N Mozafari, H Vahidnezhad, A Kariminejad, P. Toossi. Using immunofluorescence (antigen) mapping in the diagnosis and classification of epidermolysis bullosa: a first report from Iran.. Int J Dermatol. 2015;54:e416-23", "JM Burch, H Fassihi, CA Jones, SC Mengshol, JE Fitzpatrick, JA McGrath. Kindler syndrome: a new mutation and new diagnostic possibilities.. Arch Dermatol. 2006;142:620-4", "HL Almeida, GT Heckler, K Fong, J Lai-Cheong, J McGrath. Sporadic Kindler syndrome with a novel mutation.. An Bras Dermatol. 2013;88:212-5", "PO Emanuel, D Rudikoff, RG Phelps. Aggressive squamous cell carcinoma in Kindler syndrome.. Skinmed. 2006;5:305-7", "JD Fine, L Bruckner-Tuderman, RA Eady, EA Bauer, JW Bauer, C Has, A Heagerty, H Hintner, A Hovnanian, MF Jonkman, I Leigh, MP Marinkovich, AE Martinez, JA McGrath, JE Mellerio, C Moss, DF Murrell, H Shimizu, J Uitto, D Woodley, G Zambruno. Inherited epidermolysis bullosa: updated recommendations on diagnosis and classification.. J Am Acad Dermatol. 2014;70:1103-26", "JD Fine, RA Eady, EA Bauer, JW Bauer, L Bruckner-Tuderman, A Heagerty, H Hintner, A Hovnanian, MF Jonkman, I Leigh, JA McGrath, JE Mellerio, DF Murrell, H Shimizu, J Uitto, A Vahlquist, D Woodley, G Zambruno. The classification of inherited epidermolysis bullosa (EB): report of the Third International Consensus Meeting on Diagnosis and Classification of EB.. J Am Acad Dermatol. 2008;58:931-50", "S Guerrero-Aspizua, CJ Conti, MJ Escamez, D Castiglia, G Zambruno, L Youssefian, H Vahidnezhad, L Requena, P Itin, G Tadini, I Yordanova, L Martin, J Uitto, C Has, M Del Rio. Assessment of the risk and characterization of non-melanoma skin cancer in Kindler syndrome: study of a series of 91 patients.. Orphanet J Rare Dis. 2019;14:183", "C Has, B Burger, A Volz, J Kohlhase, L Bruckner-Tuderman, P Itin. Mild clinical phenotype of Kindler syndrome associated with late diagnosis and skin cancer.. Dermatology. 2010;221:309-12", "C Has, D Castiglia, M del Rio, MG Diez, E Piccinni, D Kiritsi, J Kohlhase, P Itin, L Martin, J Fischer, G Zambruno, L Bruckner-Tuderman. Kindler syndrome: extension of FERMT1 mutational spectrum and natural history.. Hum Mutat. 2011;32:1204-12", "S Hayashi, K Shimoya, S Itami, Y Murata. Pregnancy and delivery with Kindler syndrome.. Gynecol Obstet Invest. 2007;64:72-4", "MM Heidari, M Khatami, S Kargar, M Azari, H Hoseinzadeh, H Fallah. A novel nonsense mutation in exon 5 of KIND1 gene in an Iranian family with Kindler syndrome.. Arch Iran Med. 2016;19:403-8", "F Jobard, B Bouadjar, F Caux, S Hadj-Rabia, C Has, F Matsuda, J Weissenbach, M Lathrop, JF Prud'homme, J Fischer. Identification of mutations in a new gene encoding a FERM family protein with a pleckstrin homology domain in Kindler syndrome.. Hum Mol Genet. 2003;12:925-35", "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", "T. Kindler. Congenital poikiloderma with traumatic bulla formation and progressive cutaneous atrophy.. Br J Dermatol. 1954;66:104-11", "D Kiritsi, Y He, AM Pasmooij, M Onder, R Happle, MF Jonkman, L Bruckner-Tuderman, C Has. Revertant mosaicism in a human skin fragility disorder results from slipped mispairing and mitotic recombination.. J Clin Invest. 2012;122:1742-6", "CV Krishna, NV Parmar, C Has. Kindler syndrome with severe mucosal involvement in childhood.. Clin Exp Dermatol. 2014;39:340-3", "JE Lai-Cheong, JA McGrath. Kindler syndrome.. Dermatol Clin. 2010;28:119-24", "JE Lai-Cheong, A Tanaka, G Hawche, P Emanuel, C Maari, M Taskesen, S Akdeniz, L Liu, JA McGrath. Kindler syndrome: a focal adhesion genodermatosis.. Br J Dermatol. 2009;160:233-42", "CM Lanschuetzer, WH Muss, M Emberger, G Pohla-Gubo, A Klausegger, JW Bauer, H Hintner. Characteristic immunohistochemical and ultrastructural findings indicate that Kindler's syndrome is an apoptotic skin disorder.. J Cutan Pathol. 2003;30:553-60", "H Larjava, EF Plow, C Wu. Kindlins: essential regulators of integrin signalling and cell-matrix adhesion.. EMBO Rep. 2008;9:1203-8", "M Larrègue, F Prigent, G Lorette, C Canuel, P. Ramdenee. Bullous and hereditary Weary-Kindler's acrokeratotic poikiloderma (author's transl). Ann Dermatol Venereol. 1981;108:69-76", "HJ Lee, DH Shin, JS Choi, KH Kim. Hereditary sclerosing poikiloderma.. J Korean Med Sci. 2012;27:225-7", "GJ Lelli. Kindler syndrome causing severe cicatricial ectropion.. Ophthal Plast Reconstr Surg. 2010;26:368-9", "M Lotem, M Raben, R Zeltser, M Landau, M Sela, M Wygoda, ZA Tochner. Kindler syndrome complicated by squamous cell carcinoma of the hard palate: successful treatment with high-dose radiation therapy and granulocyte-macrophage colony-stimulating factor.. Br J Dermatol. 2001;144:1284-6", "K Maier, Y He, PR Esser, K Thriene, D Sarca, J Kohlhase, J Dengjel, L Martin, C Has. Single amino acid deletion in kindlin-1 results in partial protein degradation which can be rescued by chaperone treatment.. J Invest Dermatol. 2016;136:920-9", "AT Mansur, NH Elcioglu, IE Aydingöz, AD Akkaya, ZA Serdar, C Herz, L Bruckner-Tuderman, C Has. Novel and recurrent KIND1 mutations in two patients with Kindler syndrome and severe mucosal involvement.. Acta Derm Venereol. 2007;87:563-5", "BC Martignago, JE Lai-Cheong, L Liu, JA McGrath, TF Cestari. Recurrent KIND1 (C20orf42) gene mutation, c.676insC, in a Brazilian pedigree with Kindler syndrome.. Br J Dermatol. 2007;157:1281-4", "H Penagos, M Jaen, MT Sancho, MR Saborio, VG Fallas, DH Siegel, IJ Frieden. Kindler syndrome in native Americans from Panama: report of 26 cases.. Arch Dermatol. 2004;140:939-44", "T Rayinda, M van Steensel, R Danarti. Inherited skin disorders presenting with poikiloderma.. Int J Dermatol. 2021;60:1343-53", "S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24", "E Rognoni, R Ruppert, R. Fässler. The kindlin family: functions, signaling properties and implications for human disease.. Journal of cell science. 2016;129:17-27", "E Sadler, A Klausegger, W Muss, U Deinsberger, G Pohla-Gubo, M Laimer, C Lanschuetzer, JW Bauer, H Hintner. Novel KIND1 gene mutation in Kindler syndrome with severe gastrointestinal tract involvement.. Arch Dermatol. 2006;142:1619-24", "H Shimizu, M Sato, M Ban, Y Kitajima, S Ishizaki, T Harada, L Bruckner-Tuderman, JD Fine, R Burgeson, A Kon, JA McGrath, AM Christiano, J Uitto, T Nishikawa. Immunohistochemical, ultrastructural, and molecular features of Kindler syndrome distinguish it from dystrophic epidermolysis bullosa.. Arch Dermatol. 1997;133:1111-7", "DH Siegel, GH Ashton, HG Penagos, JV Lee, HS Feiler, KC Wilhelmsen, AP South, FJ Smith, AR Prescott, V Wessagowit, N Oyama, M Akiyama, D Al Aboud, K Al Aboud, A Al Githami, K Al Hawsawi, A Al Ismaily, R Al-Suwaid, DJ Atherton, R Caputo, JD Fine, IJ Frieden, E Fuchs, RM Haber, T Harada, Y Kitajima, SB Mallory, H Ogawa, S Sahin, H Shimizu, Y Suga, G Tadini, K Tsuchiya, CB Wiebe, F Wojnarowska, AB Zaghloul, T Hamada, R Mallipeddi, RA Eady, WH McLean, JA McGrath, EH Epstein. Loss of kindlin-1, a human homolog of the Caenorhabditis elegans actin-extracellular-matrix linker protein UNC-112, causes Kindler syndrome.. Am J Hum Genet. 2003;73:174-87", "I Signes-Soler, JL Rodriguez-Prats, S Carbonell, P Tañá-Rivero. Corneal erosion and Kindler syndrome.. Optom Vis Sci. 2013;90:e9-10", "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 Techanukul, G Sethuraman, A Zlotogorski, L Horev, M Macarov, A Trainer, K Fong, M Lens, L Medenica, V Ramesh, JA McGrath, JE Lai-Cheong. Novel and recurrent FERMT1 gene mutations in Kindler syndrome.. Acta Derm Venereol. 2011;91:267-70", "H Vahidnezhad, L Youssefian, AH Saeidian, LM Boyden, A Touati, N Harvey, M Naji, M Zabihi, M Barzegar, S Sotoudeh, L Liu, A Guy, A Kariminejad, S Zeinali, KA Choate, JA McGrath, J Uitto. Kindler epidermolysis bullosa-like skin phenotype and downregulated basement membrane zone gene expression in poikiloderma with neutropenia and a homozygous USB1 mutation.. Matrix Biol. 2021;99:43-57", "H Vahidnezhad, L Youssefian, AH Saeidian, H Mahmoudi, A Touati, M Abiri, AM Kajbafzadeh, S Aristodemou, L Liu, JA McGrath, A Ertel, E Londin, A Kariminejad, S Zeinali, P Fortina, J Uitto. Recessive mutation in tetraspanin CD151 causes Kindler syndrome-like epidermolysis bullosa with multi-systemic manifestations including nephropathy.. Matrix Biol. 2018;66:22-33", "LE Valinotto, MI Natale, SB Lusso, E Cella, O Gutiérrez, F Sebastiani, GB Manzur. A novel pathogenic FERMT1 variant in four families with Kindler syndrome in Argentina.. Pediatr Dermatol. 2020;37:337-341", "PE Weary, YT Hsu, DR Richardson, CM Caravati, BT Wood. Hereditary sclerosing poikiloderma. Report of two families with an unusual and distinctive genodermatosis.. Arch Dermatol. 1969;100:413-22", "PE Weary, WF Manley, GF Graham. Hereditary acrokeratotic poikiloderma.. Arch Dermatol. 1971;103:409-22", "L Youssefian, H Vahidnezhad, M Barzegar, Q Li, S Sotoudeh, A Yazdanfar, AH Ehsani, AM Kajbafzadeh, N Mozafari, N Ebrahimi Daryani, F Agha-Hosseini, S Zeinali, J Uitto. The Kindler syndrome: a spectrum of FERMT1 mutations in Iranian families.. J Invest Dermatol. 2015;135:1447-50" ]	3/3/2016	6/1/2022	1/12/2016	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
kleefstra	kleefstra	[ "9q34.3 Microdeletion Syndrome", "9qSTDS", "9q Subtelomeric Deletion Syndrome", "9q Subtelomeric Deletion Syndrome", "9qSTDS", "9q34.3 Microdeletion Syndrome", "Histone-lysine N-methyltransferase EHMT1", "EHMT1", "Kleefstra Syndrome" ]	Kleefstra Syndrome	Tjitske Kleefstra, Nicole de Leeuw	Summary Kleefstra syndrome is characterized by intellectual disability, autistic-like features, childhood hypotonia, and distinctive facial features. The majority of individuals function in the moderate-to-severe spectrum of intellectual disability although a few individuals have mild delay and total IQ within low-normal range. While most have severe expressive speech delay with little speech development, general language development is usually at a higher level, making nonverbal communication possible. A complex pattern of other findings can also be observed; these include heart defects, renal/urologic defects, genital defects in males, severe respiratory infections, epilepsy / febrile seizures, psychiatric disorders, and extreme apathy or catatonic-like features after puberty. The diagnosis of Kleefstra syndrome is established in a proband who has a heterozygous deletion at chromosome 9q34.3 that includes at least part of Kleefstra syndrome, caused by a deletion at 9q34.3 or pathogenic variants in	## Diagnosis Kleefstra syndrome is characterized by intellectual disability, childhood hypotonia, and distinctive facial features. A complex pattern of other findings can also be observed [ Kleefstra syndrome Intellectual disability, usually moderate to severe and associated with severe speech delay Distinctive facial features (See Childhood hypotonia Visual issues (hypermetropia) Hearing loss (sensorineural and/or conductive) Motor delay Heart defects Renal/urologic defects Genital defects (males) Severe infections (respiratory) Epilepsy / febrile seizures Autism spectrum disorder Psychiatric disorders (mood and psychotic disorders) Extreme apathy or catatonic(-like) features post puberty Nonspecific brain abnormalities: structural defects (corpus callosum hypoplasia), cortical hypoplasia, or white matter defects The diagnosis of Kleefstra syndrome A heterozygous deletion of 9q34.3 (~50% of affected individuals) [Author, personal experience]. In 28 unrelated individuals with a 9q34.3 deletion, three distinct categories were identified [ 50% bona fide 25% interstitial deletions 25% complex rearrangements or derivative chromosomes A heterozygous pathogenic (or likely pathogenic) variant involving 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 [ When the phenotypic findings suggest the diagnosis of Kleefstra syndrome, molecular genetic testing approaches can include Approximately 5% of individuals with Kleefstra syndrome have an intragenic deletion detectable by an assay designed to detect single-exon deletions or duplications (e.g., multiplex ligation-dependent probe amplification [MLPA], qPCR, and gene-targeted CMA). Deletions that are not intragenic but too small to be detected by CMA (e.g., containing the last part of Note: (1) FISH cannot reliably detect deletions <50-100 kb and cannot routinely size the deletion. (2) The 9q34.3 deletion cannot be identified by routine chromosome analysis. For an introduction to multigene panels click The epigenetic signature results should not be interpreted in isolation, as sensitivity and specificity are not 100%; these results only provide part of the evidence used in variant interpretation [ Molecular Genetic Testing Used in Kleefstra Syndrome See See A chromosomal microarray (CMA) that includes probe coverage of CMA testing is appropriate to define breakpoints of large deletions; however, intragenic deletions in Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and 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 methods will detect single-exon up to whole-gene deletions; however, breakpoints of large deletions and/or deletion of adjacent genes may not be determined. Gene-targeted deletion/duplication analysis of Routine karyotype will not detect the 9q34.3 deletion. Karyotype may be considered in those with features of Kleefstra syndrome in whom a pathogenic variant (mutation or deletion) of • Intellectual disability, usually moderate to severe and associated with severe speech delay • Distinctive facial features (See • Childhood hypotonia • Visual issues (hypermetropia) • Hearing loss (sensorineural and/or conductive) • Motor delay • Heart defects • Renal/urologic defects • Genital defects (males) • Severe infections (respiratory) • Epilepsy / febrile seizures • Autism spectrum disorder • Psychiatric disorders (mood and psychotic disorders) • Extreme apathy or catatonic(-like) features post puberty • Nonspecific brain abnormalities: structural defects (corpus callosum hypoplasia), cortical hypoplasia, or white matter defects • A heterozygous deletion of 9q34.3 (~50% of affected individuals) [Author, personal experience]. In 28 unrelated individuals with a 9q34.3 deletion, three distinct categories were identified [ • 50% bona fide • 25% interstitial deletions • 25% complex rearrangements or derivative chromosomes • 50% bona fide • 25% interstitial deletions • 25% complex rearrangements or derivative chromosomes • A heterozygous pathogenic (or likely pathogenic) variant involving • 50% bona fide • 25% interstitial deletions • 25% complex rearrangements or derivative chromosomes • Approximately 5% of individuals with Kleefstra syndrome have an intragenic deletion detectable by an assay designed to detect single-exon deletions or duplications (e.g., multiplex ligation-dependent probe amplification [MLPA], qPCR, and gene-targeted CMA). Deletions that are not intragenic but too small to be detected by CMA (e.g., containing the last part of • Note: (1) FISH cannot reliably detect deletions <50-100 kb and cannot routinely size the deletion. (2) The 9q34.3 deletion cannot be identified by routine chromosome analysis. • For an introduction to multigene panels click • The epigenetic signature results should not be interpreted in isolation, as sensitivity and specificity are not 100%; these results only provide part of the evidence used in variant interpretation [ ## Suggestive Findings Kleefstra syndrome Intellectual disability, usually moderate to severe and associated with severe speech delay Distinctive facial features (See Childhood hypotonia Visual issues (hypermetropia) Hearing loss (sensorineural and/or conductive) Motor delay Heart defects Renal/urologic defects Genital defects (males) Severe infections (respiratory) Epilepsy / febrile seizures Autism spectrum disorder Psychiatric disorders (mood and psychotic disorders) Extreme apathy or catatonic(-like) features post puberty Nonspecific brain abnormalities: structural defects (corpus callosum hypoplasia), cortical hypoplasia, or white matter defects • Intellectual disability, usually moderate to severe and associated with severe speech delay • Distinctive facial features (See • Childhood hypotonia • Visual issues (hypermetropia) • Hearing loss (sensorineural and/or conductive) • Motor delay • Heart defects • Renal/urologic defects • Genital defects (males) • Severe infections (respiratory) • Epilepsy / febrile seizures • Autism spectrum disorder • Psychiatric disorders (mood and psychotic disorders) • Extreme apathy or catatonic(-like) features post puberty • Nonspecific brain abnormalities: structural defects (corpus callosum hypoplasia), cortical hypoplasia, or white matter defects ## Establishing the Diagnosis The diagnosis of Kleefstra syndrome A heterozygous deletion of 9q34.3 (~50% of affected individuals) [Author, personal experience]. In 28 unrelated individuals with a 9q34.3 deletion, three distinct categories were identified [ 50% bona fide 25% interstitial deletions 25% complex rearrangements or derivative chromosomes A heterozygous pathogenic (or likely pathogenic) variant involving 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 [ When the phenotypic findings suggest the diagnosis of Kleefstra syndrome, molecular genetic testing approaches can include Approximately 5% of individuals with Kleefstra syndrome have an intragenic deletion detectable by an assay designed to detect single-exon deletions or duplications (e.g., multiplex ligation-dependent probe amplification [MLPA], qPCR, and gene-targeted CMA). Deletions that are not intragenic but too small to be detected by CMA (e.g., containing the last part of Note: (1) FISH cannot reliably detect deletions <50-100 kb and cannot routinely size the deletion. (2) The 9q34.3 deletion cannot be identified by routine chromosome analysis. For an introduction to multigene panels click The epigenetic signature results should not be interpreted in isolation, as sensitivity and specificity are not 100%; these results only provide part of the evidence used in variant interpretation [ Molecular Genetic Testing Used in Kleefstra Syndrome See See A chromosomal microarray (CMA) that includes probe coverage of CMA testing is appropriate to define breakpoints of large deletions; however, intragenic deletions in Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and 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 methods will detect single-exon up to whole-gene deletions; however, breakpoints of large deletions and/or deletion of adjacent genes may not be determined. Gene-targeted deletion/duplication analysis of Routine karyotype will not detect the 9q34.3 deletion. Karyotype may be considered in those with features of Kleefstra syndrome in whom a pathogenic variant (mutation or deletion) of • A heterozygous deletion of 9q34.3 (~50% of affected individuals) [Author, personal experience]. In 28 unrelated individuals with a 9q34.3 deletion, three distinct categories were identified [ • 50% bona fide • 25% interstitial deletions • 25% complex rearrangements or derivative chromosomes • 50% bona fide • 25% interstitial deletions • 25% complex rearrangements or derivative chromosomes • A heterozygous pathogenic (or likely pathogenic) variant involving • 50% bona fide • 25% interstitial deletions • 25% complex rearrangements or derivative chromosomes • Approximately 5% of individuals with Kleefstra syndrome have an intragenic deletion detectable by an assay designed to detect single-exon deletions or duplications (e.g., multiplex ligation-dependent probe amplification [MLPA], qPCR, and gene-targeted CMA). Deletions that are not intragenic but too small to be detected by CMA (e.g., containing the last part of • Note: (1) FISH cannot reliably detect deletions <50-100 kb and cannot routinely size the deletion. (2) The 9q34.3 deletion cannot be identified by routine chromosome analysis. • For an introduction to multigene panels click • The epigenetic signature results should not be interpreted in isolation, as sensitivity and specificity are not 100%; these results only provide part of the evidence used in variant interpretation [ ## Clinical Characteristics Kleefstra syndrome has a clinically recognizable phenotype that includes physical, developmental, and behavioral features. Males and females are affected equally [ Birth weight is usually within the normal or above-normal range; weight increases in childhood, leading to obesity (50%) [ With age, the facial appearance becomes coarser, with persisting midface retrusion and prognathism. An increased frequency of dental anomalies, specifically neonatal teeth and retention of primary dentition, has been observed. Sleep disturbance is characterized by frequent nocturnal and early-morning awakenings as well as excessive daytime wakefulness – in contrast to the sleep disturbance observed in Sleep disturbance in affected adolescents and young adults may be a precursor to severe regression, as well as the later development of psychoses, for which treatment is recommended. The disorder was first recognized following widespread subtelomeric FISH studies [ Based on incidence estimates of • Sleep disturbance is characterized by frequent nocturnal and early-morning awakenings as well as excessive daytime wakefulness – in contrast to the sleep disturbance observed in • Sleep disturbance in affected adolescents and young adults may be a precursor to severe regression, as well as the later development of psychoses, for which treatment is recommended. ## Clinical Description Kleefstra syndrome has a clinically recognizable phenotype that includes physical, developmental, and behavioral features. Males and females are affected equally [ Birth weight is usually within the normal or above-normal range; weight increases in childhood, leading to obesity (50%) [ With age, the facial appearance becomes coarser, with persisting midface retrusion and prognathism. An increased frequency of dental anomalies, specifically neonatal teeth and retention of primary dentition, has been observed. Sleep disturbance is characterized by frequent nocturnal and early-morning awakenings as well as excessive daytime wakefulness – in contrast to the sleep disturbance observed in Sleep disturbance in affected adolescents and young adults may be a precursor to severe regression, as well as the later development of psychoses, for which treatment is recommended. • Sleep disturbance is characterized by frequent nocturnal and early-morning awakenings as well as excessive daytime wakefulness – in contrast to the sleep disturbance observed in • Sleep disturbance in affected adolescents and young adults may be a precursor to severe regression, as well as the later development of psychoses, for which treatment is recommended. ## Genotype-Phenotype Correlations ## Nomenclature The disorder was first recognized following widespread subtelomeric FISH studies [ ## Prevalence Based on incidence estimates of ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Kleefstra syndrome should be distinguished from other syndromes that include developmental delay, infantile hypotonia, short stature, distinctive facies, and a behavioral phenotype. The most common of these include those in Disorders to Consider in the Differential Diagnosis of Kleefstra Syndrome Brachycephaly Protruding tongue Hypotonia Hypertelorism Midface retrusion Lethargy Sleep disturbance Midface retrusion Speech is significantly delayed & most persons are nonverbal w/receptive language often stronger than expressive language. Seizures Sleep disturbance Receptive language better than expressive language skills Sleep disturbances w/multiple awakenings Midface retrusion w/prognathism See footnote 3 for distinguishing clinical features. Currently under study to determine overlap ASD & ID ASD & ID Seizures Developmental regression AD = autosomal dominant; ASD = autism spectrum disorder; ID = intellectual disability; MOI = mode of inheritance Approximately 95% of individuals with Smith-Magenis syndrome have the disorder as a result of an interstitial 17p11.2 deletion, which may have been previously excluded by chromosomal microarray testing. The risk to sibs of a proband depends on the genetic mechanism leading to the loss of UBE3A function. Facial features that differentiate Kleefstra syndrome from Angelman syndrome include synophrys and everted vermilion of the lower lip. Some mildly affected individuals with Kleefstra syndrome have a ≥100-word vocabulary & speak in sentences, which would be very unusual in an individual with Angelman syndrome. The diagnosis of • Brachycephaly • Protruding tongue • Hypotonia • Hypertelorism • Midface retrusion • Lethargy • Sleep disturbance • Midface retrusion • Speech is significantly delayed & most persons are nonverbal w/receptive language often stronger than expressive language. • Seizures • Sleep disturbance • Receptive language better than expressive language skills • Sleep disturbances w/multiple awakenings • Midface retrusion w/prognathism • See footnote 3 for distinguishing clinical features. • Currently under study to determine overlap • ASD & ID • ASD & ID • Seizures • Developmental regression ## Management To establish the extent of disease and needs in an individual diagnosed with Kleefstra syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Kleefstra Syndrome ASD = autism spectrum disorder Treatment is primarily supportive. Ongoing routine pediatric care by a pediatrician or neurologist, psychiatrist, and/or (for adults) specialist in the care of adults with intellectual disability is recommended. Treatment of Manifestations in Individuals with Kleefstra Syndrome ASM = anti-seizure medication Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. In the US: Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, 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. Specialized neurologic and psychiatric care is advised for individuals with extreme behavior issues and/or movement disorder. Behavioral therapies include special education techniques that may help minimize behavioral outbursts in the school setting by emphasizing individualized instruction, structure, and a set daily routine. Cardiac and renal/urologic abnormalities should be monitored as needed. See Search • In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. • Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • 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 Kleefstra syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Kleefstra Syndrome ASD = autism spectrum disorder ## Treatment of Manifestations Treatment is primarily supportive. Ongoing routine pediatric care by a pediatrician or neurologist, psychiatrist, and/or (for adults) specialist in the care of adults with intellectual disability is recommended. Treatment of Manifestations in Individuals with Kleefstra Syndrome ASM = anti-seizure medication Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. In the US: Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, 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. Specialized neurologic and psychiatric care is advised for individuals with extreme behavior issues and/or movement disorder. Behavioral therapies include special education techniques that may help minimize behavioral outbursts in the school setting by emphasizing individualized instruction, structure, and a set daily routine. • In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. • Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • 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, scoliosis, hip dislocation). 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, scoliosis, hip dislocation). • 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 ## 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. Specialized neurologic and psychiatric care is advised for individuals with extreme behavior issues and/or movement disorder. Behavioral therapies include special education techniques that may help minimize behavioral outbursts in the school setting by emphasizing individualized instruction, structure, and a set daily routine. ## Surveillance Cardiac and renal/urologic abnormalities should be monitored as needed. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Kleefstra syndrome, caused by a deletion at 9q34.3 or an intragenic 9q34.3 deletion is usually To date, no parent-to-child transmission of an unbalanced derivative chromosome involving the 9q34.3 region has been observed. Recurrence in families with a parent having a balanced translocation involving the 9q34.3 region has been described [ To date, all interstitial 9q34.3 deletions detected are Recommendations for the evaluation of asymptomatic parents of a proband with a 9q34.3 deletion include routine karyotyping with additional FISH analysis to determine if a balanced chromosome rearrangement involving the 9q34.3 region is present. The risk to the sibs of the proband depends on the genetic status of the parents. In the (unlikely) event that a parent has either germline mosaicism for a 9q34.3 deletion, low-level somatic mosaicism that includes the germline, or a balanced structural chromosome rearrangement involving the 9q34.3 region, the risk to sibs is increased. The estimated risk depends on the specific chromosome rearrangement. To date, five individuals diagnosed with a mosaic 9q34.3 deletion have been known to reproduce [ Individuals who have the 9q34.3 deletion would be expected to have a 50% chance of transmitting the deletion to each child. In the vast majority of cases, To date, only one parent of an individual with an Molecular genetic testing is recommended for the parents of a proband with an apparent If the The risk to the sibs of the proband depends on the genetic status of the parents. In the (unlikely) event that a parent has germline mosaicism or low-level somatic mosaicism for an No individual with a non-mosaic Individuals who have a non-mosaic The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who may be at risk of having a child with Kleefstra syndrome. Prenatal testing for at-risk pregnancies and preimplantation genetic testing require prior identification of the 9q34.3 deletion or an • To date, no parent-to-child transmission of an unbalanced derivative chromosome involving the 9q34.3 region has been observed. • Recurrence in families with a parent having a balanced translocation involving the 9q34.3 region has been described [ • To date, all interstitial 9q34.3 deletions detected are • Recommendations for the evaluation of asymptomatic parents of a proband with a 9q34.3 deletion include routine karyotyping with additional FISH analysis to determine if a balanced chromosome rearrangement involving the 9q34.3 region is present. • The risk to the sibs of the proband depends on the genetic status of the parents. • In the (unlikely) event that a parent has either germline mosaicism for a 9q34.3 deletion, low-level somatic mosaicism that includes the germline, or a balanced structural chromosome rearrangement involving the 9q34.3 region, the risk to sibs is increased. The estimated risk depends on the specific chromosome rearrangement. • To date, five individuals diagnosed with a mosaic 9q34.3 deletion have been known to reproduce [ • Individuals who have the 9q34.3 deletion would be expected to have a 50% chance of transmitting the deletion to each child. • In the vast majority of cases, • To date, only one parent of an individual with an • Molecular genetic testing is recommended for the parents of a proband with an apparent • If the • The risk to the sibs of the proband depends on the genetic status of the parents. • In the (unlikely) event that a parent has germline mosaicism or low-level somatic mosaicism for an • No individual with a non-mosaic • Individuals who have a non-mosaic • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who may be at risk of having a child with Kleefstra syndrome. ## Mode of Inheritance Kleefstra syndrome, caused by a deletion at 9q34.3 or an intragenic ## Risk to Family Members 9q34.3 deletion is usually To date, no parent-to-child transmission of an unbalanced derivative chromosome involving the 9q34.3 region has been observed. Recurrence in families with a parent having a balanced translocation involving the 9q34.3 region has been described [ To date, all interstitial 9q34.3 deletions detected are Recommendations for the evaluation of asymptomatic parents of a proband with a 9q34.3 deletion include routine karyotyping with additional FISH analysis to determine if a balanced chromosome rearrangement involving the 9q34.3 region is present. The risk to the sibs of the proband depends on the genetic status of the parents. In the (unlikely) event that a parent has either germline mosaicism for a 9q34.3 deletion, low-level somatic mosaicism that includes the germline, or a balanced structural chromosome rearrangement involving the 9q34.3 region, the risk to sibs is increased. The estimated risk depends on the specific chromosome rearrangement. To date, five individuals diagnosed with a mosaic 9q34.3 deletion have been known to reproduce [ Individuals who have the 9q34.3 deletion would be expected to have a 50% chance of transmitting the deletion to each child. In the vast majority of cases, To date, only one parent of an individual with an Molecular genetic testing is recommended for the parents of a proband with an apparent If the The risk to the sibs of the proband depends on the genetic status of the parents. In the (unlikely) event that a parent has germline mosaicism or low-level somatic mosaicism for an No individual with a non-mosaic Individuals who have a non-mosaic • To date, no parent-to-child transmission of an unbalanced derivative chromosome involving the 9q34.3 region has been observed. • Recurrence in families with a parent having a balanced translocation involving the 9q34.3 region has been described [ • To date, all interstitial 9q34.3 deletions detected are • Recommendations for the evaluation of asymptomatic parents of a proband with a 9q34.3 deletion include routine karyotyping with additional FISH analysis to determine if a balanced chromosome rearrangement involving the 9q34.3 region is present. • The risk to the sibs of the proband depends on the genetic status of the parents. • In the (unlikely) event that a parent has either germline mosaicism for a 9q34.3 deletion, low-level somatic mosaicism that includes the germline, or a balanced structural chromosome rearrangement involving the 9q34.3 region, the risk to sibs is increased. The estimated risk depends on the specific chromosome rearrangement. • To date, five individuals diagnosed with a mosaic 9q34.3 deletion have been known to reproduce [ • Individuals who have the 9q34.3 deletion would be expected to have a 50% chance of transmitting the deletion to each child. • In the vast majority of cases, • To date, only one parent of an individual with an • Molecular genetic testing is recommended for the parents of a proband with an apparent • If the • The risk to the sibs of the proband depends on the genetic status of the parents. • In the (unlikely) event that a parent has germline mosaicism or low-level somatic mosaicism for an • No individual with a non-mosaic • Individuals who have a non-mosaic ## 9q34.3 Deletion 9q34.3 deletion is usually To date, no parent-to-child transmission of an unbalanced derivative chromosome involving the 9q34.3 region has been observed. Recurrence in families with a parent having a balanced translocation involving the 9q34.3 region has been described [ To date, all interstitial 9q34.3 deletions detected are Recommendations for the evaluation of asymptomatic parents of a proband with a 9q34.3 deletion include routine karyotyping with additional FISH analysis to determine if a balanced chromosome rearrangement involving the 9q34.3 region is present. The risk to the sibs of the proband depends on the genetic status of the parents. In the (unlikely) event that a parent has either germline mosaicism for a 9q34.3 deletion, low-level somatic mosaicism that includes the germline, or a balanced structural chromosome rearrangement involving the 9q34.3 region, the risk to sibs is increased. The estimated risk depends on the specific chromosome rearrangement. To date, five individuals diagnosed with a mosaic 9q34.3 deletion have been known to reproduce [ Individuals who have the 9q34.3 deletion would be expected to have a 50% chance of transmitting the deletion to each child. • To date, no parent-to-child transmission of an unbalanced derivative chromosome involving the 9q34.3 region has been observed. • Recurrence in families with a parent having a balanced translocation involving the 9q34.3 region has been described [ • To date, all interstitial 9q34.3 deletions detected are • Recommendations for the evaluation of asymptomatic parents of a proband with a 9q34.3 deletion include routine karyotyping with additional FISH analysis to determine if a balanced chromosome rearrangement involving the 9q34.3 region is present. • The risk to the sibs of the proband depends on the genetic status of the parents. • In the (unlikely) event that a parent has either germline mosaicism for a 9q34.3 deletion, low-level somatic mosaicism that includes the germline, or a balanced structural chromosome rearrangement involving the 9q34.3 region, the risk to sibs is increased. The estimated risk depends on the specific chromosome rearrangement. • To date, five individuals diagnosed with a mosaic 9q34.3 deletion have been known to reproduce [ • Individuals who have the 9q34.3 deletion would be expected to have a 50% chance of transmitting the deletion to each child. In the vast majority of cases, To date, only one parent of an individual with an Molecular genetic testing is recommended for the parents of a proband with an apparent If the The risk to the sibs of the proband depends on the genetic status of the parents. In the (unlikely) event that a parent has germline mosaicism or low-level somatic mosaicism for an No individual with a non-mosaic Individuals who have a non-mosaic • In the vast majority of cases, • To date, only one parent of an individual with an • Molecular genetic testing is recommended for the parents of a proband with an apparent • If the • The risk to the sibs of the proband depends on the genetic status of the parents. • In the (unlikely) event that a parent has germline mosaicism or low-level somatic mosaicism for an • No individual with a non-mosaic • Individuals who have a non-mosaic ## 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 may be at risk of having a child with Kleefstra syndrome. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who may be at risk of having a child with Kleefstra syndrome. ## Prenatal Testing and Preimplantation Genetic Testing Prenatal testing for at-risk pregnancies and preimplantation genetic testing require prior identification of the 9q34.3 deletion or an ## Resources United Kingdom • • • • United Kingdom • ## Molecular Genetics Kleefstra Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Kleefstra Syndrome ( ## Chapter Notes Nicole de Leeuw, PhD (2019-present)Tjitske Kleefstra, MD, PhD (2010-present)Willy M Nillesen, BSc; Radboud University Medical Center (2010-2019)Helger G Yntema, PhD; Radboud University Medical Center (2010-2019) 26 January 2023 (tk) Revision: 13 October 2022 (sw) Revision: epigenetic signature analysis ( 21 March 2019 (ma) Comprehensive update posted live 7 May 2015 (me) Comprehensive update posted live 5 October 2010 (me) Review posted live 28 May 2010 (tk) Original submission • 26 January 2023 (tk) Revision: • 13 October 2022 (sw) Revision: epigenetic signature analysis ( • 21 March 2019 (ma) Comprehensive update posted live • 7 May 2015 (me) Comprehensive update posted live • 5 October 2010 (me) Review posted live • 28 May 2010 (tk) Original submission ## Author History Nicole de Leeuw, PhD (2019-present)Tjitske Kleefstra, MD, PhD (2010-present)Willy M Nillesen, BSc; Radboud University Medical Center (2010-2019)Helger G Yntema, PhD; Radboud University Medical Center (2010-2019) ## Revision History 26 January 2023 (tk) Revision: 13 October 2022 (sw) Revision: epigenetic signature analysis ( 21 March 2019 (ma) Comprehensive update posted live 7 May 2015 (me) Comprehensive update posted live 5 October 2010 (me) Review posted live 28 May 2010 (tk) Original submission • 26 January 2023 (tk) Revision: • 13 October 2022 (sw) Revision: epigenetic signature analysis ( • 21 March 2019 (ma) Comprehensive update posted live • 7 May 2015 (me) Comprehensive update posted live • 5 October 2010 (me) Review posted live • 28 May 2010 (tk) Original submission ## References ## Literature Cited Photographs of affected individuals showing the characteristic facial profile comprising brachycephaly, widely spaced eyes, synophrys/arched eyebrows, midface retrusion, protruding tongue, eversion of the vermilion of the lower lip, and prognathism of chin. Five people (AB), (CD), (EF), (GH), and (IJ) with EHMT1 pathogenic variants are shown Reproduced from Photographs of affected individuals showing the characteristic facial profile comprising brachycephaly, widely spaced eyes, synophrys/arched eyebrows, midface retrusion, protruding tongue, eversion of the vermilion of the lower lip, and prognathism of the chin. Three different people (rows A, B, and C) with interstitial 9q34.3 microdeletions at different ages show evolution with age. Reproduced from	[ "E Aref-Eshghi, J Kerkhof, VP Pedro, DI Groupe. France, Barat-Houari M, Ruiz-Pallares N, Andrau JC, Lacombe D, Van-Gils J, Fergelot P, Dubourg C, Cormier-Daire V, Rondeau S, Lecoquierre F, Saugier-Veber P, Nicolas G, Lesca G, Chatron N, Sanlaville D, Vitobello A, Faivre L, Thauvin-Robinet C, Laumonnier F, Raynaud M, Alders M, Mannens M, Henneman P, Hennekam RC, Velasco G, Francastel C, Ulveling D, Ciolfi A, Pizzi S, Tartaglia M, Heide S, Héron D, Mignot C, Keren B, Whalen S, Afenjar A, Bienvenu T, Campeau PM, Rousseau J, Levy MA, Brick L, Kozenko M, Balci TB, Siu VM, Stuart A, Kadour M, Masters J, Takano K, Kleefstra T, de Leeuw N, Field M, Shaw M, Gecz J, Ainsworth PJ, Lin H, Rodenhiser DI, Friez MJ, Tedder M, Lee JA, DuPont BR, Stevenson RE, Skinner SA, Schwartz CE, Genevieve D, Sadikovic B. Evaluation of dna methylation episignatures for diagnosis and phenotype correlations in 42 mendelian neurodevelopmental disorders.. Am J Hum Genet. 2020;106:356-70", "J Ausió, DB Levin, GV de Amorim, S Bakker, PM MacLeod. Syndromes of disordered chromatin remodeling.. Clin Genet 2003;64:83-95", "I Bock, K Németh, K Pentelényi, P Balicza, A Balázs, MJ Molnár, V Román, J Nagy, G Lévay, J Kobolák, A Dinnyés. Targeted next generation sequencing of a panel of autism-related genes identifies an EHMT1 mutation in a Kleefstra syndrome patient with autism and normal intellectual performance.. Gene. 2016;595:131-41", "SE Brnich, AN Abou Tayoun, FJ Couch, GR Cutting, MS Greenblatt, CD Heinen, DM Kanavy, X Luo, SM McNulty, LM Starita, SV Tavtigian, MW Wright, SM Harrison, LG Biesecker, JS Berg. Recommendations for application of the functional evidence PS3/BS3 criterion using the ACMG/AMP sequence variant interpretation framework.. Genome Med. 2019;12:3", "V Cormier-Daire, F Molinari, M Rio, O Raoul, MC de Blois, S Romana, M Vekemans, A Munnich, L Colleaux. Cryptic terminal deletion of chromosome 9q34: a novel cause of syndromic obesity in childhood?. J Med Genet. 2003;40:300-3", "AJ Dawson, S Putnam, J Schultz, D Riordan, C Prasad, CR Greenberg, BN Chodirker, AA Mhanni, AE Chudley. Cryptic chromosome rearrangements detected by subtelomere assay in patients with mental retardation and dysmorphic features.. Clin Genet 2002;62:488-94", "A de Boer, K Vermeulen, JIM Egger, JGE Janzing, N de Leeuw, HE Veenstra-Knol, NS den Hollander, H van Bokhoven, W Staal, T Kleefstra. Mol Autism. 2018;9:5", "SJ Goodman, CL Burton, DT Butcher, MT Siu, M Lemire, E Chater-Diehl, AL Turinsky, M Brudno, N Soreni, D Rosenberg, KD Fitzgerald, GL Hanna, E Anagnostou, PD Arnold, J Crosbie, R Schachar, R Weksberg. Obsessive-compulsive disorder and attention-deficit/hyperactivity disorder: distinct associations with DNA methylation and genetic variation.. J Neurodev Disord. 2020;12:23", "S Guterman, B Hervé, J Rivière, D Fauvert, P Clement, F Vialard. First prenatal diagnosis of a 'pure' 9q34.3 deletion (Kleefstra syndrome): a case report and literature review.. J Obstet Gynaecol Res. 2018;44:570-5", "T Kleefstra, HG Brunner, J Amiel, AR Oudakker, WM Nillesen, A Magee, D Geneviève, V Cormier-Daire, H van Esch, JP Fryns, BC Hamel, EA Sistermans, BB de Vries, H van Bokhoven. Loss-of-function mutations in euchromatin histone methyl transferase 1 (EHMT1) cause the 9q34 subtelomeric deletion syndrome.. Am J Hum Genet. 2006a;79:370-7", "T Kleefstra, DA Koolen, WM Nillesen, N de Leeuw, BC Hamel, JA Veltman, EA Sistermans, H van Bokhoven, C van Ravenswaay, BB de Vries. Interstitial 2.2 Mb deletion at 9q34 in a patient with mental retardation but without classical features of the 9q subtelomeric deletion syndrome.. Am J Med Genet A. 2006b;140:618-23", "T Kleefstra, M Smidt, MJ Banning, AR Oudakker, H Van Esch, AP de Brouwer, W Nillesen, EA Sistermans, BC Hamel, D de Bruijn. Disruption of the gene euchromatin histone methyl transferase1 (Eu-HMTase1) is associated with the 9q34 subtelomeric deletion syndrome.. J Med Genet 2005;42:299-306", "T Kleefstra, WA van Zelst-Stams, WM Nillesen, V Cormier-Daire, G Houge, N Foulds, M van Dooren, MH Willemsen, R Pfundt, A Turner, M Wilson, J McGaughran, A Rauch, M Zenker, MP Adam, M Innes, C Davies, AG López, R Casalone, A Weber, LA Brueton, AD Navarro, MP Bralo, H Venselaar, SP Stegmann, HG Yntema, H van Bokhoven, HG Brunner. Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype.. J Med Genet. 2009;46:598-606", "SJ Knight, R Regan, A Nicod, SW Horsley, L Kearney, T Homfray, RM Winter, P Bolton, J Flint. Subtle chromosomal rearrangements in children with unexplained mental retardation.. Lancet 1999;354:1676-81", "TS Koemans, T Kleefstra, MC Chubak, MH Stone, MRF Reijnders, S de Munnik, MH Willemsen, M Fenckova, CTRM Stumpel, LA Bok, M Sifuentes Saenz, KA Byerly, LB Baughn, APA Stegmann, R Pfundt, H Zhou, H van Bokhoven, A Schenck, JM Kramer. Functional convergence of histone methyltransferases EHMT1 and KMT2C involved in intellectual disability and autism spectrum disorder.. PLoS Genet. 2017;13", "MA Levy, H McConkey, J Kerkhof, M Barat-Houari, S Bargiacchi, E Biamino, MP Bralo, G Cappuccio, A Ciolfi, A Clarke, BR DuPont, MW Elting, L Faivre, T Fee, RS Fletcher, F Cherik, A Foroutan, MJ Friez, C Gervasini, S Haghshenas, BA Hilton, Z Jenkins, S Kaur, S Lewis, RJ Louie, S Maitz, D Milani, AT Morgan, R Oegema, E Østergaard, NR Pallares, M Piccione, S Pizzi, AS Plomp, C Poulton, J Reilly, R Relator, R Rius, S Robertson, K Rooney, J Rousseau, GWE Santen, F Santos-Simarro, J Schijns, GM Squeo, M St John, C Thauvin-Robinet, G Traficante, PJ van der Sluijs, SA Vergano, N Vos, KK Walden, D Azmanov, T Balci, S Banka, J Gecz, P Henneman, JA Lee, MMAM Mannens, T Roscioli, V Siu, DJ Amor, G Baynam, EG Bend, K Boycott, N Brunetti-Pierri, PM Campeau, J Christodoulou, D Dyment, N Esber, JA Fahrner, MD Fleming, D Genevieve, KD Kerrnohan, A McNeill, LA Menke, G Merla, P Prontera, C Rockman-Greenberg, C Schwartz, SA Skinner, RE Stevenson, A Vitobello, M Tartaglia, M Alders, ML Tedder, B Sadikovic. Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of mendelian disorders.. HGG Adv. 2021;3", "JA López-Rivera, E Pérez-Palma, J Symonds, AS Lindy, DA McKnight, C Leu, S Zuberi, A Brunklaus, RS Møller, D Lal. A catalogue of new incidence estimates of monogenic neurodevelopmental disorders caused by de novo variants.. Brain. 2020;143:1099-105", "C Martin, Y Zhang. The diverse functions of histone lysine methylation.. Nat Rev Mol Cell Biol. 2005;6:838-49", "JF McRae, S Clayton, TW Fitzgerald, J Kaplanis, E Prigmore, D Rajan, A Sifrim, S Aitken, N Akawi, M Alvi. Prevalence and architecture of de novo mutations in developmental disorders.. Nature. 2017;542:433-8", "S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24", "A Rump, L Hildebrand, A Tzschach, R Ullmann, E Schrock, D. Mitter. A mosaic maternal splice donor mutation in the EHMT1 gene leads to aberrant transcripts and to Kleefstra syndrome in the offspring.. Eur J Hum Genet. 2013;21:887-90", "DR Stewart, A Huang, F Faravelli, BM Anderlid, L Medne, K Ciprero, M Kaur, E Rossi, R Tenconi, M Nordenskjöld, KW Gripp, L Nicholson, WS Meschino, E Capua, OW Quarrell, J Flint, M Irons, PF Giampietro, DB Schowalter, CA Zaleski, M Malacarne, EH Zackai, NB Spinner, ID Krantz. Subtelomeric deletions of chromosome 9q: a novel microdeletion syndrome.. Am J Med Genet A. 2004;128A:340-51", "DR Stewart, T Kleefstra. The chromosome 9q subtelomere deletion syndrome.. Am J Med Genet C Semin Med Genet. 2007;145C:383-92", "WM Verhoeven, T Kleefstra, JI Egger. Behavioral phenotype in the 9q subtelomeric deletion syndrome: a report about two adult patients.. Am J Med Genet B Neuropsychiatr Genet 2010;153B:536-41", "K Vermeulen, A de Boer, JGE Janzing, DA Koolen, CW Ockeloen, MH Willemsen, FM Verhoef, PAM van Deurzen, L van Dongen, H van Bokhoven, JIM Egger, WG Staal, T Kleefstra. Adaptive and maladaptive functioning in Kleefstra syndrome compared to other rare genetic disorders with intellectual disabilities.. Am J Med Genet A. 2017a;173:1821-30", "K Vermeulen, WG Staal, JG Janzing, H van Bokhoven, JIM Egger, T Kleefstra. Sleep disturbance as a precursor of severe regression in Kleefstra syndrome suggests a need for firm and rapid pharmacological treatment.. Clin Neuropharmacol. 2017b;40:185-8", "MH Willemsen, G Beunders, M Callaghan, N de Leeuw, WM Nillesen, HG Yntema, JM van Hagen, AW Nieuwint, N Morrison, ST Keijzers-Vloet, A Hoischen, HG Brunner, J Tolmie, T Kleefstra. Familial Kleefstra syndrome due to maternal somatic mosaicism for interstitial 9q34.3 microdeletions.. Clin Genet. 2011;80:31-8", "MH Willemsen, AT Vulto-van Silfhout, WM Nillesen, WM Wissink-Lindhout, H van Bokhoven, N Philip, EM Berry-Kravis, U Kini, CM van Ravenswaaij-Arts, B Delle Chiaie, AM Innes, G Houge, T Kosonen, K Cremer, M Fannemel, A Stray-Pedersen, W Reardon, J Ignatius, K Lachlan, C Mircher, PT Helderman van den Enden, M Mastebroek, PE Cohn-Hokke, HG Yntema, S Drunat, T Kleefstra. Update on Kleefstra syndrome.. Mol Syndromol. 2012;2:202-12", "SA Yatsenko, EK Brundage, EK Roney, SW Cheung, AC Chinault, JR Lupski. Molecular mechanisms for subtelomeric rearrangements associated with the 9q34.3 microdeletion syndrome.. Hum Mol Genet 2009;18:1924-36", "SA Yatsenko, SW Cheung, DA Scott, MJ Nowaczyk, M Tarnopolsky, S Naidu, G Bibat, A Patel, JG Leroy, F Scaglia. Deletion 9q34.3 syndrome: genotype-phenotype correlations and an extended deletion in a patient with features of Opitz C trigonocephaly.. J Med Genet 2005;42:328-35" ]	5/10/2010	21/3/2019	26/1/2023	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
kms	kms	[ "Idiopathic Hypogonadotropic Hypogonadism", "Isolated Hypogonadotropic Hypogonadism", "Isolated Hypogonadotropic Hypogonadism", "Idiopathic Hypogonadotropic Hypogonadism", "Normosmic Isolated Gonadotropin-Releasing Hormone Deficiency", "Anosmin-1", "Chromodomain-helicase-DNA-binding protein 7", "Coiled-coil domain-containing protein 141", "DNA-directed RNA polymerase III subunit RPC2", "Dual specificity protein phosphatase 6", "Fez family zinc finger protein 1", "Fibroblast growth factor 17", "Fibroblast growth factor 8", "Fibroblast growth factor receptor 1", "Gonadotropin-releasing hormone receptor", "Heparan-sulfate 6-O-sulfotransferase 1", "Interleukin-17 receptor D", "KiSS-1 receptor", "Leucine-rich repeat transmembrane protein FLRT3", "Metastasis-suppressor KiSS-1", "Neuromedin-K receptor", "NMDA receptor synaptonuclear signaling and neuronal migration factor", "Progonadoliberin-1", "Prokineticin receptor 2", "Prokineticin-2", "Protein sprouty homolog 4", "Semaphorin-3A", "Semaphorin-3E", "Steroid receptor RNA activator 1", "Tachykinin-3", "Transcription factor SOX-10", "Tyrosine-protein kinase receptor UFO", "WD repeat-containing protein 11", "ANOS1", "AXL", "CCDC141", "CHD7", "DUSP6", "FEZF1", "FGF17", "FGF8", "FGFR1", "FLRT3", "GNRH1", "GNRHR", "HS6ST1", "IL17RD", "KISS1", "KISS1R", "NSMF", "POLR3B", "PROK2", "PROKR2", "SEMA3A", "SEMA3E", "SOX10", "SPRY4", "SRA1", "TAC3", "TACR3", "WDR11", "Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency" ]	Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency	Ravikumar Balasubramanian, William F Crowley	Summary Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is characterized by inappropriately low serum concentrations of the gonadotropins LH (luteinizing hormone) and FSH (follicle-stimulating hormone) in the presence of low circulating concentrations of sex steroids. IGD is associated with a normal sense of smell (normosmic IGD) in approximately 40% of affected individuals and an impaired sense of smell (Kallmann syndrome) in approximately 60%. IGD can first become apparent in infancy, adolescence, or adulthood. Infant boys with congenital IGD often have micropenis and cryptorchidism. Adolescents and adults with IGD have clinical evidence of hypogonadism and incomplete sexual maturation on physical examination. Adult males with IGD tend to have prepubertal testicular volume (i.e., <4 mL), absence of secondary sexual features (e.g., facial and axillary hair growth, deepening of the voice), decreased muscle mass, diminished libido, erectile dysfunction, and infertility. Adult females have little or no breast development and primary amenorrhea. Although skeletal maturation is delayed, the rate of linear growth is usually normal except for the absence of a distinct pubertal growth spurt. IGD is typically diagnosed in adolescents presenting with absent or partial puberty using biochemical testing that reveals low serum testosterone or estradiol (hypogonadism) that results from complete or partial absence of GnRH-mediated release of LH and FSH (hypogonadotropic hypogonadism [HH]) in the setting of otherwise normal anterior pituitary anatomy and function and in the absence of secondary causes of HH. Pathogenic variants in more than 25 genes account for about half of all IGD; the genetic cause for the remaining cases of IGD is unknown. IGD can be inherited in an X-linked, autosomal dominant, or autosomal recessive manner. Almost all IGD-related genes have also been associated with indeterminate or oligogenic inheritance. Recurrence risk counseling is based on family history and the results of molecular genetic testing when available. Carrier testing for at-risk relatives in families with X-linked IGD or autosomal recessive IGD is possible if the pathogenic variant(s) in the family are known. Prenatal testing for a pregnancy at increased risk is possible if the pathogenic variant(s) in the family are known.	Normosmic isolated gonadotropin-releasing hormone deficiency Kallmann syndrome For synonyms and outdated names see • Normosmic isolated gonadotropin-releasing hormone deficiency • Kallmann syndrome ## Diagnosis Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) can be associated with a normal sense of smell (normosmic IGD) or an impaired sense of smell (Kallmann syndrome [KS]). Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) Men with IGD typically have Tanner stage I-II genitalia (prepubertal testicular volumes; i.e., <4 mL); however, some males show evidence of partial pubertal maturation [ Women with IGD typically have Tanner stage I breast development and amenorrhea; however, some have spontaneous breast development and occasional menses [ Both men and women with IGD typically have Tanner stage II-III pubic hair, since pubic hair is controlled in part by adrenal androgens. In rare males, IGD may present later in adulthood (i.e., adult-onset IGD). However, in these individuals, as puberty was not disrupted, sexual maturation is complete and secondary sexual characteristics may be fully developed. Diagnosis of adult-onset IGD relies on documentation of hypogonadotropic hypogonadism (HH) and absence of other secondary causes of HH. Total testosterone (T) <100 ng/dL in males and estradiol (E Inappropriately low or normal serum concentration of LH (luteinizing hormone) and FSH (follicle stimulating hormone) in the presence of low circulating concentrations of sex steroids. Levels of other anterior pituitary hormones are typically normal. In persons with IGD: typically, normal-appearing hypothalamus and pituitary on MRI exam In persons with KS: typically, aplasia or hypoplasia of the olfactory bulbs/sulci/tracts. Individuals with IGD with either self-reported complete anosmia or a score of hyposmia/anosmia on UPSIT testing are diagnosed with KS, while those with normal olfactory function are diagnosed with normosmic IGD (nIGD) [ Tanner Staging The diagnosis of IGD 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 [ See Molecular testing approaches can include To help prioritize the order of serial single-gene testing, the following can be considered (see Pathogenic variants in Pathogenic variants in Pathogenic variants in For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency: Most Common Genetic Causes Pathogenic variants of any one of the genes included in this table account for >2% of IGD. KS = Kallmann syndrome; nIGD = normosmic isolated gonadotropin-releasing hormone deficiency Genes are listed in alphabetic order. See Proportion of IGD attributed to these genes is determined from the author's cohort of 950 probands with IGD who were screened for rare sequence variants (<1% of control cohort). See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small 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. 12% of persons with KS had intragenic deletions in No data on detection rate of gene-targeted deletion/duplication analysis are available. Molecular Genetics of Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency: Less Common Genetic Causes Pathogenic variants of any one of the genes listed in this table are reported in only a few families (i.e., <2% of IGD) AR = autosomal recessive; KS = Kallmann syndrome; nIGD = normosmic isolated gonadotropin-releasing hormone deficiency Genes are listed in alphabetic order. See Genes are not described in detail in Proportion of IGD attributed to these genes is determined from the author's cohort of 950 probands with IGD who were screened for rare sequence variants (<1% of control cohort). Pathogenic variants in this gene are not thought to cause IGD without contributions from other IGD-related genes; thus, the proportion of IGD caused by pathogenic variants in this gene is unknown. • Men with IGD typically have Tanner stage I-II genitalia (prepubertal testicular volumes; i.e., <4 mL); however, some males show evidence of partial pubertal maturation [ • Women with IGD typically have Tanner stage I breast development and amenorrhea; however, some have spontaneous breast development and occasional menses [ • Both men and women with IGD typically have Tanner stage II-III pubic hair, since pubic hair is controlled in part by adrenal androgens. • In rare males, IGD may present later in adulthood (i.e., adult-onset IGD). However, in these individuals, as puberty was not disrupted, sexual maturation is complete and secondary sexual characteristics may be fully developed. Diagnosis of adult-onset IGD relies on documentation of hypogonadotropic hypogonadism (HH) and absence of other secondary causes of HH. • Men with IGD typically have Tanner stage I-II genitalia (prepubertal testicular volumes; i.e., <4 mL); however, some males show evidence of partial pubertal maturation [ • Women with IGD typically have Tanner stage I breast development and amenorrhea; however, some have spontaneous breast development and occasional menses [ • Both men and women with IGD typically have Tanner stage II-III pubic hair, since pubic hair is controlled in part by adrenal androgens. • Total testosterone (T) <100 ng/dL in males and estradiol (E • Inappropriately low or normal serum concentration of LH (luteinizing hormone) and FSH (follicle stimulating hormone) in the presence of low circulating concentrations of sex steroids. Levels of other anterior pituitary hormones are typically normal. • Total testosterone (T) <100 ng/dL in males and estradiol (E • Inappropriately low or normal serum concentration of LH (luteinizing hormone) and FSH (follicle stimulating hormone) in the presence of low circulating concentrations of sex steroids. Levels of other anterior pituitary hormones are typically normal. • • In persons with IGD: typically, normal-appearing hypothalamus and pituitary on MRI exam • In persons with KS: typically, aplasia or hypoplasia of the olfactory bulbs/sulci/tracts. • In persons with IGD: typically, normal-appearing hypothalamus and pituitary on MRI exam • In persons with KS: typically, aplasia or hypoplasia of the olfactory bulbs/sulci/tracts. • Individuals with IGD with either self-reported complete anosmia or a score of hyposmia/anosmia on UPSIT testing are diagnosed with KS, while those with normal olfactory function are diagnosed with normosmic IGD (nIGD) [ • Men with IGD typically have Tanner stage I-II genitalia (prepubertal testicular volumes; i.e., <4 mL); however, some males show evidence of partial pubertal maturation [ • Women with IGD typically have Tanner stage I breast development and amenorrhea; however, some have spontaneous breast development and occasional menses [ • Both men and women with IGD typically have Tanner stage II-III pubic hair, since pubic hair is controlled in part by adrenal androgens. • Total testosterone (T) <100 ng/dL in males and estradiol (E • Inappropriately low or normal serum concentration of LH (luteinizing hormone) and FSH (follicle stimulating hormone) in the presence of low circulating concentrations of sex steroids. Levels of other anterior pituitary hormones are typically normal. • In persons with IGD: typically, normal-appearing hypothalamus and pituitary on MRI exam • In persons with KS: typically, aplasia or hypoplasia of the olfactory bulbs/sulci/tracts. • • Pathogenic variants in • Pathogenic variants in • Pathogenic variants in • Pathogenic variants in • Pathogenic variants in • Pathogenic variants in • • Pathogenic variants in • Pathogenic variants in • Pathogenic variants in ## Suggestive Findings Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) Men with IGD typically have Tanner stage I-II genitalia (prepubertal testicular volumes; i.e., <4 mL); however, some males show evidence of partial pubertal maturation [ Women with IGD typically have Tanner stage I breast development and amenorrhea; however, some have spontaneous breast development and occasional menses [ Both men and women with IGD typically have Tanner stage II-III pubic hair, since pubic hair is controlled in part by adrenal androgens. In rare males, IGD may present later in adulthood (i.e., adult-onset IGD). However, in these individuals, as puberty was not disrupted, sexual maturation is complete and secondary sexual characteristics may be fully developed. Diagnosis of adult-onset IGD relies on documentation of hypogonadotropic hypogonadism (HH) and absence of other secondary causes of HH. Total testosterone (T) <100 ng/dL in males and estradiol (E Inappropriately low or normal serum concentration of LH (luteinizing hormone) and FSH (follicle stimulating hormone) in the presence of low circulating concentrations of sex steroids. Levels of other anterior pituitary hormones are typically normal. In persons with IGD: typically, normal-appearing hypothalamus and pituitary on MRI exam In persons with KS: typically, aplasia or hypoplasia of the olfactory bulbs/sulci/tracts. Individuals with IGD with either self-reported complete anosmia or a score of hyposmia/anosmia on UPSIT testing are diagnosed with KS, while those with normal olfactory function are diagnosed with normosmic IGD (nIGD) [ Tanner Staging • Men with IGD typically have Tanner stage I-II genitalia (prepubertal testicular volumes; i.e., <4 mL); however, some males show evidence of partial pubertal maturation [ • Women with IGD typically have Tanner stage I breast development and amenorrhea; however, some have spontaneous breast development and occasional menses [ • Both men and women with IGD typically have Tanner stage II-III pubic hair, since pubic hair is controlled in part by adrenal androgens. • In rare males, IGD may present later in adulthood (i.e., adult-onset IGD). However, in these individuals, as puberty was not disrupted, sexual maturation is complete and secondary sexual characteristics may be fully developed. Diagnosis of adult-onset IGD relies on documentation of hypogonadotropic hypogonadism (HH) and absence of other secondary causes of HH. • Men with IGD typically have Tanner stage I-II genitalia (prepubertal testicular volumes; i.e., <4 mL); however, some males show evidence of partial pubertal maturation [ • Women with IGD typically have Tanner stage I breast development and amenorrhea; however, some have spontaneous breast development and occasional menses [ • Both men and women with IGD typically have Tanner stage II-III pubic hair, since pubic hair is controlled in part by adrenal androgens. • Total testosterone (T) <100 ng/dL in males and estradiol (E • Inappropriately low or normal serum concentration of LH (luteinizing hormone) and FSH (follicle stimulating hormone) in the presence of low circulating concentrations of sex steroids. Levels of other anterior pituitary hormones are typically normal. • Total testosterone (T) <100 ng/dL in males and estradiol (E • Inappropriately low or normal serum concentration of LH (luteinizing hormone) and FSH (follicle stimulating hormone) in the presence of low circulating concentrations of sex steroids. Levels of other anterior pituitary hormones are typically normal. • • In persons with IGD: typically, normal-appearing hypothalamus and pituitary on MRI exam • In persons with KS: typically, aplasia or hypoplasia of the olfactory bulbs/sulci/tracts. • In persons with IGD: typically, normal-appearing hypothalamus and pituitary on MRI exam • In persons with KS: typically, aplasia or hypoplasia of the olfactory bulbs/sulci/tracts. • Individuals with IGD with either self-reported complete anosmia or a score of hyposmia/anosmia on UPSIT testing are diagnosed with KS, while those with normal olfactory function are diagnosed with normosmic IGD (nIGD) [ • Men with IGD typically have Tanner stage I-II genitalia (prepubertal testicular volumes; i.e., <4 mL); however, some males show evidence of partial pubertal maturation [ • Women with IGD typically have Tanner stage I breast development and amenorrhea; however, some have spontaneous breast development and occasional menses [ • Both men and women with IGD typically have Tanner stage II-III pubic hair, since pubic hair is controlled in part by adrenal androgens. • Total testosterone (T) <100 ng/dL in males and estradiol (E • Inappropriately low or normal serum concentration of LH (luteinizing hormone) and FSH (follicle stimulating hormone) in the presence of low circulating concentrations of sex steroids. Levels of other anterior pituitary hormones are typically normal. • In persons with IGD: typically, normal-appearing hypothalamus and pituitary on MRI exam • In persons with KS: typically, aplasia or hypoplasia of the olfactory bulbs/sulci/tracts. ## Establishing the Diagnosis The diagnosis of IGD 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 [ See Molecular testing approaches can include To help prioritize the order of serial single-gene testing, the following can be considered (see Pathogenic variants in Pathogenic variants in Pathogenic variants in For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency: Most Common Genetic Causes Pathogenic variants of any one of the genes included in this table account for >2% of IGD. KS = Kallmann syndrome; nIGD = normosmic isolated gonadotropin-releasing hormone deficiency Genes are listed in alphabetic order. See Proportion of IGD attributed to these genes is determined from the author's cohort of 950 probands with IGD who were screened for rare sequence variants (<1% of control cohort). See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small 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. 12% of persons with KS had intragenic deletions in No data on detection rate of gene-targeted deletion/duplication analysis are available. Molecular Genetics of Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency: Less Common Genetic Causes Pathogenic variants of any one of the genes listed in this table are reported in only a few families (i.e., <2% of IGD) AR = autosomal recessive; KS = Kallmann syndrome; nIGD = normosmic isolated gonadotropin-releasing hormone deficiency Genes are listed in alphabetic order. See Genes are not described in detail in Proportion of IGD attributed to these genes is determined from the author's cohort of 950 probands with IGD who were screened for rare sequence variants (<1% of control cohort). Pathogenic variants in this gene are not thought to cause IGD without contributions from other IGD-related genes; thus, the proportion of IGD caused by pathogenic variants in this gene is unknown. • • Pathogenic variants in • Pathogenic variants in • Pathogenic variants in • Pathogenic variants in • Pathogenic variants in • Pathogenic variants in • • Pathogenic variants in • Pathogenic variants in • Pathogenic variants in ## Clinical Characteristics The clinical manifestations of isolated GnRH deficiency (IGD) depend on the stage of development at which the deficiency in the reproductive axis first occurred – in infancy, adolescence, or (rarely) adulthood. Most individuals with IGD are identified at puberty; however, suggestive clinical features may be present in infancy. Although microphallus and cryptorchidism can occur in both forms of IGD (KS and normosmic IGD), these features are more common in males with KS than in those with normosmic IGD [ Female infants typically do not exhibit any clinical features that may indicate IGD. Males with IGD typically have prepubertal testicular volume (i.e., <4 mL), absence of secondary sexual features (e.g., facial and axillary hair growth and deepening of the voice), and decreased muscle mass. Females with IGD typically have little or no breast development and primary amenorrhea, but milder presentations with spontaneous menses are recognized [ Since adrenal maturation proceeds normally, the low levels of androgens produced in the adrenal glands may be sufficient for normal onset of pubic hair growth (adrenarche) in both sexes. Because of the failure of growth plates in the bone to fuse in the absence of sex hormones, most individuals with IGD, both males and females may have disproportionate arm span compared to height (arm span typically exceeds height by ≥5 cm). Whereas skeletal maturation is delayed, the rate of linear growth is usually normal (save for the absence of a distinct pubertal growth spurt) [ Isolated GnRH Deficiency (IGD) Phenotype by Gene Digital synkinesia (in ~80% males) Unilateral renal agenesis (in ~30% males) High-arched palate High-arched or cleft palate Dental agenesis Auricular dysplasia Perceptive deafness & hypoplasia of semicircular canals Coloboma Short stature Intellectual disability Cleft lip and/or palate Hearing loss Ocular hypertelorism Hyperlaxity of the digits Camptodactyly Synkinesia (in ~10%) Cleft lip and/or palate Agenesis of 1+ teeth Digit malformations (brachydactyly, syndactyly) Hearing loss Iris hypopigmentation Monogenic inheritance Oligogenic inheritance Often asymptomatic; also reported in KS of unknown cause Depending on penetrance, especially in the heterozygous state Pulsatile secretion of GnRH into the hypophyseal portal circulation represents the initial neuroendocrine step in the regulation of the hypothalamo-pituitary-gonadal (HPG) axis in both sexes. Thus, this specialized GnRH neuronal network plays a commanding role in this biologic hierarchy and controls episodic gonadotropin secretion, modulates gonadal steroid feedback, and ultimately determines the initiation or suppression of pubertal development and fertility across the life cycle [ Under normal conditions, the GnRH neuronal network undergoes a series of dynamic changes from fetal life to adulthood. The initiation of GnRH secretion is initiated in early fetal life and remains active until the first several months of infancy (representing the "mini-puberty"), and then becomes remarkably dampened during the years of the childhood "quiescence" [ In individuals with IGD, analyses of the pulsatile pattern of gonadotropins have demonstrated a rather broad spectrum of abnormal developmental patterns varying from completely absent GnRH-induced LH pulses to sleep-entrained GnRH release that is indistinguishable from that of early puberty [ Gene-specific phenotypes have been noted; see No reproductive or non-reproductive phenotype is specific to a single pathogenic variant or particular type of pathogenic variant in any of the IGD-related genes. The underlying genetic etiology typically determines the penetrance of both reproductive and non-reproductive phenotypes. The penetrance for the KS phenotype (both IGD and anosmia) is generally complete in males with an Penetrance for IGD is also fairly high when pathogenic variants occur in the biallelic state (i.e., recessive variants) ( Penetrance for anosmia in men with an The biochemical term "hypogonadotropic hypogonadism" has evolved with the increased understanding of reproductive physiology. The term “hypogonadism” refers to impaired sexual development based on findings from the individual's clinical history (e.g., amenorrhea, hot flashes, erectile dysfunction) as well as physical examination (e.g., small testes, vaginal pallor). With greater understanding of the hypothalamo-pituitary-gonadal (HPG) axis (see When anatomic (and later functional) causes of central hypogonadism were identified, "idiopathic" or "isolated" hypogonadotropic hypogonadism (IHH) came into use to indicate those individuals in whom secondary causes of hypogonadotropic hypogonadism had been excluded. Subsequently the ability to measure the effect of exogenous GnRH administration demonstrated that the vast majority of individuals with "idiopathic" HH had a functional deficiency of GnRH resulting from a defect in GnRH biosynthesis, secretion, and/or action (hence "isolated GnRH deficiency" [IGD]). Aside from hypothalamic GnRH deficiency, individuals with IGD typically have normal pituitary function tests and their hypogonadism typically responds to a physiologic regimen of exogenous GnRH [ At this point, the term "isolated GnRH deficiency" (IGD) more properly reflects the current understanding of the clinical entity rather than the previous biochemical description of IHH and, thus, is the better term for what was previously called IHH. A recent epidemiologic study in Finland showed a minimal incidence of KS of 1:30,000 in males and 1:125,000 in females [ In the authors' cohort of 250 individuals with IGD, males predominate with a male-to-female ratio of nearly 4:1 [ KS accounts for nearly two thirds of individuals with isolated GnRH deficiency (IGD). • Digital synkinesia (in ~80% males) • Unilateral renal agenesis (in ~30% males) • High-arched palate • High-arched or cleft palate • Dental agenesis • Auricular dysplasia • Perceptive deafness & hypoplasia of semicircular canals • Coloboma • Short stature • Intellectual disability • Cleft lip and/or palate • Hearing loss • Ocular hypertelorism • Hyperlaxity of the digits • Camptodactyly • Synkinesia (in ~10%) • Cleft lip and/or palate • Agenesis of 1+ teeth • Digit malformations (brachydactyly, syndactyly) • Hearing loss • Iris hypopigmentation ## Clinical Description The clinical manifestations of isolated GnRH deficiency (IGD) depend on the stage of development at which the deficiency in the reproductive axis first occurred – in infancy, adolescence, or (rarely) adulthood. Most individuals with IGD are identified at puberty; however, suggestive clinical features may be present in infancy. Although microphallus and cryptorchidism can occur in both forms of IGD (KS and normosmic IGD), these features are more common in males with KS than in those with normosmic IGD [ Female infants typically do not exhibit any clinical features that may indicate IGD. Males with IGD typically have prepubertal testicular volume (i.e., <4 mL), absence of secondary sexual features (e.g., facial and axillary hair growth and deepening of the voice), and decreased muscle mass. Females with IGD typically have little or no breast development and primary amenorrhea, but milder presentations with spontaneous menses are recognized [ Since adrenal maturation proceeds normally, the low levels of androgens produced in the adrenal glands may be sufficient for normal onset of pubic hair growth (adrenarche) in both sexes. Because of the failure of growth plates in the bone to fuse in the absence of sex hormones, most individuals with IGD, both males and females may have disproportionate arm span compared to height (arm span typically exceeds height by ≥5 cm). Whereas skeletal maturation is delayed, the rate of linear growth is usually normal (save for the absence of a distinct pubertal growth spurt) [ Isolated GnRH Deficiency (IGD) Phenotype by Gene Digital synkinesia (in ~80% males) Unilateral renal agenesis (in ~30% males) High-arched palate High-arched or cleft palate Dental agenesis Auricular dysplasia Perceptive deafness & hypoplasia of semicircular canals Coloboma Short stature Intellectual disability Cleft lip and/or palate Hearing loss Ocular hypertelorism Hyperlaxity of the digits Camptodactyly Synkinesia (in ~10%) Cleft lip and/or palate Agenesis of 1+ teeth Digit malformations (brachydactyly, syndactyly) Hearing loss Iris hypopigmentation Monogenic inheritance Oligogenic inheritance Often asymptomatic; also reported in KS of unknown cause Depending on penetrance, especially in the heterozygous state • Digital synkinesia (in ~80% males) • Unilateral renal agenesis (in ~30% males) • High-arched palate • High-arched or cleft palate • Dental agenesis • Auricular dysplasia • Perceptive deafness & hypoplasia of semicircular canals • Coloboma • Short stature • Intellectual disability • Cleft lip and/or palate • Hearing loss • Ocular hypertelorism • Hyperlaxity of the digits • Camptodactyly • Synkinesia (in ~10%) • Cleft lip and/or palate • Agenesis of 1+ teeth • Digit malformations (brachydactyly, syndactyly) • Hearing loss • Iris hypopigmentation ## Reproductive Phenotype Although microphallus and cryptorchidism can occur in both forms of IGD (KS and normosmic IGD), these features are more common in males with KS than in those with normosmic IGD [ Female infants typically do not exhibit any clinical features that may indicate IGD. Males with IGD typically have prepubertal testicular volume (i.e., <4 mL), absence of secondary sexual features (e.g., facial and axillary hair growth and deepening of the voice), and decreased muscle mass. Females with IGD typically have little or no breast development and primary amenorrhea, but milder presentations with spontaneous menses are recognized [ Since adrenal maturation proceeds normally, the low levels of androgens produced in the adrenal glands may be sufficient for normal onset of pubic hair growth (adrenarche) in both sexes. Because of the failure of growth plates in the bone to fuse in the absence of sex hormones, most individuals with IGD, both males and females may have disproportionate arm span compared to height (arm span typically exceeds height by ≥5 cm). Whereas skeletal maturation is delayed, the rate of linear growth is usually normal (save for the absence of a distinct pubertal growth spurt) [ ## Olfactory Phenotype ## Reproductive and Non-Reproductive Phenotypes by Gene Isolated GnRH Deficiency (IGD) Phenotype by Gene Digital synkinesia (in ~80% males) Unilateral renal agenesis (in ~30% males) High-arched palate High-arched or cleft palate Dental agenesis Auricular dysplasia Perceptive deafness & hypoplasia of semicircular canals Coloboma Short stature Intellectual disability Cleft lip and/or palate Hearing loss Ocular hypertelorism Hyperlaxity of the digits Camptodactyly Synkinesia (in ~10%) Cleft lip and/or palate Agenesis of 1+ teeth Digit malformations (brachydactyly, syndactyly) Hearing loss Iris hypopigmentation Monogenic inheritance Oligogenic inheritance Often asymptomatic; also reported in KS of unknown cause Depending on penetrance, especially in the heterozygous state • Digital synkinesia (in ~80% males) • Unilateral renal agenesis (in ~30% males) • High-arched palate • High-arched or cleft palate • Dental agenesis • Auricular dysplasia • Perceptive deafness & hypoplasia of semicircular canals • Coloboma • Short stature • Intellectual disability • Cleft lip and/or palate • Hearing loss • Ocular hypertelorism • Hyperlaxity of the digits • Camptodactyly • Synkinesia (in ~10%) • Cleft lip and/or palate • Agenesis of 1+ teeth • Digit malformations (brachydactyly, syndactyly) • Hearing loss • Iris hypopigmentation ## Pathophysiology Pulsatile secretion of GnRH into the hypophyseal portal circulation represents the initial neuroendocrine step in the regulation of the hypothalamo-pituitary-gonadal (HPG) axis in both sexes. Thus, this specialized GnRH neuronal network plays a commanding role in this biologic hierarchy and controls episodic gonadotropin secretion, modulates gonadal steroid feedback, and ultimately determines the initiation or suppression of pubertal development and fertility across the life cycle [ Under normal conditions, the GnRH neuronal network undergoes a series of dynamic changes from fetal life to adulthood. The initiation of GnRH secretion is initiated in early fetal life and remains active until the first several months of infancy (representing the "mini-puberty"), and then becomes remarkably dampened during the years of the childhood "quiescence" [ In individuals with IGD, analyses of the pulsatile pattern of gonadotropins have demonstrated a rather broad spectrum of abnormal developmental patterns varying from completely absent GnRH-induced LH pulses to sleep-entrained GnRH release that is indistinguishable from that of early puberty [ ## Genotype-Phenotype Correlations Gene-specific phenotypes have been noted; see No reproductive or non-reproductive phenotype is specific to a single pathogenic variant or particular type of pathogenic variant in any of the IGD-related genes. ## Penetrance The underlying genetic etiology typically determines the penetrance of both reproductive and non-reproductive phenotypes. The penetrance for the KS phenotype (both IGD and anosmia) is generally complete in males with an Penetrance for IGD is also fairly high when pathogenic variants occur in the biallelic state (i.e., recessive variants) ( Penetrance for anosmia in men with an ## Nomenclature The biochemical term "hypogonadotropic hypogonadism" has evolved with the increased understanding of reproductive physiology. The term “hypogonadism” refers to impaired sexual development based on findings from the individual's clinical history (e.g., amenorrhea, hot flashes, erectile dysfunction) as well as physical examination (e.g., small testes, vaginal pallor). With greater understanding of the hypothalamo-pituitary-gonadal (HPG) axis (see When anatomic (and later functional) causes of central hypogonadism were identified, "idiopathic" or "isolated" hypogonadotropic hypogonadism (IHH) came into use to indicate those individuals in whom secondary causes of hypogonadotropic hypogonadism had been excluded. Subsequently the ability to measure the effect of exogenous GnRH administration demonstrated that the vast majority of individuals with "idiopathic" HH had a functional deficiency of GnRH resulting from a defect in GnRH biosynthesis, secretion, and/or action (hence "isolated GnRH deficiency" [IGD]). Aside from hypothalamic GnRH deficiency, individuals with IGD typically have normal pituitary function tests and their hypogonadism typically responds to a physiologic regimen of exogenous GnRH [ At this point, the term "isolated GnRH deficiency" (IGD) more properly reflects the current understanding of the clinical entity rather than the previous biochemical description of IHH and, thus, is the better term for what was previously called IHH. ## Prevalence A recent epidemiologic study in Finland showed a minimal incidence of KS of 1:30,000 in males and 1:125,000 in females [ In the authors' cohort of 250 individuals with IGD, males predominate with a male-to-female ratio of nearly 4:1 [ KS accounts for nearly two thirds of individuals with isolated GnRH deficiency (IGD). ## Genetically Related (Allelic) Disorders Of the pathogenic variants that cause Pfeiffer syndrome, 95% occur in Mosaic activating pathogenic variants in • Of the pathogenic variants that cause Pfeiffer syndrome, 95% occur in ## Differential Diagnosis Hypogonadotropic hypogonadism refers to a diverse group of clinical conditions with characteristic biochemical findings of inappropriately low serum concentrations of LH (luteinizing hormone) and FSH (follicle stimulating hormone) occurring in the setting of hypogonadism. Distinguishing between isolated GnRH deficiency (IGD) and secondary causes of hypogonadotropic hypogonadism and syndromic/genetic causes of hypogonadotropic hypogonadism often requires additional clinical, laboratory, and radiologic evaluations. These may include physical examination for other systemic findings, family history, and measurement of serum concentration of other pituitary hormones, serum iron studies, and hypothalamic/pituitary imaging. Of note, despite a thorough evaluation, IGD can sometimes be difficult to distinguish from other causes of decreased gonadotropin secretion. Hence, molecular genetic testing of the known IGD-related genes ( CNS or pituitary tumors Pituitary apoplexy Brain/pituitary radiation Head trauma Drugs: GnRH agonists/antagonists, glucocorticoids, narcotics, chemotherapy, drugs causing hyperprolactinemia Functional deficiency resulting from hyperprolactinemia, chronic systemic illness, eating disorders, malnutrition, hypothyroidism, diabetes mellitus, Cushing's disease Systemic diseases such as sarcoidosis and histiocytosis Syndromes Associated with Hypogonadotropic Hypogonadism At least 19 genes are associated with BBS: Although the distinction between CDP and IGD cannot be reliably made at any age, age 18 years has traditionally been suggested as the age at which IGD can be diagnosed; however, the recent description of IGD "reversal" occurring in persons in their 20s and later raises the possibility that such individuals may have a severe form of CDP [ Currently, no clinically available test can reliably differentiate CDP from IGD. Data analyses have suggested that the mean serum concentrations of LH and sex hormones after GnRH or hCG (human chorionic gonadotropin) stimulation vary significantly between individuals with CDP and those with IGD. However, the clinical utility of measuring serum LH and sex hormone concentrations after stimulation with GnRH and hCG is limited by the significant variation in individual LH and sex hormone serum concentrations, resulting in considerable overlap between groups [ A peak-to-basal ratio of free alpha subunit (FAS) after the administration of GnRH has been proposed to help distinguish between CDP and IGD with a sensitivity and specificity in the 95% range and an overlap rate of 10% [ • CNS or pituitary tumors • Pituitary apoplexy • Brain/pituitary radiation • Head trauma • Drugs: GnRH agonists/antagonists, glucocorticoids, narcotics, chemotherapy, drugs causing hyperprolactinemia • Functional deficiency resulting from hyperprolactinemia, chronic systemic illness, eating disorders, malnutrition, hypothyroidism, diabetes mellitus, Cushing's disease • Systemic diseases such as sarcoidosis and histiocytosis ## Other Causes of Hypogonadotropic Hypogonadism Hypogonadotropic hypogonadism refers to a diverse group of clinical conditions with characteristic biochemical findings of inappropriately low serum concentrations of LH (luteinizing hormone) and FSH (follicle stimulating hormone) occurring in the setting of hypogonadism. Distinguishing between isolated GnRH deficiency (IGD) and secondary causes of hypogonadotropic hypogonadism and syndromic/genetic causes of hypogonadotropic hypogonadism often requires additional clinical, laboratory, and radiologic evaluations. These may include physical examination for other systemic findings, family history, and measurement of serum concentration of other pituitary hormones, serum iron studies, and hypothalamic/pituitary imaging. Of note, despite a thorough evaluation, IGD can sometimes be difficult to distinguish from other causes of decreased gonadotropin secretion. Hence, molecular genetic testing of the known IGD-related genes ( CNS or pituitary tumors Pituitary apoplexy Brain/pituitary radiation Head trauma Drugs: GnRH agonists/antagonists, glucocorticoids, narcotics, chemotherapy, drugs causing hyperprolactinemia Functional deficiency resulting from hyperprolactinemia, chronic systemic illness, eating disorders, malnutrition, hypothyroidism, diabetes mellitus, Cushing's disease Systemic diseases such as sarcoidosis and histiocytosis Syndromes Associated with Hypogonadotropic Hypogonadism At least 19 genes are associated with BBS: • CNS or pituitary tumors • Pituitary apoplexy • Brain/pituitary radiation • Head trauma • Drugs: GnRH agonists/antagonists, glucocorticoids, narcotics, chemotherapy, drugs causing hyperprolactinemia • Functional deficiency resulting from hyperprolactinemia, chronic systemic illness, eating disorders, malnutrition, hypothyroidism, diabetes mellitus, Cushing's disease • Systemic diseases such as sarcoidosis and histiocytosis ## Differential Diagnosis of IGD at Specific Developmental Stages Although the distinction between CDP and IGD cannot be reliably made at any age, age 18 years has traditionally been suggested as the age at which IGD can be diagnosed; however, the recent description of IGD "reversal" occurring in persons in their 20s and later raises the possibility that such individuals may have a severe form of CDP [ Currently, no clinically available test can reliably differentiate CDP from IGD. Data analyses have suggested that the mean serum concentrations of LH and sex hormones after GnRH or hCG (human chorionic gonadotropin) stimulation vary significantly between individuals with CDP and those with IGD. However, the clinical utility of measuring serum LH and sex hormone concentrations after stimulation with GnRH and hCG is limited by the significant variation in individual LH and sex hormone serum concentrations, resulting in considerable overlap between groups [ A peak-to-basal ratio of free alpha subunit (FAS) after the administration of GnRH has been proposed to help distinguish between CDP and IGD with a sensitivity and specificity in the 95% range and an overlap rate of 10% [ ## Management To establish the extent of disease and needs of an individual diagnosed with IGD, the following evaluations are recommended: Assessment of clinical manifestations of hypogonadism based on the age and sex of the individual, if not already performed as part of the diagnostic work up (See Assessment of laboratory findings* of hypogonadotropic hypogonadism if not already performed as part of the diagnostic work up * Serum concentration of LH (luteinizing hormone) and FSH (follicle-stimulating hormone) and in males total testosterone (T) <100 ng/dL and in females estradiol (E Assessment for presence of possible non-reproductive features including: renal ultrasound examination (to detect unilateral renal agenesis), hearing tests (to detect sensorineural hearing loss), skeletal survey (to detect limb/spine bony abnormalities), dental exam (to detect dental agenesis), eye exam (to detect iris and/or chorioretinal coloboma) and developmental assessment (if there is evidence of developmental delay) In addition to assessing the degree of hypogonadism/GnRH deficiency, potential deterioration in bone health that may have resulted from periods of low-circulating sex hormones needs to be addressed. Depending on the timing of puberty, duration of GnRH deficiency, and other osteoporotic risk factors (e.g., glucocorticoid excess, smoking), one should consider obtaining a bone mineral density study (see Consultation with a clinical geneticist and/or genetic counselor An expert European consensus statement on the management of IGD has recently been published [ Typically, a definitive diagnosis of IGD is made around age 18 years. Occasionally, however, a high clinical suspicion of IGD may be present in an adolescent presenting with anosmia and delayed puberty or in an infant with microphallus and cryptorchidism. Treatment options include sex steroids, gonadotropins, and pulsatile GnRH administration. Choice of therapy in adults is determined by the goal(s) of treatment (i.e., to induce and maintain secondary sex characteristics and/or to induce and maintain fertility). The selection of hormone replacement therapy is also based on the preference of the individual being treated; however, when fertility is not immediately desired, replacement with testosterone therapy is the most practical option. As the majority of individuals with IGD have not progressed through puberty at the time of diagnosis, initial therapy should be started at low doses and gradually increased to adult doses once the development of secondary sexual characteristics is achieved. The injectable testosterone preparations have a "roller-coaster" pharmacokinetic effect, with peak and trough levels that can go to extraphysiologic levels; thus, the transdermal preparations have the added benefit of offering a more favorable pharmacokinetic profile. A typical adult dose of testosterone replacement is 200 mg of testosterone ester injection every two weeks or 5 g of a 1% testosterone gel every day. Doses do vary with newer testosterone preparations; manufacturer's instructions should be followed for individual testosterone preparations. Men using topical androgen replacement must take care to avoid exposing other individuals to treated skin. Anecdotal reports suggest that the transmission of clinically effective levels of testosterone from the affected individual to other family members (including women and children) is possible, with undesirable side effects. Once puberty is initiated, testosterone replacement therapy is usually required indefinitely to ensure normal sexual function and maintenance of proper muscle, bone, and red blood cell mass. However, in approximately 10% of males, reversal of IGD may occur; thus, if clinical evidence shows endogenous activity of the hypothalamo-pituitary-axis (e.g., testicular growth on testosterone, maintained testosterone levels despite missing/withholding therapy), a brief washout of testosterone therapy should be done with monitoring of testosterone levels. If testosterone levels fall, therapy should be reinitiated. If levels are normal, no further testosterone therapy will be required; serial monitoring of levels should be undertaken, as some individuals may require reinitiation of therapy. In adults, treatment with hCG is usually initiated at 1,500 IU intramuscularly or subcutaneously every other day to normalize serum testosterone concentrations. Dose should be increased by increments of 250 IU if serum testosterone levels remain low. Treatment with hCG must be weighed against the increased risk of developing gynecomastia (resulting from the estrogen produced by stimulation of the testes with hCG). To some extent the risk of gynecomastia can be minimized by gradually reducing the dose of hCG to the minimum required to sustain a serum testosterone concentration in the mid-normal range (~500 ng/dL). If IGD is clinically suspected (e.g., low testosterone levels with low/normal gonadotropins) low-dose testosterone or hCG therapy can be given in early infancy to boys with microphallus to increase penile length [ Since a definitive diagnosis of IGD may not be possible until age 18 years, after infancy these boys do not generally need to be treated until around the time of puberty. At this time, if a high suspicion of IGD remains (e.g., associated anosmia and delay in onset puberty), these subjects may benefit from early initiation of hormonal replacement therapy with either testosterone or hCG treatment early in the pubertal period. A suggestive puberty induction regimen in adolescents is to start a long-acting testosterone ester at a dose of 25-50 mg, given intramuscularly every two weeks. The doses can be gradually increased by 25-50 mg every two to three months until full virilization is achieved. Once adult doses (~200 mg/2 weeks) are reached, further adjustments are based on serum testosterone levels. In males with higher baseline testicular volumes, treatment with hCG alone may be sufficient to achieve spermatogenesis and conception [ In either treatment, testicular volume must be tracked, as this is one of the primary determinants of successful spermatogenesis. In fact, sperm are rarely seen in the semen analysis until testicular volume reaches 8 mL [ If a pituitary defect exists, gonadotropin therapy becomes the treatment of choice. Subcutaneous administration of GnRH in a pulsatile manner through a portable pump that delivers a GnRH bolus every two hours is an efficient way of inducing testicular growth and spermatogenesis [ To allow optimal breast development, initial treatment should consist of unopposed estrogen replacement via oral or topical preparations. Many formulations of estrogens are available; a suggested oral regimen is using premarin 0.3 mg daily to be increased gradually to an adult replacement dose of 1-1.25 mg daily. Once breast development is optimal, a progestin should be added for endometrial protection (e.g., cyclical Prometrium Although preference of the individual plays an important role in choice of treatment plan, low-estrogen formulations should be considered in women with clotting abnormalities (see Similarly, if spontaneous conception fails to occur in women with IGD who have undergone ovulation induction, IVF may be an option. Optimal calcium and vitamin D intake should be encouraged and specific treatment for decreased bone mass with bisphosphonates should be considered depending on the degree of bone mineralization (see Assessment of sexual maturation by Tanner staging ( Measurement of serum concentrations of LH, FSH, and total testosterone (T) in males and estradiol (E Bone age determinations 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 prompt initiation of treatment. Evaluations can include: Molecular genetic testing if the pathogenic variant(s) in the family are known. However, a prepubertal child with a known pathogenic variant may progress through puberty in a normal fashion, delayed fashion, or not at all. Therefore, reevaluation of such individuals over time is important, and hormone treatment should be initiated only when IGD with impaired pubertal development is diagnosed. If the pathogenic variant(s) in the family are not known, clinical review of at-risk relatives of pubertal age to assess clinical onset of signs of puberty and if delayed, to initiate appropriate therapy for pubertal induction. See Search • Assessment of clinical manifestations of hypogonadism based on the age and sex of the individual, if not already performed as part of the diagnostic work up (See • Assessment of laboratory findings* of hypogonadotropic hypogonadism if not already performed as part of the diagnostic work up • * Serum concentration of LH (luteinizing hormone) and FSH (follicle-stimulating hormone) and in males total testosterone (T) <100 ng/dL and in females estradiol (E • Assessment for presence of possible non-reproductive features including: renal ultrasound examination (to detect unilateral renal agenesis), hearing tests (to detect sensorineural hearing loss), skeletal survey (to detect limb/spine bony abnormalities), dental exam (to detect dental agenesis), eye exam (to detect iris and/or chorioretinal coloboma) and developmental assessment (if there is evidence of developmental delay) • In addition to assessing the degree of hypogonadism/GnRH deficiency, potential deterioration in bone health that may have resulted from periods of low-circulating sex hormones needs to be addressed. Depending on the timing of puberty, duration of GnRH deficiency, and other osteoporotic risk factors (e.g., glucocorticoid excess, smoking), one should consider obtaining a bone mineral density study (see • Consultation with a clinical geneticist and/or genetic counselor • The injectable testosterone preparations have a "roller-coaster" pharmacokinetic effect, with peak and trough levels that can go to extraphysiologic levels; thus, the transdermal preparations have the added benefit of offering a more favorable pharmacokinetic profile. A typical adult dose of testosterone replacement is 200 mg of testosterone ester injection every two weeks or 5 g of a 1% testosterone gel every day. Doses do vary with newer testosterone preparations; manufacturer's instructions should be followed for individual testosterone preparations. • Men using topical androgen replacement must take care to avoid exposing other individuals to treated skin. Anecdotal reports suggest that the transmission of clinically effective levels of testosterone from the affected individual to other family members (including women and children) is possible, with undesirable side effects. • Once puberty is initiated, testosterone replacement therapy is usually required indefinitely to ensure normal sexual function and maintenance of proper muscle, bone, and red blood cell mass. • However, in approximately 10% of males, reversal of IGD may occur; thus, if clinical evidence shows endogenous activity of the hypothalamo-pituitary-axis (e.g., testicular growth on testosterone, maintained testosterone levels despite missing/withholding therapy), a brief washout of testosterone therapy should be done with monitoring of testosterone levels. If testosterone levels fall, therapy should be reinitiated. If levels are normal, no further testosterone therapy will be required; serial monitoring of levels should be undertaken, as some individuals may require reinitiation of therapy. • In adults, treatment with hCG is usually initiated at 1,500 IU intramuscularly or subcutaneously every other day to normalize serum testosterone concentrations. Dose should be increased by increments of 250 IU if serum testosterone levels remain low. • Treatment with hCG must be weighed against the increased risk of developing gynecomastia (resulting from the estrogen produced by stimulation of the testes with hCG). To some extent the risk of gynecomastia can be minimized by gradually reducing the dose of hCG to the minimum required to sustain a serum testosterone concentration in the mid-normal range (~500 ng/dL). • In males with higher baseline testicular volumes, treatment with hCG alone may be sufficient to achieve spermatogenesis and conception [ • In either treatment, testicular volume must be tracked, as this is one of the primary determinants of successful spermatogenesis. In fact, sperm are rarely seen in the semen analysis until testicular volume reaches 8 mL [ • If a pituitary defect exists, gonadotropin therapy becomes the treatment of choice. • Subcutaneous administration of GnRH in a pulsatile manner through a portable pump that delivers a GnRH bolus every two hours is an efficient way of inducing testicular growth and spermatogenesis [ • To allow optimal breast development, initial treatment should consist of unopposed estrogen replacement via oral or topical preparations. Many formulations of estrogens are available; a suggested oral regimen is using premarin 0.3 mg daily to be increased gradually to an adult replacement dose of 1-1.25 mg daily. • Once breast development is optimal, a progestin should be added for endometrial protection (e.g., cyclical Prometrium • Although preference of the individual plays an important role in choice of treatment plan, low-estrogen formulations should be considered in women with clotting abnormalities (see • Assessment of sexual maturation by Tanner staging ( • Measurement of serum concentrations of LH, FSH, and total testosterone (T) in males and estradiol (E • Bone age determinations • Molecular genetic testing if the pathogenic variant(s) in the family are known. However, a prepubertal child with a known pathogenic variant may progress through puberty in a normal fashion, delayed fashion, or not at all. Therefore, reevaluation of such individuals over time is important, and hormone treatment should be initiated only when IGD with impaired pubertal development is diagnosed. • If the pathogenic variant(s) in the family are not known, clinical review of at-risk relatives of pubertal age to assess clinical onset of signs of puberty and if delayed, to initiate appropriate therapy for pubertal induction. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with IGD, the following evaluations are recommended: Assessment of clinical manifestations of hypogonadism based on the age and sex of the individual, if not already performed as part of the diagnostic work up (See Assessment of laboratory findings* of hypogonadotropic hypogonadism if not already performed as part of the diagnostic work up * Serum concentration of LH (luteinizing hormone) and FSH (follicle-stimulating hormone) and in males total testosterone (T) <100 ng/dL and in females estradiol (E Assessment for presence of possible non-reproductive features including: renal ultrasound examination (to detect unilateral renal agenesis), hearing tests (to detect sensorineural hearing loss), skeletal survey (to detect limb/spine bony abnormalities), dental exam (to detect dental agenesis), eye exam (to detect iris and/or chorioretinal coloboma) and developmental assessment (if there is evidence of developmental delay) In addition to assessing the degree of hypogonadism/GnRH deficiency, potential deterioration in bone health that may have resulted from periods of low-circulating sex hormones needs to be addressed. Depending on the timing of puberty, duration of GnRH deficiency, and other osteoporotic risk factors (e.g., glucocorticoid excess, smoking), one should consider obtaining a bone mineral density study (see Consultation with a clinical geneticist and/or genetic counselor • Assessment of clinical manifestations of hypogonadism based on the age and sex of the individual, if not already performed as part of the diagnostic work up (See • Assessment of laboratory findings* of hypogonadotropic hypogonadism if not already performed as part of the diagnostic work up • * Serum concentration of LH (luteinizing hormone) and FSH (follicle-stimulating hormone) and in males total testosterone (T) <100 ng/dL and in females estradiol (E • Assessment for presence of possible non-reproductive features including: renal ultrasound examination (to detect unilateral renal agenesis), hearing tests (to detect sensorineural hearing loss), skeletal survey (to detect limb/spine bony abnormalities), dental exam (to detect dental agenesis), eye exam (to detect iris and/or chorioretinal coloboma) and developmental assessment (if there is evidence of developmental delay) • In addition to assessing the degree of hypogonadism/GnRH deficiency, potential deterioration in bone health that may have resulted from periods of low-circulating sex hormones needs to be addressed. Depending on the timing of puberty, duration of GnRH deficiency, and other osteoporotic risk factors (e.g., glucocorticoid excess, smoking), one should consider obtaining a bone mineral density study (see • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations An expert European consensus statement on the management of IGD has recently been published [ Typically, a definitive diagnosis of IGD is made around age 18 years. Occasionally, however, a high clinical suspicion of IGD may be present in an adolescent presenting with anosmia and delayed puberty or in an infant with microphallus and cryptorchidism. Treatment options include sex steroids, gonadotropins, and pulsatile GnRH administration. Choice of therapy in adults is determined by the goal(s) of treatment (i.e., to induce and maintain secondary sex characteristics and/or to induce and maintain fertility). The selection of hormone replacement therapy is also based on the preference of the individual being treated; however, when fertility is not immediately desired, replacement with testosterone therapy is the most practical option. As the majority of individuals with IGD have not progressed through puberty at the time of diagnosis, initial therapy should be started at low doses and gradually increased to adult doses once the development of secondary sexual characteristics is achieved. The injectable testosterone preparations have a "roller-coaster" pharmacokinetic effect, with peak and trough levels that can go to extraphysiologic levels; thus, the transdermal preparations have the added benefit of offering a more favorable pharmacokinetic profile. A typical adult dose of testosterone replacement is 200 mg of testosterone ester injection every two weeks or 5 g of a 1% testosterone gel every day. Doses do vary with newer testosterone preparations; manufacturer's instructions should be followed for individual testosterone preparations. Men using topical androgen replacement must take care to avoid exposing other individuals to treated skin. Anecdotal reports suggest that the transmission of clinically effective levels of testosterone from the affected individual to other family members (including women and children) is possible, with undesirable side effects. Once puberty is initiated, testosterone replacement therapy is usually required indefinitely to ensure normal sexual function and maintenance of proper muscle, bone, and red blood cell mass. However, in approximately 10% of males, reversal of IGD may occur; thus, if clinical evidence shows endogenous activity of the hypothalamo-pituitary-axis (e.g., testicular growth on testosterone, maintained testosterone levels despite missing/withholding therapy), a brief washout of testosterone therapy should be done with monitoring of testosterone levels. If testosterone levels fall, therapy should be reinitiated. If levels are normal, no further testosterone therapy will be required; serial monitoring of levels should be undertaken, as some individuals may require reinitiation of therapy. In adults, treatment with hCG is usually initiated at 1,500 IU intramuscularly or subcutaneously every other day to normalize serum testosterone concentrations. Dose should be increased by increments of 250 IU if serum testosterone levels remain low. Treatment with hCG must be weighed against the increased risk of developing gynecomastia (resulting from the estrogen produced by stimulation of the testes with hCG). To some extent the risk of gynecomastia can be minimized by gradually reducing the dose of hCG to the minimum required to sustain a serum testosterone concentration in the mid-normal range (~500 ng/dL). If IGD is clinically suspected (e.g., low testosterone levels with low/normal gonadotropins) low-dose testosterone or hCG therapy can be given in early infancy to boys with microphallus to increase penile length [ Since a definitive diagnosis of IGD may not be possible until age 18 years, after infancy these boys do not generally need to be treated until around the time of puberty. At this time, if a high suspicion of IGD remains (e.g., associated anosmia and delay in onset puberty), these subjects may benefit from early initiation of hormonal replacement therapy with either testosterone or hCG treatment early in the pubertal period. A suggestive puberty induction regimen in adolescents is to start a long-acting testosterone ester at a dose of 25-50 mg, given intramuscularly every two weeks. The doses can be gradually increased by 25-50 mg every two to three months until full virilization is achieved. Once adult doses (~200 mg/2 weeks) are reached, further adjustments are based on serum testosterone levels. In males with higher baseline testicular volumes, treatment with hCG alone may be sufficient to achieve spermatogenesis and conception [ In either treatment, testicular volume must be tracked, as this is one of the primary determinants of successful spermatogenesis. In fact, sperm are rarely seen in the semen analysis until testicular volume reaches 8 mL [ If a pituitary defect exists, gonadotropin therapy becomes the treatment of choice. Subcutaneous administration of GnRH in a pulsatile manner through a portable pump that delivers a GnRH bolus every two hours is an efficient way of inducing testicular growth and spermatogenesis [ To allow optimal breast development, initial treatment should consist of unopposed estrogen replacement via oral or topical preparations. Many formulations of estrogens are available; a suggested oral regimen is using premarin 0.3 mg daily to be increased gradually to an adult replacement dose of 1-1.25 mg daily. Once breast development is optimal, a progestin should be added for endometrial protection (e.g., cyclical Prometrium Although preference of the individual plays an important role in choice of treatment plan, low-estrogen formulations should be considered in women with clotting abnormalities (see Similarly, if spontaneous conception fails to occur in women with IGD who have undergone ovulation induction, IVF may be an option. • The injectable testosterone preparations have a "roller-coaster" pharmacokinetic effect, with peak and trough levels that can go to extraphysiologic levels; thus, the transdermal preparations have the added benefit of offering a more favorable pharmacokinetic profile. A typical adult dose of testosterone replacement is 200 mg of testosterone ester injection every two weeks or 5 g of a 1% testosterone gel every day. Doses do vary with newer testosterone preparations; manufacturer's instructions should be followed for individual testosterone preparations. • Men using topical androgen replacement must take care to avoid exposing other individuals to treated skin. Anecdotal reports suggest that the transmission of clinically effective levels of testosterone from the affected individual to other family members (including women and children) is possible, with undesirable side effects. • Once puberty is initiated, testosterone replacement therapy is usually required indefinitely to ensure normal sexual function and maintenance of proper muscle, bone, and red blood cell mass. • However, in approximately 10% of males, reversal of IGD may occur; thus, if clinical evidence shows endogenous activity of the hypothalamo-pituitary-axis (e.g., testicular growth on testosterone, maintained testosterone levels despite missing/withholding therapy), a brief washout of testosterone therapy should be done with monitoring of testosterone levels. If testosterone levels fall, therapy should be reinitiated. If levels are normal, no further testosterone therapy will be required; serial monitoring of levels should be undertaken, as some individuals may require reinitiation of therapy. • In adults, treatment with hCG is usually initiated at 1,500 IU intramuscularly or subcutaneously every other day to normalize serum testosterone concentrations. Dose should be increased by increments of 250 IU if serum testosterone levels remain low. • Treatment with hCG must be weighed against the increased risk of developing gynecomastia (resulting from the estrogen produced by stimulation of the testes with hCG). To some extent the risk of gynecomastia can be minimized by gradually reducing the dose of hCG to the minimum required to sustain a serum testosterone concentration in the mid-normal range (~500 ng/dL). • In males with higher baseline testicular volumes, treatment with hCG alone may be sufficient to achieve spermatogenesis and conception [ • In either treatment, testicular volume must be tracked, as this is one of the primary determinants of successful spermatogenesis. In fact, sperm are rarely seen in the semen analysis until testicular volume reaches 8 mL [ • If a pituitary defect exists, gonadotropin therapy becomes the treatment of choice. • Subcutaneous administration of GnRH in a pulsatile manner through a portable pump that delivers a GnRH bolus every two hours is an efficient way of inducing testicular growth and spermatogenesis [ • To allow optimal breast development, initial treatment should consist of unopposed estrogen replacement via oral or topical preparations. Many formulations of estrogens are available; a suggested oral regimen is using premarin 0.3 mg daily to be increased gradually to an adult replacement dose of 1-1.25 mg daily. • Once breast development is optimal, a progestin should be added for endometrial protection (e.g., cyclical Prometrium • Although preference of the individual plays an important role in choice of treatment plan, low-estrogen formulations should be considered in women with clotting abnormalities (see ## Males with IGD Age ≥18 Years Treatment options include sex steroids, gonadotropins, and pulsatile GnRH administration. Choice of therapy in adults is determined by the goal(s) of treatment (i.e., to induce and maintain secondary sex characteristics and/or to induce and maintain fertility). The selection of hormone replacement therapy is also based on the preference of the individual being treated; however, when fertility is not immediately desired, replacement with testosterone therapy is the most practical option. As the majority of individuals with IGD have not progressed through puberty at the time of diagnosis, initial therapy should be started at low doses and gradually increased to adult doses once the development of secondary sexual characteristics is achieved. The injectable testosterone preparations have a "roller-coaster" pharmacokinetic effect, with peak and trough levels that can go to extraphysiologic levels; thus, the transdermal preparations have the added benefit of offering a more favorable pharmacokinetic profile. A typical adult dose of testosterone replacement is 200 mg of testosterone ester injection every two weeks or 5 g of a 1% testosterone gel every day. Doses do vary with newer testosterone preparations; manufacturer's instructions should be followed for individual testosterone preparations. Men using topical androgen replacement must take care to avoid exposing other individuals to treated skin. Anecdotal reports suggest that the transmission of clinically effective levels of testosterone from the affected individual to other family members (including women and children) is possible, with undesirable side effects. Once puberty is initiated, testosterone replacement therapy is usually required indefinitely to ensure normal sexual function and maintenance of proper muscle, bone, and red blood cell mass. However, in approximately 10% of males, reversal of IGD may occur; thus, if clinical evidence shows endogenous activity of the hypothalamo-pituitary-axis (e.g., testicular growth on testosterone, maintained testosterone levels despite missing/withholding therapy), a brief washout of testosterone therapy should be done with monitoring of testosterone levels. If testosterone levels fall, therapy should be reinitiated. If levels are normal, no further testosterone therapy will be required; serial monitoring of levels should be undertaken, as some individuals may require reinitiation of therapy. In adults, treatment with hCG is usually initiated at 1,500 IU intramuscularly or subcutaneously every other day to normalize serum testosterone concentrations. Dose should be increased by increments of 250 IU if serum testosterone levels remain low. Treatment with hCG must be weighed against the increased risk of developing gynecomastia (resulting from the estrogen produced by stimulation of the testes with hCG). To some extent the risk of gynecomastia can be minimized by gradually reducing the dose of hCG to the minimum required to sustain a serum testosterone concentration in the mid-normal range (~500 ng/dL). • The injectable testosterone preparations have a "roller-coaster" pharmacokinetic effect, with peak and trough levels that can go to extraphysiologic levels; thus, the transdermal preparations have the added benefit of offering a more favorable pharmacokinetic profile. A typical adult dose of testosterone replacement is 200 mg of testosterone ester injection every two weeks or 5 g of a 1% testosterone gel every day. Doses do vary with newer testosterone preparations; manufacturer's instructions should be followed for individual testosterone preparations. • Men using topical androgen replacement must take care to avoid exposing other individuals to treated skin. Anecdotal reports suggest that the transmission of clinically effective levels of testosterone from the affected individual to other family members (including women and children) is possible, with undesirable side effects. • Once puberty is initiated, testosterone replacement therapy is usually required indefinitely to ensure normal sexual function and maintenance of proper muscle, bone, and red blood cell mass. • However, in approximately 10% of males, reversal of IGD may occur; thus, if clinical evidence shows endogenous activity of the hypothalamo-pituitary-axis (e.g., testicular growth on testosterone, maintained testosterone levels despite missing/withholding therapy), a brief washout of testosterone therapy should be done with monitoring of testosterone levels. If testosterone levels fall, therapy should be reinitiated. If levels are normal, no further testosterone therapy will be required; serial monitoring of levels should be undertaken, as some individuals may require reinitiation of therapy. • In adults, treatment with hCG is usually initiated at 1,500 IU intramuscularly or subcutaneously every other day to normalize serum testosterone concentrations. Dose should be increased by increments of 250 IU if serum testosterone levels remain low. • Treatment with hCG must be weighed against the increased risk of developing gynecomastia (resulting from the estrogen produced by stimulation of the testes with hCG). To some extent the risk of gynecomastia can be minimized by gradually reducing the dose of hCG to the minimum required to sustain a serum testosterone concentration in the mid-normal range (~500 ng/dL). ## Male Infants/Adolescents with Suspicion of IGD If IGD is clinically suspected (e.g., low testosterone levels with low/normal gonadotropins) low-dose testosterone or hCG therapy can be given in early infancy to boys with microphallus to increase penile length [ Since a definitive diagnosis of IGD may not be possible until age 18 years, after infancy these boys do not generally need to be treated until around the time of puberty. At this time, if a high suspicion of IGD remains (e.g., associated anosmia and delay in onset puberty), these subjects may benefit from early initiation of hormonal replacement therapy with either testosterone or hCG treatment early in the pubertal period. A suggestive puberty induction regimen in adolescents is to start a long-acting testosterone ester at a dose of 25-50 mg, given intramuscularly every two weeks. The doses can be gradually increased by 25-50 mg every two to three months until full virilization is achieved. Once adult doses (~200 mg/2 weeks) are reached, further adjustments are based on serum testosterone levels. In males with higher baseline testicular volumes, treatment with hCG alone may be sufficient to achieve spermatogenesis and conception [ In either treatment, testicular volume must be tracked, as this is one of the primary determinants of successful spermatogenesis. In fact, sperm are rarely seen in the semen analysis until testicular volume reaches 8 mL [ If a pituitary defect exists, gonadotropin therapy becomes the treatment of choice. Subcutaneous administration of GnRH in a pulsatile manner through a portable pump that delivers a GnRH bolus every two hours is an efficient way of inducing testicular growth and spermatogenesis [ • In males with higher baseline testicular volumes, treatment with hCG alone may be sufficient to achieve spermatogenesis and conception [ • In either treatment, testicular volume must be tracked, as this is one of the primary determinants of successful spermatogenesis. In fact, sperm are rarely seen in the semen analysis until testicular volume reaches 8 mL [ • If a pituitary defect exists, gonadotropin therapy becomes the treatment of choice. • Subcutaneous administration of GnRH in a pulsatile manner through a portable pump that delivers a GnRH bolus every two hours is an efficient way of inducing testicular growth and spermatogenesis [ ## Females with IGD To allow optimal breast development, initial treatment should consist of unopposed estrogen replacement via oral or topical preparations. Many formulations of estrogens are available; a suggested oral regimen is using premarin 0.3 mg daily to be increased gradually to an adult replacement dose of 1-1.25 mg daily. Once breast development is optimal, a progestin should be added for endometrial protection (e.g., cyclical Prometrium Although preference of the individual plays an important role in choice of treatment plan, low-estrogen formulations should be considered in women with clotting abnormalities (see • To allow optimal breast development, initial treatment should consist of unopposed estrogen replacement via oral or topical preparations. Many formulations of estrogens are available; a suggested oral regimen is using premarin 0.3 mg daily to be increased gradually to an adult replacement dose of 1-1.25 mg daily. • Once breast development is optimal, a progestin should be added for endometrial protection (e.g., cyclical Prometrium • Although preference of the individual plays an important role in choice of treatment plan, low-estrogen formulations should be considered in women with clotting abnormalities (see ## Fertility Options in Individuals with IGD If Fertility Induction Is Unsuccessful Similarly, if spontaneous conception fails to occur in women with IGD who have undergone ovulation induction, IVF may be an option. ## Prevention of Secondary Complications Optimal calcium and vitamin D intake should be encouraged and specific treatment for decreased bone mass with bisphosphonates should be considered depending on the degree of bone mineralization (see ## Surveillance Assessment of sexual maturation by Tanner staging ( Measurement of serum concentrations of LH, FSH, and total testosterone (T) in males and estradiol (E Bone age determinations • Assessment of sexual maturation by Tanner staging ( • Measurement of serum concentrations of LH, FSH, and total testosterone (T) in males and estradiol (E • Bone age determinations ## 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 prompt initiation of treatment. Evaluations can include: Molecular genetic testing if the pathogenic variant(s) in the family are known. However, a prepubertal child with a known pathogenic variant may progress through puberty in a normal fashion, delayed fashion, or not at all. Therefore, reevaluation of such individuals over time is important, and hormone treatment should be initiated only when IGD with impaired pubertal development is diagnosed. If the pathogenic variant(s) in the family are not known, clinical review of at-risk relatives of pubertal age to assess clinical onset of signs of puberty and if delayed, to initiate appropriate therapy for pubertal induction. See • Molecular genetic testing if the pathogenic variant(s) in the family are known. However, a prepubertal child with a known pathogenic variant may progress through puberty in a normal fashion, delayed fashion, or not at all. Therefore, reevaluation of such individuals over time is important, and hormone treatment should be initiated only when IGD with impaired pubertal development is diagnosed. • If the pathogenic variant(s) in the family are not known, clinical review of at-risk relatives of pubertal age to assess clinical onset of signs of puberty and if delayed, to initiate appropriate therapy for pubertal induction. ## Therapies Under Investigation Search ## Genetic Counseling Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) can be inherited in an X-linked, autosomal dominant, or autosomal recessive manner (see Almost all IGD-related genes have also been associated with indeterminate or oligogenic inheritance (especially when an IGD-related pathogenic variant occurs in the heterozygous state [ A three-generation family history should be obtained to understand the mode of inheritance of IGD to aid genetic testing and genetic counseling. Detailed histories including questions regarding consanguinity, reproductive features (e.g., microphallus and cryptorchidism, pubertal development, fertility/infertility), olfactory function (normal sense of smell, hyposmia, anosmia), and non-reproductive features (e.g., craniofacial abnormalities including cleft lip/palate/missing teeth, hearing loss, synkinesia of the digits, and renal agenesis) should be obtained for all family members. If other individuals with IGD or these associated findings are identified in the family, the mode of inheritance may become apparent. In the majority of individuals, however, no such family history is present. 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 pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism (maternal germline mosaicism has not been reported to date for 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 a 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 theoretic possibility of maternal germline mosaicism. With treatment, males with IGD can be fertile. Affected males transmit the All of their daughters, who will be heterozygous and may display some clinical features. None of their sons. Note: (1) Females heterozygous for an Some individuals with autosomal dominant IGD have an affected parent. A proband with autosomal dominant IGD may have the disorder as the result of a Recommendations for the evaluation of parents of a proband with an apparent A detailed pubertal history of both parents; and Molecular genetic testing of both parents for the pathogenic variant identified in the proband. If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a Evaluation of parents may determine that a parent has the pathogenic variant identified in the proband but has escaped previous diagnosis because of a milder phenotypic presentation, reduced penetrance, or late onset of the disorder. Therefore, an apparently negative family history cannot be fully confirmed until appropriate evaluations have been performed. If a parent of the proband is affected and/or has a pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50% although their actual risk may be lower due to variable expressivity and reduced penetrance. If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [ The parents of a child with autosomal recessive IGD are obligate heterozygotes (i.e., carriers of one pathogenic variant). Heterozygotes are typically unaffected. Occasionally, heterozygotes display clinical features diagnostic of IGD [ At conception, each sib of an individual with autosomal recessive IGD 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. Occasionally, heterozygotes display clinical features diagnostic of IGD [ The exact risk for IGD to the family members of a simplex proband (a single individual with a disorder in a family) with IGD of unknown cause or a proband with an indeterminate or oligogenic inheritance is uncertain but may be up to 50%. 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 IGD-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for IGD 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 pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism (maternal germline mosaicism has not been reported to date for • 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 a • 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 theoretic possibility of maternal germline mosaicism. • With treatment, males with IGD can be fertile. • Affected males transmit the • All of their daughters, who will be heterozygous and may display some clinical features. • None of their sons. • All of their daughters, who will be heterozygous and may display some clinical features. • None of their sons. • All of their daughters, who will be heterozygous and may display some clinical features. • None of their sons. • Some individuals with autosomal dominant IGD have an affected parent. • A proband with autosomal dominant IGD may have the disorder as the result of a • Recommendations for the evaluation of parents of a proband with an apparent • A detailed pubertal history of both parents; and • Molecular genetic testing of both parents for the pathogenic variant identified in the proband. • A detailed pubertal history of both parents; and • Molecular genetic testing of both parents for the pathogenic variant identified in the proband. • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a • Evaluation of parents may determine that a parent has the pathogenic variant identified in the proband but has escaped previous diagnosis because of a milder phenotypic presentation, reduced penetrance, or late onset of the disorder. Therefore, an apparently negative family history cannot be fully confirmed until appropriate evaluations have been performed. • A detailed pubertal history of both parents; and • Molecular genetic testing of both parents for the pathogenic variant identified in the proband. • If a parent of the proband is affected and/or has a pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50% although their actual risk may be lower due to variable expressivity and reduced penetrance. • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [ • The parents of a child with autosomal recessive IGD are obligate heterozygotes (i.e., carriers of one pathogenic variant). • Heterozygotes are typically unaffected. • Occasionally, heterozygotes display clinical features diagnostic of IGD [ • At conception, each sib of an individual with autosomal recessive IGD 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. • Occasionally, heterozygotes display clinical features diagnostic of IGD [ • 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 Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) can be inherited in an X-linked, autosomal dominant, or autosomal recessive manner (see Almost all IGD-related genes have also been associated with indeterminate or oligogenic inheritance (especially when an IGD-related pathogenic variant occurs in the heterozygous state [ A three-generation family history should be obtained to understand the mode of inheritance of IGD to aid genetic testing and genetic counseling. Detailed histories including questions regarding consanguinity, reproductive features (e.g., microphallus and cryptorchidism, pubertal development, fertility/infertility), olfactory function (normal sense of smell, hyposmia, anosmia), and non-reproductive features (e.g., craniofacial abnormalities including cleft lip/palate/missing teeth, hearing loss, synkinesia of the digits, and renal agenesis) should be obtained for all family members. If other individuals with IGD or these associated findings are identified in the family, the mode of inheritance may become apparent. In the majority of individuals, however, no such family history is present. ## 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 pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism (maternal germline mosaicism has not been reported to date for 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 a 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 theoretic possibility of maternal germline mosaicism. With treatment, males with IGD can be fertile. Affected males transmit the All of their daughters, who will be heterozygous and may display some clinical features. None of their sons. Note: (1) 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 pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism (maternal germline mosaicism has not been reported to date for • 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 a • 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 theoretic possibility of maternal germline mosaicism. • With treatment, males with IGD can be fertile. • Affected males transmit the • All of their daughters, who will be heterozygous and may display some clinical features. • None of their sons. • All of their daughters, who will be heterozygous and may display some clinical features. • None of their sons. • All of their daughters, who will be heterozygous and may display some clinical features. • None of their sons. ## Autosomal Dominant Inheritance – Risk to Family Members Some individuals with autosomal dominant IGD have an affected parent. A proband with autosomal dominant IGD may have the disorder as the result of a Recommendations for the evaluation of parents of a proband with an apparent A detailed pubertal history of both parents; and Molecular genetic testing of both parents for the pathogenic variant identified in the proband. If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a Evaluation of parents may determine that a parent has the pathogenic variant identified in the proband but has escaped previous diagnosis because of a milder phenotypic presentation, reduced penetrance, or late onset of the disorder. Therefore, an apparently negative family history cannot be fully confirmed until appropriate evaluations have been performed. If a parent of the proband is affected and/or has a pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50% although their actual risk may be lower due to variable expressivity and reduced penetrance. If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [ • Some individuals with autosomal dominant IGD have an affected parent. • A proband with autosomal dominant IGD may have the disorder as the result of a • Recommendations for the evaluation of parents of a proband with an apparent • A detailed pubertal history of both parents; and • Molecular genetic testing of both parents for the pathogenic variant identified in the proband. • A detailed pubertal history of both parents; and • Molecular genetic testing of both parents for the pathogenic variant identified in the proband. • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a • Evaluation of parents may determine that a parent has the pathogenic variant identified in the proband but has escaped previous diagnosis because of a milder phenotypic presentation, reduced penetrance, or late onset of the disorder. Therefore, an apparently negative family history cannot be fully confirmed until appropriate evaluations have been performed. • A detailed pubertal history of both parents; and • Molecular genetic testing of both parents for the pathogenic variant identified in the proband. • If a parent of the proband is affected and/or has a pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50% although their actual risk may be lower due to variable expressivity and reduced penetrance. • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [ ## Autosomal Recessive Inheritance – Risk to Family Members The parents of a child with autosomal recessive IGD are obligate heterozygotes (i.e., carriers of one pathogenic variant). Heterozygotes are typically unaffected. Occasionally, heterozygotes display clinical features diagnostic of IGD [ At conception, each sib of an individual with autosomal recessive IGD 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. Occasionally, heterozygotes display clinical features diagnostic of IGD [ • The parents of a child with autosomal recessive IGD are obligate heterozygotes (i.e., carriers of one pathogenic variant). • Heterozygotes are typically unaffected. • Occasionally, heterozygotes display clinical features diagnostic of IGD [ • At conception, each sib of an individual with autosomal recessive IGD 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. • Occasionally, heterozygotes display clinical features diagnostic of IGD [ ## Indeterminate or Oligogenic Inheritance – Risk to Family Members The exact risk for IGD to the family members of a simplex proband (a single individual with a disorder in a family) with IGD of unknown cause or a proband with an indeterminate or oligogenic inheritance is uncertain but may be up to 50%. ## 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 IGD-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for IGD are possible. ## Resources United Kingdom • • • • United Kingdom • • • ## Molecular Genetics Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency ( Over the last three decades, a combination of clinical investigational strategies and contemporary genetic approaches has revealed more than 25 causal/contributory genes for the nonsyndromic forms of IGD, with varied modes of inheritance. Broadly, two groups of genetic pathways are linked to IGD: (i) Neurodevelopmental genes govern the origin of the GnRH neurons and typically cause the Kallmann syndrome (KS) form of IGD. (ii) A group of neuroendocrine genes that control the secretion or action of GnRH cause the normosmic isolated GnRH deficiency (nIGD) form IGD. A small subset of genes may cause both KS and nIGD forms of IGD and this suggests that they govern both GnRH migration and GnRH secretion/action. (see In addition to Mendelian modes of inheritance, a complex genetic architecture for IGD (occurring in 10%-15% of cases) has now been documented wherein pathogenic variants in two or more IGD-related genes are present in a single individual. These pathogenic variants are typically heterozygous and by themselves are not sufficient to cause IGD but require the presence of additional pathogenic variants in a second gene to cause IGD [ For information about genes in ## Molecular Pathogenesis Over the last three decades, a combination of clinical investigational strategies and contemporary genetic approaches has revealed more than 25 causal/contributory genes for the nonsyndromic forms of IGD, with varied modes of inheritance. Broadly, two groups of genetic pathways are linked to IGD: (i) Neurodevelopmental genes govern the origin of the GnRH neurons and typically cause the Kallmann syndrome (KS) form of IGD. (ii) A group of neuroendocrine genes that control the secretion or action of GnRH cause the normosmic isolated GnRH deficiency (nIGD) form IGD. A small subset of genes may cause both KS and nIGD forms of IGD and this suggests that they govern both GnRH migration and GnRH secretion/action. (see In addition to Mendelian modes of inheritance, a complex genetic architecture for IGD (occurring in 10%-15% of cases) has now been documented wherein pathogenic variants in two or more IGD-related genes are present in a single individual. These pathogenic variants are typically heterozygous and by themselves are not sufficient to cause IGD but require the presence of additional pathogenic variants in a second gene to cause IGD [ For information about genes in ## ## ## ## ## ## ## For information about genes in ## Chapter Notes Margaret Au, MBE, MS, CGC; Massachusetts General Hospital (2010-2013)Ravikumar Balasubramanian, MD, PhD (2013-present)Cassandra Buck, MS, CGC; Massachusetts General Hospital (2013-2017)Marissa Caudill; University of Connecticut Health Center (2007-2010)William F Crowley Jr, MD (2007-present)J Carl Pallais, MD, MPH; Massachusetts General Hospital (2007-2013)Nelly Pitteloud, MD; Massachusetts General Hospital (2007-2013)Stephanie Seminara, MD; Massachusetts General Hospital (2007-2013) 12 May 2022 (aa) Revision: encephalocraniocutaneous lipomatosis added to 2 March 2017 (ha) Comprehensive update posted live 18 July 2013 (me) Comprehensive update posted live 8 April 2010 (me) Comprehensive update posted live 23 May 2007 (me) Review posted live 1 June 2006 (jcp) Original submission • 12 May 2022 (aa) Revision: encephalocraniocutaneous lipomatosis added to • 2 March 2017 (ha) Comprehensive update posted live • 18 July 2013 (me) Comprehensive update posted live • 8 April 2010 (me) Comprehensive update posted live • 23 May 2007 (me) Review posted live • 1 June 2006 (jcp) Original submission ## Author History Margaret Au, MBE, MS, CGC; Massachusetts General Hospital (2010-2013)Ravikumar Balasubramanian, MD, PhD (2013-present)Cassandra Buck, MS, CGC; Massachusetts General Hospital (2013-2017)Marissa Caudill; University of Connecticut Health Center (2007-2010)William F Crowley Jr, MD (2007-present)J Carl Pallais, MD, MPH; Massachusetts General Hospital (2007-2013)Nelly Pitteloud, MD; Massachusetts General Hospital (2007-2013)Stephanie Seminara, MD; Massachusetts General Hospital (2007-2013) ## Revision History 12 May 2022 (aa) Revision: encephalocraniocutaneous lipomatosis added to 2 March 2017 (ha) Comprehensive update posted live 18 July 2013 (me) Comprehensive update posted live 8 April 2010 (me) Comprehensive update posted live 23 May 2007 (me) Review posted live 1 June 2006 (jcp) Original submission • 12 May 2022 (aa) Revision: encephalocraniocutaneous lipomatosis added to • 2 March 2017 (ha) Comprehensive update posted live • 18 July 2013 (me) Comprehensive update posted live • 8 April 2010 (me) Comprehensive update posted live • 23 May 2007 (me) Review posted live • 1 June 2006 (jcp) Original submission ## References Boehm U, Bouloux PM, Dattani MT, de Roux N, Dodé C, Dunkel L, Dwyer AA, Giacobini P, Hardelin JP, Juul A, Maghnie M, Pitteloud N, Prevot V, Raivio T, Tena-Sempere M, Quinton R, Young J. Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism--pathogenesis, diagnosis and treatment. Available • Boehm U, Bouloux PM, Dattani MT, de Roux N, Dodé C, Dunkel L, Dwyer AA, Giacobini P, Hardelin JP, Juul A, Maghnie M, Pitteloud N, Prevot V, Raivio T, Tena-Sempere M, Quinton R, Young J. Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism--pathogenesis, diagnosis and treatment. Available ## Published Guidelines / Consensus Statements Boehm U, Bouloux PM, Dattani MT, de Roux N, Dodé C, Dunkel L, Dwyer AA, Giacobini P, Hardelin JP, Juul A, Maghnie M, Pitteloud N, Prevot V, Raivio T, Tena-Sempere M, Quinton R, Young J. Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism--pathogenesis, diagnosis and treatment. Available • Boehm U, Bouloux PM, Dattani MT, de Roux N, Dodé C, Dunkel L, Dwyer AA, Giacobini P, Hardelin JP, Juul A, Maghnie M, Pitteloud N, Prevot V, Raivio T, Tena-Sempere M, Quinton R, Young J. Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism--pathogenesis, diagnosis and treatment. Available ## Literature Cited Testing algorithm to establish the diagnosis of isolated GnRH deficiency (IGD) in males Testing algorithm to establish the diagnosis of isolated GnRH deficiency (IGD) in females Genes associated with isolated GnRH deficiency (IGD) by sense of smell and mode of inheritance Suggested guidelines for prioritization of genetic testing for persons with IGD based on phenotype [modified from	[]	23/5/2007	2/3/2017	12/5/2022	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
kmt2b-dystonia	kmt2b-dystonia	[ "KMT2B-Related Dystonia (DYT-KMT2B)", "KMT2B-Related Neurodevelopmental Disorder (KMT2B-Related NDD)", "Histone-lysine N-methyltransferase 2B", "KMT2B", "KMT2B-Related Disorders" ]		Lucia Abela, Manju Ann Kurian	Summary DYT- The diagnosis of a DYT-	For synonyms and outdated names, see For other genetic causes of these phenotypes, see ## Diagnosis No consensus clinical diagnostic criteria for DYT- Dystonia Typical presentation. Early onset, progressive, and often complex (median age: 6 years; range: 0-43 years) [ Atypical presentation. Upper-limb dystonia or cervical, oromandibular/laryngeal, and/or trunk dystonia without limb involvement Developmental delay (DD) /intellectual disability (ID) Developmental delay, in particular speech delay, preceding onset of dystonia Intellectual disability ranging from mild to severe Neurobehavioral/psychiatric manifestations including but not limited to autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), anxiety, obsessive-compulsive disorder, and depression. Note: This pattern may be an age-dependent phenomenon, as these features may become less prominent over time and are often not evident in adults. Indeed, in five individuals such MRI changes were less evident on subsequent MRIs [ Cerebellar atrophy was described in three individuals [ DaTscan was normal in four individuals, while two others showed decreased striatal uptake [ Mild-to-severe DD/ID Neurobehavioral/psychiatric manifestations including ASD, ADHD, and behavioral abnormalities Other Intrauterine growth restriction (IUGR) Short stature Endocrinopathies including hypothyroidism and precocious puberty The diagnosis of a A heterozygous pathogenic (or likely pathogenic) variant involving A heterozygous deletion of 19q13.11-19q13.12 involving Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Note: Single-gene testing (sequence analysis of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in CMA = chromosomal microarray analysis; ES = exome sequencing; GS = genome sequencing See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including For an introduction to epigenetic signature analysis click • Dystonia • Typical presentation. Early onset, progressive, and often complex (median age: 6 years; range: 0-43 years) [ • Atypical presentation. Upper-limb dystonia or cervical, oromandibular/laryngeal, and/or trunk dystonia without limb involvement • Typical presentation. Early onset, progressive, and often complex (median age: 6 years; range: 0-43 years) [ • Atypical presentation. Upper-limb dystonia or cervical, oromandibular/laryngeal, and/or trunk dystonia without limb involvement • Developmental delay (DD) /intellectual disability (ID) • Developmental delay, in particular speech delay, preceding onset of dystonia • Intellectual disability ranging from mild to severe • Developmental delay, in particular speech delay, preceding onset of dystonia • Intellectual disability ranging from mild to severe • Neurobehavioral/psychiatric manifestations including but not limited to autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), anxiety, obsessive-compulsive disorder, and depression. • Typical presentation. Early onset, progressive, and often complex (median age: 6 years; range: 0-43 years) [ • Atypical presentation. Upper-limb dystonia or cervical, oromandibular/laryngeal, and/or trunk dystonia without limb involvement • Developmental delay, in particular speech delay, preceding onset of dystonia • Intellectual disability ranging from mild to severe • Mild-to-severe DD/ID • Neurobehavioral/psychiatric manifestations including ASD, ADHD, and behavioral abnormalities • Other • Intrauterine growth restriction (IUGR) • Short stature • Endocrinopathies including hypothyroidism and precocious puberty • Intrauterine growth restriction (IUGR) • Short stature • Endocrinopathies including hypothyroidism and precocious puberty • Intrauterine growth restriction (IUGR) • Short stature • Endocrinopathies including hypothyroidism and precocious puberty • A heterozygous pathogenic (or likely pathogenic) variant involving • A heterozygous deletion of 19q13.11-19q13.12 involving ## Suggestive Findings DYT- Dystonia Typical presentation. Early onset, progressive, and often complex (median age: 6 years; range: 0-43 years) [ Atypical presentation. Upper-limb dystonia or cervical, oromandibular/laryngeal, and/or trunk dystonia without limb involvement Developmental delay (DD) /intellectual disability (ID) Developmental delay, in particular speech delay, preceding onset of dystonia Intellectual disability ranging from mild to severe Neurobehavioral/psychiatric manifestations including but not limited to autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), anxiety, obsessive-compulsive disorder, and depression. Note: This pattern may be an age-dependent phenomenon, as these features may become less prominent over time and are often not evident in adults. Indeed, in five individuals such MRI changes were less evident on subsequent MRIs [ Cerebellar atrophy was described in three individuals [ DaTscan was normal in four individuals, while two others showed decreased striatal uptake [ Mild-to-severe DD/ID Neurobehavioral/psychiatric manifestations including ASD, ADHD, and behavioral abnormalities Other Intrauterine growth restriction (IUGR) Short stature Endocrinopathies including hypothyroidism and precocious puberty • Dystonia • Typical presentation. Early onset, progressive, and often complex (median age: 6 years; range: 0-43 years) [ • Atypical presentation. Upper-limb dystonia or cervical, oromandibular/laryngeal, and/or trunk dystonia without limb involvement • Typical presentation. Early onset, progressive, and often complex (median age: 6 years; range: 0-43 years) [ • Atypical presentation. Upper-limb dystonia or cervical, oromandibular/laryngeal, and/or trunk dystonia without limb involvement • Developmental delay (DD) /intellectual disability (ID) • Developmental delay, in particular speech delay, preceding onset of dystonia • Intellectual disability ranging from mild to severe • Developmental delay, in particular speech delay, preceding onset of dystonia • Intellectual disability ranging from mild to severe • Neurobehavioral/psychiatric manifestations including but not limited to autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), anxiety, obsessive-compulsive disorder, and depression. • Typical presentation. Early onset, progressive, and often complex (median age: 6 years; range: 0-43 years) [ • Atypical presentation. Upper-limb dystonia or cervical, oromandibular/laryngeal, and/or trunk dystonia without limb involvement • Developmental delay, in particular speech delay, preceding onset of dystonia • Intellectual disability ranging from mild to severe • Mild-to-severe DD/ID • Neurobehavioral/psychiatric manifestations including ASD, ADHD, and behavioral abnormalities • Other • Intrauterine growth restriction (IUGR) • Short stature • Endocrinopathies including hypothyroidism and precocious puberty • Intrauterine growth restriction (IUGR) • Short stature • Endocrinopathies including hypothyroidism and precocious puberty • Intrauterine growth restriction (IUGR) • Short stature • Endocrinopathies including hypothyroidism and precocious puberty DYT- Dystonia Typical presentation. Early onset, progressive, and often complex (median age: 6 years; range: 0-43 years) [ Atypical presentation. Upper-limb dystonia or cervical, oromandibular/laryngeal, and/or trunk dystonia without limb involvement Developmental delay (DD) /intellectual disability (ID) Developmental delay, in particular speech delay, preceding onset of dystonia Intellectual disability ranging from mild to severe Neurobehavioral/psychiatric manifestations including but not limited to autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), anxiety, obsessive-compulsive disorder, and depression. Note: This pattern may be an age-dependent phenomenon, as these features may become less prominent over time and are often not evident in adults. Indeed, in five individuals such MRI changes were less evident on subsequent MRIs [ Cerebellar atrophy was described in three individuals [ DaTscan was normal in four individuals, while two others showed decreased striatal uptake [ • Dystonia • Typical presentation. Early onset, progressive, and often complex (median age: 6 years; range: 0-43 years) [ • Atypical presentation. Upper-limb dystonia or cervical, oromandibular/laryngeal, and/or trunk dystonia without limb involvement • Typical presentation. Early onset, progressive, and often complex (median age: 6 years; range: 0-43 years) [ • Atypical presentation. Upper-limb dystonia or cervical, oromandibular/laryngeal, and/or trunk dystonia without limb involvement • Developmental delay (DD) /intellectual disability (ID) • Developmental delay, in particular speech delay, preceding onset of dystonia • Intellectual disability ranging from mild to severe • Developmental delay, in particular speech delay, preceding onset of dystonia • Intellectual disability ranging from mild to severe • Neurobehavioral/psychiatric manifestations including but not limited to autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), anxiety, obsessive-compulsive disorder, and depression. • Typical presentation. Early onset, progressive, and often complex (median age: 6 years; range: 0-43 years) [ • Atypical presentation. Upper-limb dystonia or cervical, oromandibular/laryngeal, and/or trunk dystonia without limb involvement • Developmental delay, in particular speech delay, preceding onset of dystonia • Intellectual disability ranging from mild to severe Mild-to-severe DD/ID Neurobehavioral/psychiatric manifestations including ASD, ADHD, and behavioral abnormalities Other Intrauterine growth restriction (IUGR) Short stature Endocrinopathies including hypothyroidism and precocious puberty • Mild-to-severe DD/ID • Neurobehavioral/psychiatric manifestations including ASD, ADHD, and behavioral abnormalities • Other • Intrauterine growth restriction (IUGR) • Short stature • Endocrinopathies including hypothyroidism and precocious puberty • Intrauterine growth restriction (IUGR) • Short stature • Endocrinopathies including hypothyroidism and precocious puberty • Intrauterine growth restriction (IUGR) • Short stature • Endocrinopathies including hypothyroidism and precocious puberty ## Establishing the Diagnosis The diagnosis of a A heterozygous pathogenic (or likely pathogenic) variant involving A heterozygous deletion of 19q13.11-19q13.12 involving Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Note: Single-gene testing (sequence analysis of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in CMA = chromosomal microarray analysis; ES = exome sequencing; GS = genome sequencing See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including For an introduction to epigenetic signature analysis click • A heterozygous pathogenic (or likely pathogenic) variant involving • A heterozygous deletion of 19q13.11-19q13.12 involving ## Option 1 For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in CMA = chromosomal microarray analysis; ES = exome sequencing; GS = genome sequencing See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including For an introduction to epigenetic signature analysis click ## Clinical Characteristics DYT- Although many affected individuals follow a similar disease course, an increasing number have milder and atypical findings. Atypical first disease presentations include isolated upper limb, neck, trunk, or oromandibular/laryngeal dystonia or dystonic tremor [ To date, about 238 individuals with a pathogenic variant in DYT- Including myoclonus, spasticity, tremor, and ataxia Bulbar dysfunction is difficult to assess in publications. This percentage assumes that laryngeal dysfunction is part of bulbar dysfunction, which is only included here if explicitly mentioned in the publication. (The actual percentage is probably higher.) Autism spectrum disorder (ASD) (4%), attention-deficit/hyperactivity disorder (ADHD) (10%), anxiety / obsessive-compulsive disorder (11%), depression / behavioral abnormalities not further specified (1.5%) ASD (7%), ADHD (7%), behavioral abnormalities not further specified (7%) Lower-limb dystonia characterized by foot posturing, toe walking, and gait disturbance (in ~66% individuals) Upper-limb dystonia leading to abnormal hand/arm posturing, dystonic tremor, and difficulties in handwriting and hand dexterity (~15%) Laryngeal dystonia / oromandibular dystonia (~10%) Cervical dystonia (~5.5%) Truncal/axial dystonia (~2%) Dystonic tremor (~2%) Over time, most individuals developed progressive cranial and cervical dystonia (retrocollis, torticollis). Generalized dystonia becomes evident in most individuals (~68%) within two to 11 years of initial presentation [ The spectrum of gross motor disability is broad, ranging from minor gait disturbance to wheelchair dependence (Gross Motor Function Classification System II-V (GMFCS II-V) [ Presenting manifestations of Prominent cervical dystonia [ Prominent upper-limb dystonia [ Oromandibular or laryngeal features without clinical evidence of limb dystonia [ Bilateral mirror movements (one individual) [ Development of parkinsonism (one individual) [ Microcephaly (~44%) Other systemic features possibly related to the endocrine system (~38%) including short stature, precocious puberty, and hypothyroidism Ophthalmologic findings, including refractive errors, end-gaze nystagmus, strabismus, slow saccades (~8%) Dermatologic features (~4%) of ectodermal dysplasia including cutis aplasia, sparse hair, sparse to absent eyelashes or brows, hypertrichosis, and ichthyotic skin with criss-cross pattern under the feet and at the knees. Although broad postsurgical scarring and "phimosis" have been reported, it is not currently known if these features are incidental or truly disease related. Seizures have been reported in four individuals: absence seizures (2), focal epilepsy (1), and unspecified epilepsy (1). A Seventeen individuals had heterozygous Nine individuals had deletions on chromosome 19q13.11-19q13.12 encompassing These individuals share similar clinical findings: pre- and postnatal growth restriction, feeding difficulties, microcephaly, developmental delay / intellectual disability (speech delay), ectodermal dysplasia, and genital malformations in males. DYT- DYT- In a cohort of 68 individuals with In larger cohorts of individuals with Disease prevalence is not yet established. To date, 246 individuals from 229 families with DYT- • Lower-limb dystonia characterized by foot posturing, toe walking, and gait disturbance (in ~66% individuals) • Upper-limb dystonia leading to abnormal hand/arm posturing, dystonic tremor, and difficulties in handwriting and hand dexterity (~15%) • Laryngeal dystonia / oromandibular dystonia (~10%) • Cervical dystonia (~5.5%) • Truncal/axial dystonia (~2%) • Dystonic tremor (~2%) • Prominent cervical dystonia [ • Prominent upper-limb dystonia [ • Oromandibular or laryngeal features without clinical evidence of limb dystonia [ • Bilateral mirror movements (one individual) [ • Development of parkinsonism (one individual) [ • Microcephaly (~44%) • Other systemic features possibly related to the endocrine system (~38%) including short stature, precocious puberty, and hypothyroidism • Ophthalmologic findings, including refractive errors, end-gaze nystagmus, strabismus, slow saccades (~8%) • Dermatologic features (~4%) of ectodermal dysplasia including cutis aplasia, sparse hair, sparse to absent eyelashes or brows, hypertrichosis, and ichthyotic skin with criss-cross pattern under the feet and at the knees. Although broad postsurgical scarring and "phimosis" have been reported, it is not currently known if these features are incidental or truly disease related. • Seizures have been reported in four individuals: absence seizures (2), focal epilepsy (1), and unspecified epilepsy (1). • Seventeen individuals had heterozygous • Nine individuals had deletions on chromosome 19q13.11-19q13.12 encompassing • In a cohort of 68 individuals with • In larger cohorts of individuals with ## Clinical Description DYT- Although many affected individuals follow a similar disease course, an increasing number have milder and atypical findings. Atypical first disease presentations include isolated upper limb, neck, trunk, or oromandibular/laryngeal dystonia or dystonic tremor [ To date, about 238 individuals with a pathogenic variant in DYT- Including myoclonus, spasticity, tremor, and ataxia Bulbar dysfunction is difficult to assess in publications. This percentage assumes that laryngeal dysfunction is part of bulbar dysfunction, which is only included here if explicitly mentioned in the publication. (The actual percentage is probably higher.) Autism spectrum disorder (ASD) (4%), attention-deficit/hyperactivity disorder (ADHD) (10%), anxiety / obsessive-compulsive disorder (11%), depression / behavioral abnormalities not further specified (1.5%) ASD (7%), ADHD (7%), behavioral abnormalities not further specified (7%) Lower-limb dystonia characterized by foot posturing, toe walking, and gait disturbance (in ~66% individuals) Upper-limb dystonia leading to abnormal hand/arm posturing, dystonic tremor, and difficulties in handwriting and hand dexterity (~15%) Laryngeal dystonia / oromandibular dystonia (~10%) Cervical dystonia (~5.5%) Truncal/axial dystonia (~2%) Dystonic tremor (~2%) Over time, most individuals developed progressive cranial and cervical dystonia (retrocollis, torticollis). Generalized dystonia becomes evident in most individuals (~68%) within two to 11 years of initial presentation [ The spectrum of gross motor disability is broad, ranging from minor gait disturbance to wheelchair dependence (Gross Motor Function Classification System II-V (GMFCS II-V) [ Presenting manifestations of Prominent cervical dystonia [ Prominent upper-limb dystonia [ Oromandibular or laryngeal features without clinical evidence of limb dystonia [ Bilateral mirror movements (one individual) [ Development of parkinsonism (one individual) [ Microcephaly (~44%) Other systemic features possibly related to the endocrine system (~38%) including short stature, precocious puberty, and hypothyroidism Ophthalmologic findings, including refractive errors, end-gaze nystagmus, strabismus, slow saccades (~8%) Dermatologic features (~4%) of ectodermal dysplasia including cutis aplasia, sparse hair, sparse to absent eyelashes or brows, hypertrichosis, and ichthyotic skin with criss-cross pattern under the feet and at the knees. Although broad postsurgical scarring and "phimosis" have been reported, it is not currently known if these features are incidental or truly disease related. Seizures have been reported in four individuals: absence seizures (2), focal epilepsy (1), and unspecified epilepsy (1). A Seventeen individuals had heterozygous Nine individuals had deletions on chromosome 19q13.11-19q13.12 encompassing These individuals share similar clinical findings: pre- and postnatal growth restriction, feeding difficulties, microcephaly, developmental delay / intellectual disability (speech delay), ectodermal dysplasia, and genital malformations in males. • Lower-limb dystonia characterized by foot posturing, toe walking, and gait disturbance (in ~66% individuals) • Upper-limb dystonia leading to abnormal hand/arm posturing, dystonic tremor, and difficulties in handwriting and hand dexterity (~15%) • Laryngeal dystonia / oromandibular dystonia (~10%) • Cervical dystonia (~5.5%) • Truncal/axial dystonia (~2%) • Dystonic tremor (~2%) • Prominent cervical dystonia [ • Prominent upper-limb dystonia [ • Oromandibular or laryngeal features without clinical evidence of limb dystonia [ • Bilateral mirror movements (one individual) [ • Development of parkinsonism (one individual) [ • Microcephaly (~44%) • Other systemic features possibly related to the endocrine system (~38%) including short stature, precocious puberty, and hypothyroidism • Ophthalmologic findings, including refractive errors, end-gaze nystagmus, strabismus, slow saccades (~8%) • Dermatologic features (~4%) of ectodermal dysplasia including cutis aplasia, sparse hair, sparse to absent eyelashes or brows, hypertrichosis, and ichthyotic skin with criss-cross pattern under the feet and at the knees. Although broad postsurgical scarring and "phimosis" have been reported, it is not currently known if these features are incidental or truly disease related. • Seizures have been reported in four individuals: absence seizures (2), focal epilepsy (1), and unspecified epilepsy (1). • Seventeen individuals had heterozygous • Nine individuals had deletions on chromosome 19q13.11-19q13.12 encompassing ## DYT- Lower-limb dystonia characterized by foot posturing, toe walking, and gait disturbance (in ~66% individuals) Upper-limb dystonia leading to abnormal hand/arm posturing, dystonic tremor, and difficulties in handwriting and hand dexterity (~15%) Laryngeal dystonia / oromandibular dystonia (~10%) Cervical dystonia (~5.5%) Truncal/axial dystonia (~2%) Dystonic tremor (~2%) Over time, most individuals developed progressive cranial and cervical dystonia (retrocollis, torticollis). Generalized dystonia becomes evident in most individuals (~68%) within two to 11 years of initial presentation [ The spectrum of gross motor disability is broad, ranging from minor gait disturbance to wheelchair dependence (Gross Motor Function Classification System II-V (GMFCS II-V) [ Presenting manifestations of Prominent cervical dystonia [ Prominent upper-limb dystonia [ Oromandibular or laryngeal features without clinical evidence of limb dystonia [ Bilateral mirror movements (one individual) [ Development of parkinsonism (one individual) [ Microcephaly (~44%) Other systemic features possibly related to the endocrine system (~38%) including short stature, precocious puberty, and hypothyroidism Ophthalmologic findings, including refractive errors, end-gaze nystagmus, strabismus, slow saccades (~8%) Dermatologic features (~4%) of ectodermal dysplasia including cutis aplasia, sparse hair, sparse to absent eyelashes or brows, hypertrichosis, and ichthyotic skin with criss-cross pattern under the feet and at the knees. Although broad postsurgical scarring and "phimosis" have been reported, it is not currently known if these features are incidental or truly disease related. Seizures have been reported in four individuals: absence seizures (2), focal epilepsy (1), and unspecified epilepsy (1). • Lower-limb dystonia characterized by foot posturing, toe walking, and gait disturbance (in ~66% individuals) • Upper-limb dystonia leading to abnormal hand/arm posturing, dystonic tremor, and difficulties in handwriting and hand dexterity (~15%) • Laryngeal dystonia / oromandibular dystonia (~10%) • Cervical dystonia (~5.5%) • Truncal/axial dystonia (~2%) • Dystonic tremor (~2%) • Prominent cervical dystonia [ • Prominent upper-limb dystonia [ • Oromandibular or laryngeal features without clinical evidence of limb dystonia [ • Bilateral mirror movements (one individual) [ • Development of parkinsonism (one individual) [ • Microcephaly (~44%) • Other systemic features possibly related to the endocrine system (~38%) including short stature, precocious puberty, and hypothyroidism • Ophthalmologic findings, including refractive errors, end-gaze nystagmus, strabismus, slow saccades (~8%) • Dermatologic features (~4%) of ectodermal dysplasia including cutis aplasia, sparse hair, sparse to absent eyelashes or brows, hypertrichosis, and ichthyotic skin with criss-cross pattern under the feet and at the knees. Although broad postsurgical scarring and "phimosis" have been reported, it is not currently known if these features are incidental or truly disease related. • Seizures have been reported in four individuals: absence seizures (2), focal epilepsy (1), and unspecified epilepsy (1). A Seventeen individuals had heterozygous Nine individuals had deletions on chromosome 19q13.11-19q13.12 encompassing These individuals share similar clinical findings: pre- and postnatal growth restriction, feeding difficulties, microcephaly, developmental delay / intellectual disability (speech delay), ectodermal dysplasia, and genital malformations in males. • Seventeen individuals had heterozygous • Nine individuals had deletions on chromosome 19q13.11-19q13.12 encompassing ## Genotype-Phenotype Correlations ## Penetrance DYT- ## Nomenclature DYT- In a cohort of 68 individuals with In larger cohorts of individuals with • In a cohort of 68 individuals with • In larger cohorts of individuals with ## Prevalence Disease prevalence is not yet established. To date, 246 individuals from 229 families with DYT- ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The differential diagnosis of Complex dystonias (i.e., disorders with dystonia and other neurologic or systemic manifestations) include genetic neurodegenerative and metabolic disorders (see Genetic Disorders with Early-Onset Generalized Dystonia to Consider in the Differential Diagnosis of Parkinsonism, spasticity, eye movement abnormalities, optic atrophy, axonal neuropathy, seizures Characteristic T Prominent dystonia phenotype, parkinsonism, DD, neuropsychiatric features, seizures ↓ tracer uptake on DaTscan Psychiatric comorbidities Tremor, liver disease, Kayser-Fleischer corneal ring Face-of-the-giant-panda sign on MRI Low serum ceruloplasmin concentration, high serum non-ceruloplasmin-bound copper concentration Progressive parkinsonism-dystonia, eye movement disorder, delayed motor milestones, hypotonia ↓ tracer uptake on DaTscan CSF neurotransmitter abnormalities Prominent dystonia phenotype, parkinsonism, DD, neuropsychiatric features, seizures ↓ tracer uptake on DaTscan Encephalopathic crisis assoc w/infections/fever (age 6-18 mos); macrocephaly Frontotemporal atrophy, widening of sylvian fissures, T ↑ urinary 3-hydroxyglutaric acid & glutarylcarnitine Progressive parkinsonism-dystonia, eye movement disorder, delayed motor milestones, hypotonia ↓ tracer uptake on DaTscan CSF neurotransmitter abnormalities Pyramidal signs, self-mutilation Hyperuricemia Growth failure, renal syndromes, ID, metabolic stroke-like events, hypotonia, psychiatric features ↑ plasma & urine methylmalonic acid w/normal B Spasticity, hepatomegaly/splenomegaly, supranuclear gaze palsy, cataplexy, seizures, psychiatric comorbidities ↑ oxysterol levels Poor growth, DD, ID, gastrointestinal symptoms, hypotonia, psychiatric features ↑ propionylcarnitine (C3) in plasma, ↑ 3-hydroxypropionate in urine, hyperammonemia, lactic acidosis Multisystemic involvement Commonly shows "Leigh" radiologic appearance of T Leukodystrophy ↑ lactate concentration Metabolic acidosis Prominent dystonia phenotype, parkinsonism, DD, neuropsychiatric features, seizures ↓ tracer uptake on DaTscan Progressive parkinsonism-dystonia, eye movement disorder, delayed motor milestones, hypotonia ↓ tracer uptake on DaTscan CSF neurotransmitter abnormalities Parkinsonism, liver disease T Hypermanganesemia, polycythemia Parkinsonism, spasticity, dysarthria, bulbar dysfunction T Hypermanganesemia Progressive parkinsonism-dystonia, eye movement disorder, delayed motor milestones, hypotonia ↓ tracer uptake on DaTscan CSF neurotransmitter abnormalities Progressive parkinsonism-dystonia, eye movement disorder, delayed motor milestones, hypotonia ↓ tracer uptake on DaTscan CSF neurotransmitter abnormalities Progressive parkinsonism-dystonia, eye movement disorder, delayed motor milestones, hypotonia ↓ tracer uptake on DaTscan CSF neurotransmitter abnormalities Early craniofacial involvement & laryngeal dystonia Isolated dystonia w/older average age of onset Prominent dystonia phenotype, ID, motor delay, spasticity Hypomyelinating leukodystrophy, cerebellar & basal ganglia atrophy on MRI Multisystemic involvement Commonly shows "Leigh" radiologic appearance of T Leukodystrophy ↑ lactate & pyruvate concentrations Metabolic acidosis AD = autosomal dominant; AR = autosomal recessive; CSF = cerebrospinal fluid; DD = developmental delay; ID = intellectual disability; MT = mitochondrial; MOI = mode of inheritance; XL = X-linked Neurodegeneration with brain iron accumulation (NBIA) disorders caused by pathogenic variants in In most individuals reported to date, The phenotypic features associated with See OMIM Phenotypic Series for genes associated with: The disorders in Selected Disorders in the Differential Diagnosis of AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; IUGR = intrauterine growth restriction; MOI = mode of inheritance; PV = pathogenic variant; upd(7)mat = maternal uniparental disomy of chromosome 7; XL = X-linked Silver-Russell syndrome (SRS) is a genetically heterogeneous condition. Genetic testing confirms clinical diagnosis in ~60% of affected individuals. Accurate assessment of SRS recurrence requires identification of the causative genetic mechanism in the proband. • Parkinsonism, spasticity, eye movement abnormalities, optic atrophy, axonal neuropathy, seizures • Characteristic T • Prominent dystonia phenotype, parkinsonism, DD, neuropsychiatric features, seizures • ↓ tracer uptake on DaTscan • Psychiatric comorbidities • Tremor, liver disease, Kayser-Fleischer corneal ring • Face-of-the-giant-panda sign on MRI • Low serum ceruloplasmin concentration, high serum non-ceruloplasmin-bound copper concentration • Progressive parkinsonism-dystonia, eye movement disorder, delayed motor milestones, hypotonia • ↓ tracer uptake on DaTscan • CSF neurotransmitter abnormalities • Prominent dystonia phenotype, parkinsonism, DD, neuropsychiatric features, seizures • ↓ tracer uptake on DaTscan • Encephalopathic crisis assoc w/infections/fever (age 6-18 mos); macrocephaly • Frontotemporal atrophy, widening of sylvian fissures, T • ↑ urinary 3-hydroxyglutaric acid & glutarylcarnitine • Progressive parkinsonism-dystonia, eye movement disorder, delayed motor milestones, hypotonia • ↓ tracer uptake on DaTscan • CSF neurotransmitter abnormalities • Pyramidal signs, self-mutilation • Hyperuricemia • Growth failure, renal syndromes, ID, metabolic stroke-like events, hypotonia, psychiatric features • ↑ plasma & urine methylmalonic acid w/normal B • Spasticity, hepatomegaly/splenomegaly, supranuclear gaze palsy, cataplexy, seizures, psychiatric comorbidities • ↑ oxysterol levels • Poor growth, DD, ID, gastrointestinal symptoms, hypotonia, psychiatric features • ↑ propionylcarnitine (C3) in plasma, ↑ 3-hydroxypropionate in urine, hyperammonemia, lactic acidosis • Multisystemic involvement • Commonly shows "Leigh" radiologic appearance of T • Leukodystrophy • ↑ lactate concentration • Metabolic acidosis • Prominent dystonia phenotype, parkinsonism, DD, neuropsychiatric features, seizures • ↓ tracer uptake on DaTscan • Progressive parkinsonism-dystonia, eye movement disorder, delayed motor milestones, hypotonia • ↓ tracer uptake on DaTscan • CSF neurotransmitter abnormalities • Parkinsonism, liver disease • T • Hypermanganesemia, polycythemia • Parkinsonism, spasticity, dysarthria, bulbar dysfunction • T • Hypermanganesemia • Progressive parkinsonism-dystonia, eye movement disorder, delayed motor milestones, hypotonia • ↓ tracer uptake on DaTscan • CSF neurotransmitter abnormalities • Progressive parkinsonism-dystonia, eye movement disorder, delayed motor milestones, hypotonia • ↓ tracer uptake on DaTscan • CSF neurotransmitter abnormalities • Progressive parkinsonism-dystonia, eye movement disorder, delayed motor milestones, hypotonia • ↓ tracer uptake on DaTscan • CSF neurotransmitter abnormalities • Early craniofacial involvement & laryngeal dystonia • Isolated dystonia w/older average age of onset • Prominent dystonia phenotype, ID, motor delay, spasticity • Hypomyelinating leukodystrophy, cerebellar & basal ganglia atrophy on MRI • Multisystemic involvement • Commonly shows "Leigh" radiologic appearance of T • Leukodystrophy • ↑ lactate & pyruvate concentrations • Metabolic acidosis The differential diagnosis of Complex dystonias (i.e., disorders with dystonia and other neurologic or systemic manifestations) include genetic neurodegenerative and metabolic disorders (see Genetic Disorders with Early-Onset Generalized Dystonia to Consider in the Differential Diagnosis of Parkinsonism, spasticity, eye movement abnormalities, optic atrophy, axonal neuropathy, seizures Characteristic T Prominent dystonia phenotype, parkinsonism, DD, neuropsychiatric features, seizures ↓ tracer uptake on DaTscan Psychiatric comorbidities Tremor, liver disease, Kayser-Fleischer corneal ring Face-of-the-giant-panda sign on MRI Low serum ceruloplasmin concentration, high serum non-ceruloplasmin-bound copper concentration Progressive parkinsonism-dystonia, eye movement disorder, delayed motor milestones, hypotonia ↓ tracer uptake on DaTscan CSF neurotransmitter abnormalities Prominent dystonia phenotype, parkinsonism, DD, neuropsychiatric features, seizures ↓ tracer uptake on DaTscan Encephalopathic crisis assoc w/infections/fever (age 6-18 mos); macrocephaly Frontotemporal atrophy, widening of sylvian fissures, T ↑ urinary 3-hydroxyglutaric acid & glutarylcarnitine Progressive parkinsonism-dystonia, eye movement disorder, delayed motor milestones, hypotonia ↓ tracer uptake on DaTscan CSF neurotransmitter abnormalities Pyramidal signs, self-mutilation Hyperuricemia Growth failure, renal syndromes, ID, metabolic stroke-like events, hypotonia, psychiatric features ↑ plasma & urine methylmalonic acid w/normal B Spasticity, hepatomegaly/splenomegaly, supranuclear gaze palsy, cataplexy, seizures, psychiatric comorbidities ↑ oxysterol levels Poor growth, DD, ID, gastrointestinal symptoms, hypotonia, psychiatric features ↑ propionylcarnitine (C3) in plasma, ↑ 3-hydroxypropionate in urine, hyperammonemia, lactic acidosis Multisystemic involvement Commonly shows "Leigh" radiologic appearance of T Leukodystrophy ↑ lactate concentration Metabolic acidosis Prominent dystonia phenotype, parkinsonism, DD, neuropsychiatric features, seizures ↓ tracer uptake on DaTscan Progressive parkinsonism-dystonia, eye movement disorder, delayed motor milestones, hypotonia ↓ tracer uptake on DaTscan CSF neurotransmitter abnormalities Parkinsonism, liver disease T Hypermanganesemia, polycythemia Parkinsonism, spasticity, dysarthria, bulbar dysfunction T Hypermanganesemia Progressive parkinsonism-dystonia, eye movement disorder, delayed motor milestones, hypotonia ↓ tracer uptake on DaTscan CSF neurotransmitter abnormalities Progressive parkinsonism-dystonia, eye movement disorder, delayed motor milestones, hypotonia ↓ tracer uptake on DaTscan CSF neurotransmitter abnormalities Progressive parkinsonism-dystonia, eye movement disorder, delayed motor milestones, hypotonia ↓ tracer uptake on DaTscan CSF neurotransmitter abnormalities Early craniofacial involvement & laryngeal dystonia Isolated dystonia w/older average age of onset Prominent dystonia phenotype, ID, motor delay, spasticity Hypomyelinating leukodystrophy, cerebellar & basal ganglia atrophy on MRI Multisystemic involvement Commonly shows "Leigh" radiologic appearance of T Leukodystrophy ↑ lactate & pyruvate concentrations Metabolic acidosis AD = autosomal dominant; AR = autosomal recessive; CSF = cerebrospinal fluid; DD = developmental delay; ID = intellectual disability; MT = mitochondrial; MOI = mode of inheritance; XL = X-linked Neurodegeneration with brain iron accumulation (NBIA) disorders caused by pathogenic variants in In most individuals reported to date, • Parkinsonism, spasticity, eye movement abnormalities, optic atrophy, axonal neuropathy, seizures • Characteristic T • Prominent dystonia phenotype, parkinsonism, DD, neuropsychiatric features, seizures • ↓ tracer uptake on DaTscan • Psychiatric comorbidities • Tremor, liver disease, Kayser-Fleischer corneal ring • Face-of-the-giant-panda sign on MRI • Low serum ceruloplasmin concentration, high serum non-ceruloplasmin-bound copper concentration • Progressive parkinsonism-dystonia, eye movement disorder, delayed motor milestones, hypotonia • ↓ tracer uptake on DaTscan • CSF neurotransmitter abnormalities • Prominent dystonia phenotype, parkinsonism, DD, neuropsychiatric features, seizures • ↓ tracer uptake on DaTscan • Encephalopathic crisis assoc w/infections/fever (age 6-18 mos); macrocephaly • Frontotemporal atrophy, widening of sylvian fissures, T • ↑ urinary 3-hydroxyglutaric acid & glutarylcarnitine • Progressive parkinsonism-dystonia, eye movement disorder, delayed motor milestones, hypotonia • ↓ tracer uptake on DaTscan • CSF neurotransmitter abnormalities • Pyramidal signs, self-mutilation • Hyperuricemia • Growth failure, renal syndromes, ID, metabolic stroke-like events, hypotonia, psychiatric features • ↑ plasma & urine methylmalonic acid w/normal B • Spasticity, hepatomegaly/splenomegaly, supranuclear gaze palsy, cataplexy, seizures, psychiatric comorbidities • ↑ oxysterol levels • Poor growth, DD, ID, gastrointestinal symptoms, hypotonia, psychiatric features • ↑ propionylcarnitine (C3) in plasma, ↑ 3-hydroxypropionate in urine, hyperammonemia, lactic acidosis • Multisystemic involvement • Commonly shows "Leigh" radiologic appearance of T • Leukodystrophy • ↑ lactate concentration • Metabolic acidosis • Prominent dystonia phenotype, parkinsonism, DD, neuropsychiatric features, seizures • ↓ tracer uptake on DaTscan • Progressive parkinsonism-dystonia, eye movement disorder, delayed motor milestones, hypotonia • ↓ tracer uptake on DaTscan • CSF neurotransmitter abnormalities • Parkinsonism, liver disease • T • Hypermanganesemia, polycythemia • Parkinsonism, spasticity, dysarthria, bulbar dysfunction • T • Hypermanganesemia • Progressive parkinsonism-dystonia, eye movement disorder, delayed motor milestones, hypotonia • ↓ tracer uptake on DaTscan • CSF neurotransmitter abnormalities • Progressive parkinsonism-dystonia, eye movement disorder, delayed motor milestones, hypotonia • ↓ tracer uptake on DaTscan • CSF neurotransmitter abnormalities • Progressive parkinsonism-dystonia, eye movement disorder, delayed motor milestones, hypotonia • ↓ tracer uptake on DaTscan • CSF neurotransmitter abnormalities • Early craniofacial involvement & laryngeal dystonia • Isolated dystonia w/older average age of onset • Prominent dystonia phenotype, ID, motor delay, spasticity • Hypomyelinating leukodystrophy, cerebellar & basal ganglia atrophy on MRI • Multisystemic involvement • Commonly shows "Leigh" radiologic appearance of T • Leukodystrophy • ↑ lactate & pyruvate concentrations • Metabolic acidosis The phenotypic features associated with See OMIM Phenotypic Series for genes associated with: The disorders in Selected Disorders in the Differential Diagnosis of AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; IUGR = intrauterine growth restriction; MOI = mode of inheritance; PV = pathogenic variant; upd(7)mat = maternal uniparental disomy of chromosome 7; XL = X-linked Silver-Russell syndrome (SRS) is a genetically heterogeneous condition. Genetic testing confirms clinical diagnosis in ~60% of affected individuals. Accurate assessment of SRS recurrence requires identification of the causative genetic mechanism in the proband. ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with a Dystonia, myoclonus, spasticity Possible effectiveness of deep brain stimulation Young children: developmental assessment by developmental pediatrician / pediatric psychologist Older children / adults: neuropsychiatric testing by psychiatrist Community or Social work involvement for parental support Home nursing referral IEP = individualized education plan; MOI = mode of inheritance; OT = occupational therapist; PT = physical therapist; SNHL = sensorineural hearing loss Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) There is no cure for A mean reduction of ~49.2% (range: 2%-98%) in the Burke-Fahn-Marsden Dystonia Rating Scale, Movement subscale (BFMDRS-M) was reported at follow-up times of two to 16 months after DBS in 45 individuals for whom data were available. A mean reduction of ~38.3% (range: 9%-91%) in the Burke-Fahn-Marsden Dystonia Rating Scale, Disability subscale (BFMDRS-D) was reported at follow-up times of two to 12 months after DBS in 45 individuals for whom data were available. Sustained clinical effect was observed in five-year long-term follow up, which demonstrated sustained improvement for trunk, neck, upper limb, and oromandibular dystonia [ However, despite initial improvement, DBS was less effective for lower-limb dystonia, with worsening of gait and loss of ambulation in all individuals [ DBS has not been effective in the treatment of laryngeal dystonia [ Freezing of gait is increasingly recognized as a complication of GPi-DBS in individuals with truncating Alternative means of communication (e.g., augmentative and alternative communication [AAC]) may benefit individuals who have expressive language difficulties. Children may qualify for and benefit from interventions such as applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses; it is typically performed one on one with a board-certified behavior analyst. Videofluoroscopy can be used to evaluate the risk of aspiration and the need for alternative means of feeding. 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. Physical therapy (PT), occupational therapy (OT), and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As an individual enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in For children: measure weight & height using age-appropriate & sex-matched growth charts. Evaluate nutritional status. AAC = augmentative and alternative communication; ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy; SLP = speech-language pathologist See Data on the use of anti-dystonic agents in pregnancy are limited. Although single case reports of medical treatment with trixhexyphenidyl, levodopa/carbidopa, and clonazepam during pregnancy have not reported adverse effects on the affected mother or the fetus [ See Search • Dystonia, myoclonus, spasticity • Possible effectiveness of deep brain stimulation • Young children: developmental assessment by developmental pediatrician / pediatric psychologist • Older children / adults: neuropsychiatric testing by psychiatrist • Community or • Social work involvement for parental support • Home nursing referral • A mean reduction of ~49.2% (range: 2%-98%) in the Burke-Fahn-Marsden Dystonia Rating Scale, Movement subscale (BFMDRS-M) was reported at follow-up times of two to 16 months after DBS in 45 individuals for whom data were available. • A mean reduction of ~38.3% (range: 9%-91%) in the Burke-Fahn-Marsden Dystonia Rating Scale, Disability subscale (BFMDRS-D) was reported at follow-up times of two to 12 months after DBS in 45 individuals for whom data were available. • Sustained clinical effect was observed in five-year long-term follow up, which demonstrated sustained improvement for trunk, neck, upper limb, and oromandibular dystonia [ • However, despite initial improvement, DBS was less effective for lower-limb dystonia, with worsening of gait and loss of ambulation in all individuals [ • DBS has not been effective in the treatment of laryngeal dystonia [ • Freezing of gait is increasingly recognized as a complication of GPi-DBS in individuals with truncating • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an 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. • Physical therapy (PT), occupational therapy (OT), and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As an individual enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • Physical therapy (PT), occupational therapy (OT), and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As an individual enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • Physical therapy (PT), occupational therapy (OT), and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As an individual enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years. • For children: measure weight & height using age-appropriate & sex-matched growth charts. • Evaluate nutritional status. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with a Dystonia, myoclonus, spasticity Possible effectiveness of deep brain stimulation Young children: developmental assessment by developmental pediatrician / pediatric psychologist Older children / adults: neuropsychiatric testing by psychiatrist Community or Social work involvement for parental support Home nursing referral IEP = individualized education plan; MOI = mode of inheritance; OT = occupational therapist; PT = physical therapist; SNHL = sensorineural hearing loss Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Dystonia, myoclonus, spasticity • Possible effectiveness of deep brain stimulation • Young children: developmental assessment by developmental pediatrician / pediatric psychologist • Older children / adults: neuropsychiatric testing by psychiatrist • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations There is no cure for A mean reduction of ~49.2% (range: 2%-98%) in the Burke-Fahn-Marsden Dystonia Rating Scale, Movement subscale (BFMDRS-M) was reported at follow-up times of two to 16 months after DBS in 45 individuals for whom data were available. A mean reduction of ~38.3% (range: 9%-91%) in the Burke-Fahn-Marsden Dystonia Rating Scale, Disability subscale (BFMDRS-D) was reported at follow-up times of two to 12 months after DBS in 45 individuals for whom data were available. Sustained clinical effect was observed in five-year long-term follow up, which demonstrated sustained improvement for trunk, neck, upper limb, and oromandibular dystonia [ However, despite initial improvement, DBS was less effective for lower-limb dystonia, with worsening of gait and loss of ambulation in all individuals [ DBS has not been effective in the treatment of laryngeal dystonia [ Freezing of gait is increasingly recognized as a complication of GPi-DBS in individuals with truncating Alternative means of communication (e.g., augmentative and alternative communication [AAC]) may benefit individuals who have expressive language difficulties. Children may qualify for and benefit from interventions such as applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses; it is typically performed one on one with a board-certified behavior analyst. Videofluoroscopy can be used to evaluate the risk of aspiration and the need for alternative means of feeding. 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. Physical therapy (PT), occupational therapy (OT), and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As an individual enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • A mean reduction of ~49.2% (range: 2%-98%) in the Burke-Fahn-Marsden Dystonia Rating Scale, Movement subscale (BFMDRS-M) was reported at follow-up times of two to 16 months after DBS in 45 individuals for whom data were available. • A mean reduction of ~38.3% (range: 9%-91%) in the Burke-Fahn-Marsden Dystonia Rating Scale, Disability subscale (BFMDRS-D) was reported at follow-up times of two to 12 months after DBS in 45 individuals for whom data were available. • Sustained clinical effect was observed in five-year long-term follow up, which demonstrated sustained improvement for trunk, neck, upper limb, and oromandibular dystonia [ • However, despite initial improvement, DBS was less effective for lower-limb dystonia, with worsening of gait and loss of ambulation in all individuals [ • DBS has not been effective in the treatment of laryngeal dystonia [ • Freezing of gait is increasingly recognized as a complication of GPi-DBS in individuals with truncating • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an 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. • Physical therapy (PT), occupational therapy (OT), and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As an individual enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • Physical therapy (PT), occupational therapy (OT), and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As an individual enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • Physical therapy (PT), occupational therapy (OT), and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As an individual enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years. ## 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. Physical therapy (PT), occupational therapy (OT), and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As an individual enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • Physical therapy (PT), occupational therapy (OT), and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As an individual enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • Physical therapy (PT), occupational therapy (OT), and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As an individual enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • Physical therapy (PT), occupational therapy (OT), and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As an individual enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in For children: measure weight & height using age-appropriate & sex-matched growth charts. Evaluate nutritional status. AAC = augmentative and alternative communication; ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy; SLP = speech-language pathologist • For children: measure weight & height using age-appropriate & sex-matched growth charts. • Evaluate nutritional status. ## Evaluation of Relatives at Risk See ## Pregnancy Management Data on the use of anti-dystonic agents in pregnancy are limited. Although single case reports of medical treatment with trixhexyphenidyl, levodopa/carbidopa, and clonazepam during pregnancy have not reported adverse effects on the affected mother or the fetus [ See ## Therapies Under Investigation Search ## Genetic Counseling Most individuals reported to date with a About 84% of individuals diagnosed with DYT- About 91% of individuals diagnosed with Some individuals diagnosed with a About 16% of individuals diagnosed with DYT- About 11% of individuals diagnosed with Intrafamilial variability is reported. 58% of individuals with DYT- In some families, the affected parent presents a milder, non-generalized, and later-onset dystonia phenotype compared to their offspring, who exhibit an early-onset, generalized dystonia phenotype [ If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of a parent before the onset of symptoms, or late onset of the disease in an affected parent. Therefore, If the genetic alteration identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a genetic alteration from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. * A parent with somatic/gonadal mosaicism for a genetic alteration may be mildly/minimally affected. If a parent of the proband is affected and/or is known to have the genetic alteration identified in the proband, the risk to the sibs of inheriting the genetic alteration is 50%. Intrafamilial variability and reduced penetrance have been observed in If the genetic alteration identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [ If the proband represents a simplex case and the parents are clinically unaffected but have not been tested for the genetic alteration identified in the proband, sibs of the proband are still at increased risk 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. Prior to conception, counseling a woman with DYT- Once a Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • Most individuals reported to date with a • About 84% of individuals diagnosed with DYT- • About 91% of individuals diagnosed with • About 84% of individuals diagnosed with DYT- • About 91% of individuals diagnosed with • Some individuals diagnosed with a • About 16% of individuals diagnosed with DYT- • About 11% of individuals diagnosed with • About 16% of individuals diagnosed with DYT- • About 11% of individuals diagnosed with • Intrafamilial variability is reported. • 58% of individuals with DYT- • In some families, the affected parent presents a milder, non-generalized, and later-onset dystonia phenotype compared to their offspring, who exhibit an early-onset, generalized dystonia phenotype [ • 58% of individuals with DYT- • In some families, the affected parent presents a milder, non-generalized, and later-onset dystonia phenotype compared to their offspring, who exhibit an early-onset, generalized dystonia phenotype [ • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of a parent before the onset of symptoms, or late onset of the disease in an affected parent. Therefore, • If the genetic alteration identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a genetic alteration from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * A parent with somatic/gonadal mosaicism for a genetic alteration may be mildly/minimally affected. • The proband has a • The proband inherited a genetic alteration from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * A parent with somatic/gonadal mosaicism for a genetic alteration may be mildly/minimally affected. • About 84% of individuals diagnosed with DYT- • About 91% of individuals diagnosed with • About 16% of individuals diagnosed with DYT- • About 11% of individuals diagnosed with • 58% of individuals with DYT- • In some families, the affected parent presents a milder, non-generalized, and later-onset dystonia phenotype compared to their offspring, who exhibit an early-onset, generalized dystonia phenotype [ • The proband has a • The proband inherited a genetic alteration from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * A parent with somatic/gonadal mosaicism for a genetic alteration may be mildly/minimally affected. • If a parent of the proband is affected and/or is known to have the genetic alteration identified in the proband, the risk to the sibs of inheriting the genetic alteration is 50%. Intrafamilial variability and reduced penetrance have been observed in • If the genetic alteration identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [ • If the proband represents a simplex case and the parents are clinically unaffected but have not been tested for the genetic alteration identified in the proband, sibs of the proband are still at increased risk 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. • Prior to conception, counseling a woman with DYT- ## Mode of Inheritance ## Risk to Family Members Most individuals reported to date with a About 84% of individuals diagnosed with DYT- About 91% of individuals diagnosed with Some individuals diagnosed with a About 16% of individuals diagnosed with DYT- About 11% of individuals diagnosed with Intrafamilial variability is reported. 58% of individuals with DYT- In some families, the affected parent presents a milder, non-generalized, and later-onset dystonia phenotype compared to their offspring, who exhibit an early-onset, generalized dystonia phenotype [ If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of a parent before the onset of symptoms, or late onset of the disease in an affected parent. Therefore, If the genetic alteration identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a genetic alteration from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. * A parent with somatic/gonadal mosaicism for a genetic alteration may be mildly/minimally affected. If a parent of the proband is affected and/or is known to have the genetic alteration identified in the proband, the risk to the sibs of inheriting the genetic alteration is 50%. Intrafamilial variability and reduced penetrance have been observed in If the genetic alteration identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [ If the proband represents a simplex case and the parents are clinically unaffected but have not been tested for the genetic alteration identified in the proband, sibs of the proband are still at increased risk for a • Most individuals reported to date with a • About 84% of individuals diagnosed with DYT- • About 91% of individuals diagnosed with • About 84% of individuals diagnosed with DYT- • About 91% of individuals diagnosed with • Some individuals diagnosed with a • About 16% of individuals diagnosed with DYT- • About 11% of individuals diagnosed with • About 16% of individuals diagnosed with DYT- • About 11% of individuals diagnosed with • Intrafamilial variability is reported. • 58% of individuals with DYT- • In some families, the affected parent presents a milder, non-generalized, and later-onset dystonia phenotype compared to their offspring, who exhibit an early-onset, generalized dystonia phenotype [ • 58% of individuals with DYT- • In some families, the affected parent presents a milder, non-generalized, and later-onset dystonia phenotype compared to their offspring, who exhibit an early-onset, generalized dystonia phenotype [ • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of a parent before the onset of symptoms, or late onset of the disease in an affected parent. Therefore, • If the genetic alteration identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a genetic alteration from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * A parent with somatic/gonadal mosaicism for a genetic alteration may be mildly/minimally affected. • The proband has a • The proband inherited a genetic alteration from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * A parent with somatic/gonadal mosaicism for a genetic alteration may be mildly/minimally affected. • About 84% of individuals diagnosed with DYT- • About 91% of individuals diagnosed with • About 16% of individuals diagnosed with DYT- • About 11% of individuals diagnosed with • 58% of individuals with DYT- • In some families, the affected parent presents a milder, non-generalized, and later-onset dystonia phenotype compared to their offspring, who exhibit an early-onset, generalized dystonia phenotype [ • The proband has a • The proband inherited a genetic alteration from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * A parent with somatic/gonadal mosaicism for a genetic alteration may be mildly/minimally affected. • If a parent of the proband is affected and/or is known to have the genetic alteration identified in the proband, the risk to the sibs of inheriting the genetic alteration is 50%. Intrafamilial variability and reduced penetrance have been observed in • If the genetic alteration identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [ • If the proband represents a simplex case and the parents are clinically unaffected but have not been tested for the genetic alteration identified in the proband, sibs of the proband are still at increased risk for a ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Prior to conception, counseling a woman with DYT- • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • Prior to conception, counseling a woman with DYT- ## Prenatal Testing and Preimplantation Genetic Testing Once a Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom Germany Connecting People for Dystonia Belgium Dystonia Medical Research Foundation • • • • • • United Kingdom • • • Germany • • • • • Connecting People for Dystonia • Belgium • • • Dystonia Medical Research Foundation • ## Molecular Genetics KMT2B-Related Disorders: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for KMT2B-Related Disorders ( The exact pathogenic mechanisms in ## Molecular Pathogenesis The exact pathogenic mechanisms in ## Chapter Notes Dr Abela is a pediatric neurologist with a special clinical and research interest in childhood movement disorders. Professor Kurian is a pediatric neurologist and clinician-scientist with a clinical and research interest in childhood movement disorders. Contact Dr Kurian to inquire about review of Dr Kurian is funded by an NIHR Research Professorship and the Wellcome Trust. Dr Abela was funded by a Swiss National Foundation Advanced Postdoc Mobility fellowship. 22 May 2025 (bp) Comprehensive update posted live 26 April 2018 (bp) Review posted live 19 October 2017 (la/mak) Original submission • 22 May 2025 (bp) Comprehensive update posted live • 26 April 2018 (bp) Review posted live • 19 October 2017 (la/mak) Original submission ## Author Notes Dr Abela is a pediatric neurologist with a special clinical and research interest in childhood movement disorders. Professor Kurian is a pediatric neurologist and clinician-scientist with a clinical and research interest in childhood movement disorders. Contact Dr Kurian to inquire about review of ## Acknowledgments Dr Kurian is funded by an NIHR Research Professorship and the Wellcome Trust. Dr Abela was funded by a Swiss National Foundation Advanced Postdoc Mobility fellowship. ## Revision History 22 May 2025 (bp) Comprehensive update posted live 26 April 2018 (bp) Review posted live 19 October 2017 (la/mak) Original submission • 22 May 2025 (bp) Comprehensive update posted live • 26 April 2018 (bp) Review posted live • 19 October 2017 (la/mak) Original submission ## References ## Literature Cited Radiologic MRI features of individuals with a-l. T a,e,i. Representative MR images from control individuals for T Imaging abnormalities are indicated by yellow arrows and demonstrate subtle, bilateral hypointense lateral streaks in the external globus pallidus. Patient 1, age 9 years, 5 months (b,f,j); patient 13, age 11 years, 3 months (c,g,k); patient 9, age 15 years, 1 month (d); patient 22, age 13 years, 1 month (h); patient 25, age 16 years (l). Reprinted with permission from	[]	26/4/2018	22/5/2025	29/9/2022	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
kmt2e-ndd	kmt2e-ndd	[ "O'Donnell-Luria-Rodan Syndrome (ODLURO)", "O'Donnell-Luria-Rodan Syndrome (ODLURO)", "Inactive histone-lysine N-methyltransferase 2E", "KMT2E", "KMT2E-Related Neurodevelopmental Disorder" ]		Lynn Pais, Lance Rodan, Anne O'Donnell-Luria	Summary The diagnosis of	## Diagnosis No consensus clinical diagnostic criteria for Mild-to-profound developmental delay (DD) or intellectual disability (ID), although most individuals fall within the mild-to-moderate range AND Any of the following features presenting in infancy or childhood: Generalized hypotonia of infancy Gastrointestinal symptoms, including vomiting and reduced bowel motility Seizures, including febrile seizures Autism spectrum disorder Behavioral issues Macrocephaly (often relative to length/height) Microcephaly (in some individuals with missense pathogenic variants) (See Sleep disturbance, including frequent awakenings and difficulty falling asleep Minor dysmorphic features (See Nonspecific brain abnormalities, including hypoplasia of the corpus callosum, ventriculomegaly, cerebral cysts, and/or delayed myelination 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 Six individuals with contiguous gene deletions have been reported and are also included in this calculation (see Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by No data on detection rate of gene-targeted deletion/duplication analysis are available, but this methodology should detect at least all of those deletions/duplications involving CMA uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including • Mild-to-profound developmental delay (DD) or intellectual disability (ID), although most individuals fall within the mild-to-moderate range • Any of the following features presenting in infancy or childhood: • Generalized hypotonia of infancy • Gastrointestinal symptoms, including vomiting and reduced bowel motility • Seizures, including febrile seizures • Autism spectrum disorder • Behavioral issues • Macrocephaly (often relative to length/height) • Microcephaly (in some individuals with missense pathogenic variants) (See • Sleep disturbance, including frequent awakenings and difficulty falling asleep • Minor dysmorphic features (See • Nonspecific brain abnormalities, including hypoplasia of the corpus callosum, ventriculomegaly, cerebral cysts, and/or delayed myelination • Generalized hypotonia of infancy • Gastrointestinal symptoms, including vomiting and reduced bowel motility • Seizures, including febrile seizures • Autism spectrum disorder • Behavioral issues • Macrocephaly (often relative to length/height) • Microcephaly (in some individuals with missense pathogenic variants) (See • Sleep disturbance, including frequent awakenings and difficulty falling asleep • Minor dysmorphic features (See • Nonspecific brain abnormalities, including hypoplasia of the corpus callosum, ventriculomegaly, cerebral cysts, and/or delayed myelination • Generalized hypotonia of infancy • Gastrointestinal symptoms, including vomiting and reduced bowel motility • Seizures, including febrile seizures • Autism spectrum disorder • Behavioral issues • Macrocephaly (often relative to length/height) • Microcephaly (in some individuals with missense pathogenic variants) (See • Sleep disturbance, including frequent awakenings and difficulty falling asleep • Minor dysmorphic features (See • Nonspecific brain abnormalities, including hypoplasia of the corpus callosum, ventriculomegaly, cerebral cysts, and/or delayed myelination • 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), although most individuals fall within the mild-to-moderate range AND Any of the following features presenting in infancy or childhood: Generalized hypotonia of infancy Gastrointestinal symptoms, including vomiting and reduced bowel motility Seizures, including febrile seizures Autism spectrum disorder Behavioral issues Macrocephaly (often relative to length/height) Microcephaly (in some individuals with missense pathogenic variants) (See Sleep disturbance, including frequent awakenings and difficulty falling asleep Minor dysmorphic features (See Nonspecific brain abnormalities, including hypoplasia of the corpus callosum, ventriculomegaly, cerebral cysts, and/or delayed myelination • Mild-to-profound developmental delay (DD) or intellectual disability (ID), although most individuals fall within the mild-to-moderate range • Any of the following features presenting in infancy or childhood: • Generalized hypotonia of infancy • Gastrointestinal symptoms, including vomiting and reduced bowel motility • Seizures, including febrile seizures • Autism spectrum disorder • Behavioral issues • Macrocephaly (often relative to length/height) • Microcephaly (in some individuals with missense pathogenic variants) (See • Sleep disturbance, including frequent awakenings and difficulty falling asleep • Minor dysmorphic features (See • Nonspecific brain abnormalities, including hypoplasia of the corpus callosum, ventriculomegaly, cerebral cysts, and/or delayed myelination • Generalized hypotonia of infancy • Gastrointestinal symptoms, including vomiting and reduced bowel motility • Seizures, including febrile seizures • Autism spectrum disorder • Behavioral issues • Macrocephaly (often relative to length/height) • Microcephaly (in some individuals with missense pathogenic variants) (See • Sleep disturbance, including frequent awakenings and difficulty falling asleep • Minor dysmorphic features (See • Nonspecific brain abnormalities, including hypoplasia of the corpus callosum, ventriculomegaly, cerebral cysts, and/or delayed myelination • Generalized hypotonia of infancy • Gastrointestinal symptoms, including vomiting and reduced bowel motility • Seizures, including febrile seizures • Autism spectrum disorder • Behavioral issues • Macrocephaly (often relative to length/height) • Microcephaly (in some individuals with missense pathogenic variants) (See • Sleep disturbance, including frequent awakenings and difficulty falling asleep • Minor dysmorphic features (See • Nonspecific brain abnormalities, including hypoplasia of the corpus callosum, ventriculomegaly, cerebral cysts, and/or delayed myelination ## 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 Six individuals with contiguous gene deletions have been reported and are also included in this calculation (see Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by No data on detection rate of gene-targeted deletion/duplication analysis are available, but this methodology should detect at least all of those deletions/duplications involving CMA uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics About 14% of individuals with protein-truncating pathogenic variants have been reported to have seizures (two with unprovoked seizures, one with a single seizure, and two with treatment-resistant epilepsy). All five individuals with pathogenic missense variants had epilepsy, four of whom had treatment-resistant infantile epilepsy [ Three affected individuals were noted to have febrile seizures [ Sex-related differences have also been noted, with epilepsy reported in 43% of females (3/7) but in only 5% of males (1/21) in one study [ Two individuals (one with a missense pathogenic variant and the other with a frameshift pathogenic variant) are known to have experienced developmental regression with some improvement in epilepsy when started on a ketogenic diet, so careful monitoring should be in place if this therapy is considered (see Autism spectrum disorder (ASD) is seen more frequently in males with Some affected individuals have behavioral concerns other than ASD; stereotypies, skin-picking behavior, self-injurious behavior, aggression, anxiety, and sensory integration disorder has been reported in 17% of individuals. At least two affected individuals have been diagnosed with attention-deficit/hyperactivity disorder (ADHD) [ Hypotonia is reported in about 46% of individuals with General joint laxity is reported in some affected individuals [ Only five individuals have been reported with pathogenic missense variants. Individuals with pathogenic missense variants in To date, 61 individuals have been identified with a pathogenic variant in • About 14% of individuals with protein-truncating pathogenic variants have been reported to have seizures (two with unprovoked seizures, one with a single seizure, and two with treatment-resistant epilepsy). • All five individuals with pathogenic missense variants had epilepsy, four of whom had treatment-resistant infantile epilepsy [ • Three affected individuals were noted to have febrile seizures [ • Sex-related differences have also been noted, with epilepsy reported in 43% of females (3/7) but in only 5% of males (1/21) in one study [ • Autism spectrum disorder (ASD) is seen more frequently in males with • Some affected individuals have behavioral concerns other than ASD; stereotypies, skin-picking behavior, self-injurious behavior, aggression, anxiety, and sensory integration disorder has been reported in 17% of individuals. At least two affected individuals have been diagnosed with attention-deficit/hyperactivity disorder (ADHD) [ • Hypotonia is reported in about 46% of individuals with • General joint laxity is reported in some affected individuals [ ## Clinical Description About 14% of individuals with protein-truncating pathogenic variants have been reported to have seizures (two with unprovoked seizures, one with a single seizure, and two with treatment-resistant epilepsy). All five individuals with pathogenic missense variants had epilepsy, four of whom had treatment-resistant infantile epilepsy [ Three affected individuals were noted to have febrile seizures [ Sex-related differences have also been noted, with epilepsy reported in 43% of females (3/7) but in only 5% of males (1/21) in one study [ Two individuals (one with a missense pathogenic variant and the other with a frameshift pathogenic variant) are known to have experienced developmental regression with some improvement in epilepsy when started on a ketogenic diet, so careful monitoring should be in place if this therapy is considered (see Autism spectrum disorder (ASD) is seen more frequently in males with Some affected individuals have behavioral concerns other than ASD; stereotypies, skin-picking behavior, self-injurious behavior, aggression, anxiety, and sensory integration disorder has been reported in 17% of individuals. At least two affected individuals have been diagnosed with attention-deficit/hyperactivity disorder (ADHD) [ Hypotonia is reported in about 46% of individuals with General joint laxity is reported in some affected individuals [ • About 14% of individuals with protein-truncating pathogenic variants have been reported to have seizures (two with unprovoked seizures, one with a single seizure, and two with treatment-resistant epilepsy). • All five individuals with pathogenic missense variants had epilepsy, four of whom had treatment-resistant infantile epilepsy [ • Three affected individuals were noted to have febrile seizures [ • Sex-related differences have also been noted, with epilepsy reported in 43% of females (3/7) but in only 5% of males (1/21) in one study [ • Autism spectrum disorder (ASD) is seen more frequently in males with • Some affected individuals have behavioral concerns other than ASD; stereotypies, skin-picking behavior, self-injurious behavior, aggression, anxiety, and sensory integration disorder has been reported in 17% of individuals. At least two affected individuals have been diagnosed with attention-deficit/hyperactivity disorder (ADHD) [ • Hypotonia is reported in about 46% of individuals with • General joint laxity is reported in some affected individuals [ ## Genotype-Phenotype Correlations Only five individuals have been reported with pathogenic missense variants. Individuals with pathogenic missense variants in ## Prevalence To date, 61 individuals have been identified with a pathogenic variant in ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Because the phenotypic features associated with • • • • ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with Consider referral to a neurologist. Consider brain MRI as clinically indicated for seizures or focal neurologic concerns. 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, activities of daily living, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) To incl eval of nutritional status Consider eval for gastrostomy tube placement in persons who have inadequate nutrition or concern for dysphagia. Community or Social work involvement for parental support Home nursing referral ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; GERD = gastroesophageal reflux disease; 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. 1 affected person experienced developmental regression while being treated w/ketogenic diet; more data is required to determine if ketogenic diet is contraindicated in this condition. 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. 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. 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 changes in tone. OT = occupational therapy; PT = physical therapy To assess for macrocephaly, relative macrocephaly, and microcephaly (see Careful monitoring is required if an affected individual is placed on a ketogenic diet, given that one affected individual placed on this therapy experienced developmental regression (without improvement in seizure control) [ See Search • Consider referral to a neurologist. • Consider brain MRI as clinically indicated for seizures or focal neurologic concerns. • 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, activities of daily living, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • To incl eval of nutritional status • Consider eval for gastrostomy tube placement in persons who have inadequate nutrition or concern for dysphagia. • 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. • 1 affected person experienced developmental regression while being treated w/ketogenic diet; more data is required to determine if ketogenic diet is contraindicated in this condition. • 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. • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as seizures or changes in tone. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Consider referral to a neurologist. Consider brain MRI as clinically indicated for seizures or focal neurologic concerns. 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, activities of daily living, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) To incl eval of nutritional status Consider eval for gastrostomy tube placement in persons who have inadequate nutrition or concern for dysphagia. Community or Social work involvement for parental support Home nursing referral ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; GERD = gastroesophageal reflux disease; Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Consider referral to a neurologist. • Consider brain MRI as clinically indicated for seizures or focal neurologic concerns. • 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, activities of daily living, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • To incl eval of nutritional status • Consider eval for gastrostomy tube placement in persons who have inadequate nutrition or concern for dysphagia. • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations There is no cure for Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. 1 affected person experienced developmental regression while being treated w/ketogenic diet; more data is required to determine if ketogenic diet is contraindicated in this condition. 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. 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. 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. • 1 affected person experienced developmental regression while being treated w/ketogenic diet; more data is required to determine if ketogenic diet is contraindicated in this condition. • 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. ## 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 ## 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. 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 changes in tone. OT = occupational therapy; PT = physical therapy To assess for macrocephaly, relative macrocephaly, and microcephaly (see Careful monitoring is required if an affected individual is placed on a ketogenic diet, given that one affected individual placed on this therapy experienced developmental regression (without improvement in seizure control) [ • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as seizures or changes in tone. ## 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 evaluate their genetic status and inform recurrence risk assessment. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. * Theoretically, a parent with somatic and germline mosaicism for a If a parent of the proband is known to have the If the The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal 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 evaluate their genetic status and inform recurrence risk assessment. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • * Theoretically, 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. • * Theoretically, 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. • * Theoretically, a parent with somatic and germline mosaicism for a • If a parent of the proband is known to have the • If the • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. ## Mode of Inheritance ## Risk to Family Members Most 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 pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. * Theoretically, a parent with somatic and germline mosaicism for a 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 evaluate their genetic status and inform recurrence risk assessment. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • * Theoretically, 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. • * Theoretically, 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. • * Theoretically, a parent with somatic and germline mosaicism for a • If a parent of the proband is known to have the • If the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal 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 KMT2E-Related Neurodevelopmental Disorder: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for KMT2E-Related Neurodevelopmental Disorder ( ## Molecular Pathogenesis ## Chapter Notes Web page: Email: Web page: Email: Web page: Email: Support was provided by the National Institutes of Health's National Institute of Child Health and Human Development (NICHD) (K12HD052896), the National Human Genome Research Institute-funded Broad Center for Mendelian Genomics (UM1HG008900, U01HG011755), and the Manton Center for Orphan Disease Research to A.O'D.L. 18 April 2024 (ma) Review posted live 1 February 2023 (aol) Original submission • 18 April 2024 (ma) Review posted live • 1 February 2023 (aol) Original submission ## Author Notes Web page: Email: Web page: Email: Web page: Email: ## Acknowledgments Support was provided by the National Institutes of Health's National Institute of Child Health and Human Development (NICHD) (K12HD052896), the National Human Genome Research Institute-funded Broad Center for Mendelian Genomics (UM1HG008900, U01HG011755), and the Manton Center for Orphan Disease Research to A.O'D.L. ## Revision History 18 April 2024 (ma) Review posted live 1 February 2023 (aol) Original submission • 18 April 2024 (ma) Review posted live • 1 February 2023 (aol) Original submission ## References ## Literature Cited Consistent facial features of individuals with (A) Individual 9 – age 11 years; (B) Individual 11 – age 1 year, 10 months; (C) Individual 12 – age 4.5 years; (D) Individual 13 – age 6 years; (E) Individual 15 – age 1 year, 7 months; (F) Individual 20 – age 6 years; (G) Individual 24 – age 5 years; (H) Individual 25 – age 12 years; (I) Individual 30 – age 18 years; (J) Individual 31 – age 22 years; (K) Individual 32 – age 7 years; (L) Individual 33 – age 16 years. Included on the bottom right of each cluster is the individual's sex. NMD = nonsense mediated decay Reprinted with permission from Composite figure analysis of the facial phenotype of individuals with Reprinted with permission from	[]	18/4/2024			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
kos	kos	[ "Blepharophimosis-Ptosis-Intellectual Disability (BPID) Syndrome", "Blepharophimosis-Ptosis-Intellectual Disability (BPID) Syndrome", "Ubiquitin-protein ligase E3B", "UBE3B", "Kaufman Oculocerebrofacial Syndrome" ]	Kaufman Oculocerebrofacial Syndrome	Dana Brabbing-Goldstein, Lina Basel-Salmon	Summary Kaufman oculocerebrofacial syndrome (KOS) is characterized by developmental delay, severe intellectual disability, and distinctive craniofacial features. Most affected children have prenatal-onset microcephaly, hypotonia, and growth deficiency. Feeding issues, ocular abnormalities, hearing impairment, and respiratory tract abnormalities are common. Ocular abnormalities can include structural abnormalities (microcornea or microphthalmia, coloboma, optic nerve hypoplasia), refractive errors (myopia ± astigmatism, hyperopia), strabismus, and entropion. Both conductive and sensorineural hearing loss have been reported as well as mixed conductive-sensorineural hearing loss of variable severity. Breathing problems can lead to prolonged hospitalization after birth in more than half of individuals. Less common findings include ectodermal abnormalities, cardiac manifestations, urogenital abnormalities, seizures, and skeletal abnormalities. The diagnosis of KOS is established in a proband with developmental delay/intellectual disability and biallelic KOS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a	## Diagnosis No consensus clinical diagnostic criteria for Kaufman oculocerebrofacial syndrome (KOS) have been published. KOS Microcephaly Developmental delay and severe intellectual disability Growth deficiency (poor weight gain and/or short stature) Ocular anomalies (microcornea, microphthalmia, coloboma, optic nerve hypoplasia, refractive errors, strabismus, entropion) A typical and recognizable pattern of craniofacial features* (see Eyebrows: highly arched, laterally broad with flaring (medial or lateral) Telecanthus, blepharophimosis with epicanthal folds, ptosis, upslanted palpebral fissures Ears: often apparently low set with overfolded helices and small lobes; variably seen: cupped ears, underdeveloped crus helix, preauricular tags Narrow nasal bridge, wide nasal base, anteverted nares Flat zygomata Long, flat philtrum Narrow mouth, thin vermilion of the upper lip with absent Cupid's bow Micrognathia With age, the face becomes more elongated, the zygomata become flatter and the palpebral fissures more upslanted, and the alae nasi thicken [ The diagnosis of KOS 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 Kaufman Oculocerebrofacial 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 gene-targeted microarray designed to detect single-exon deletions or duplications. • Microcephaly • Developmental delay and severe intellectual disability • Growth deficiency (poor weight gain and/or short stature) • Ocular anomalies (microcornea, microphthalmia, coloboma, optic nerve hypoplasia, refractive errors, strabismus, entropion) • A typical and recognizable pattern of craniofacial features (see • Eyebrows: highly arched, laterally broad with flaring (medial or lateral) • Telecanthus, blepharophimosis with epicanthal folds, ptosis, upslanted palpebral fissures • Ears: often apparently low set with overfolded helices and small lobes; variably seen: cupped ears, underdeveloped crus helix, preauricular tags • Narrow nasal bridge, wide nasal base, anteverted nares • Flat zygomata • Long, flat philtrum • Narrow mouth, thin vermilion of the upper lip with absent Cupid's bow • Micrognathia • With age, the face becomes more elongated, the zygomata become flatter and the palpebral fissures more upslanted, and the alae nasi thicken [ • Eyebrows: highly arched, laterally broad with flaring (medial or lateral) • Telecanthus, blepharophimosis with epicanthal folds, ptosis, upslanted palpebral fissures • Ears: often apparently low set with overfolded helices and small lobes; variably seen: cupped ears, underdeveloped crus helix, preauricular tags • Narrow nasal bridge, wide nasal base, anteverted nares • Flat zygomata • Long, flat philtrum • Narrow mouth, thin vermilion of the upper lip with absent Cupid's bow • Micrognathia • Eyebrows: highly arched, laterally broad with flaring (medial or lateral) • Telecanthus, blepharophimosis with epicanthal folds, ptosis, upslanted palpebral fissures • Ears: often apparently low set with overfolded helices and small lobes; variably seen: cupped ears, underdeveloped crus helix, preauricular tags • Narrow nasal bridge, wide nasal base, anteverted nares • Flat zygomata • Long, flat philtrum • Narrow mouth, thin vermilion of the upper lip with absent Cupid's bow • Micrognathia ## Suggestive Findings KOS Microcephaly Developmental delay and severe intellectual disability Growth deficiency (poor weight gain and/or short stature) Ocular anomalies (microcornea, microphthalmia, coloboma, optic nerve hypoplasia, refractive errors, strabismus, entropion) A typical and recognizable pattern of craniofacial features (see Eyebrows: highly arched, laterally broad with flaring (medial or lateral) Telecanthus, blepharophimosis with epicanthal folds, ptosis, upslanted palpebral fissures Ears: often apparently low set with overfolded helices and small lobes; variably seen: cupped ears, underdeveloped crus helix, preauricular tags Narrow nasal bridge, wide nasal base, anteverted nares Flat zygomata Long, flat philtrum Narrow mouth, thin vermilion of the upper lip with absent Cupid's bow Micrognathia With age, the face becomes more elongated, the zygomata become flatter and the palpebral fissures more upslanted, and the alae nasi thicken [ • Microcephaly • Developmental delay and severe intellectual disability • Growth deficiency (poor weight gain and/or short stature) • Ocular anomalies (microcornea, microphthalmia, coloboma, optic nerve hypoplasia, refractive errors, strabismus, entropion) • A typical and recognizable pattern of craniofacial features (see • Eyebrows: highly arched, laterally broad with flaring (medial or lateral) • Telecanthus, blepharophimosis with epicanthal folds, ptosis, upslanted palpebral fissures • Ears: often apparently low set with overfolded helices and small lobes; variably seen: cupped ears, underdeveloped crus helix, preauricular tags • Narrow nasal bridge, wide nasal base, anteverted nares • Flat zygomata • Long, flat philtrum • Narrow mouth, thin vermilion of the upper lip with absent Cupid's bow • Micrognathia • *With age, the face becomes more elongated, the zygomata become flatter and the palpebral fissures more upslanted, and the alae nasi thicken [ • Eyebrows: highly arched, laterally broad with flaring (medial or lateral) • Telecanthus, blepharophimosis with epicanthal folds, ptosis, upslanted palpebral fissures • Ears: often apparently low set with overfolded helices and small lobes; variably seen: cupped ears, underdeveloped crus helix, preauricular tags • Narrow nasal bridge, wide nasal base, anteverted nares • Flat zygomata • Long, flat philtrum • Narrow mouth, thin vermilion of the upper lip with absent Cupid's bow • Micrognathia • Eyebrows: highly arched, laterally broad with flaring (medial or lateral) • Telecanthus, blepharophimosis with epicanthal folds, ptosis, upslanted palpebral fissures • Ears: often apparently low set with overfolded helices and small lobes; variably seen: cupped ears, underdeveloped crus helix, preauricular tags • Narrow nasal bridge, wide nasal base, anteverted nares • Flat zygomata • Long, flat philtrum • Narrow mouth, thin vermilion of the upper lip with absent Cupid's bow • Micrognathia ## Establishing the Diagnosis The diagnosis of KOS 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 Kaufman Oculocerebrofacial 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 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 Kaufman Oculocerebrofacial 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 gene-targeted microarray designed to detect single-exon deletions or duplications. ## Clinical Characteristics Kaufman oculocerebrofacial syndrome (KOS) is characterized by prenatal-onset microcephaly, growth deficiency, developmental delay, severe intellectual disability, and distinct facial features. To date, 36 individuals have been identified with biallelic pathogenic variants in Kaufman Oculocerebrofacial Syndrome: Frequency of Select Features Postnatal microcephaly is frequently present and more than 60% of affected children have prenatal microcephaly or a small occipitofrontal circumference (OFC) at birth (<10 Hypotonia and delayed motor milestones are universal findings. The onset of independent ambulation varies; in most it is achieved by age four to five years. Gait is frequently described as unsteady. Intellectual disability is severe to profound in the individuals reported to date; rare, affected individuals develop limited speech. Seizures are reported in approximately 20% of individuals and are usually fever related. Abnormal brain MRI was reported in 19/26 individuals. Anomalies included corpus callosum hypoplasia or agenesis (13 individuals), dilated ventricles (3 individuals), Chiari 1 malformation (2), small pituitary (2), ectopic pituitary gland and hypoplastic vermis (1) [ Significant behavior problems do not appear to be prominent; six individuals were described as having a cheerful disposition [ Growth deficiency is common during infancy and most affected children have poor weight gain and short stature [ Stature is usually below the 10 Feeding difficulties are a main complication and manifest as poor weight gain, generalized hypotonia, poor suck, poor swallowing, small oral cavity, palate defects, gastroesophageal reflux, and poor dietary intake. Feeding by nasogastric tube or gastrostomy is needed in some individuals. Constipation has been reported in several individuals. Three individuals had intestinal malrotation. Eyebrows: highly arched, laterally broad with flaring (medial or lateral) Telecanthus, blepharophimosis with epicanthal folds, ptosis, upslanted palpebral fissures Ears: often apparently low set with overfolded helices and small lobes; variably seen: cupped ears, underdeveloped crus helix, preauricular tags Narrow nasal bridge, wide nasal base, anteverted nares Flat zygomata Long, flat philtrum Narrow mouth, thin vermilion of the upper lip with absent Cupid's bow Micrognathia Prominent cheeks Structural abnormalities (microcornea or microphthalmia, coloboma, optic nerve hypoplasia, spherophakia); Refractive errors (myopia with or without astigmatism, hyperopia); Abnormal alignment of the eyes (strabismus); Entropion (inward turning of the lower eyelid); Epibulbar dermoid in one individual [ Hearing impairment is common. Both conductive and sensorineural hearing loss have been reported as well as mixed conductive-sensorineural hearing loss of variable severity. Ear anomalies include stenotic auditory canals, dysplastic ears, and cupped ears; ear tags are present in about 30%-40% of individuals. Two affected individuals had cholesteatoma [ Breathing problems are quite common leading to a complicated course with prolonged hospitalization after birth in more than half of individuals. Breathing problems include a spectrum of abnormalities including laryngomalacia, micrognathia, stridor or noisy breathing at the mild end to subglottic stenosis, tracheomalacia, and tracheostomy with or without mechanical ventilation at the severe end. A severe respiratory course was described in at least seven individuals including mechanical ventilation (in 2 individuals), tracheostomy placements (in 4 individuals), laryngeal reconstruction (in 3), and mandibular advancement (in 3) [ Obstructive sleep apnea is noted in some individuals. Sparse scalp hair, thin skin, dry skin, and hyperkeratosis are noted in some infants. The appearance of the scalp hair improves with age. Small teeth and nail dysplasia or hypoplasia have also been described [ Pulmonary artery stenosis; Atrial septal defect; Ventricular septal defect; Aortic coarctation, supravalvular or subvalvular aortic stenosis; Dysplastic mitral valve; Hypertrophic cardiomyopathy (may be obstructive, may involve the left ventricle or the septum only). Genital abnormalities are more frequent in females than males and include hypoplastic labia majora and/or minora or clitoromegaly. Micropenis was described in some males. Renal abnormalities are not common and include vesicoureteral reflux (grade V reflux has been reported) and duplicated renal pelvis. Small kidneys with borderline function were reported in one individual. Chest is abnormal in shape (bell-shaped thorax, pectus carinatum). Fingers and toes are long and slender, and fingers may be tapering. Other findings include bilateral postaxial polydactyly, fifth finger clinodactyly, and metatarsus adductus. Absent or hypoplastic distal phalanges of the fingers are probably rare but a valuable diagnostic clue. Congenital hip dysplasia or coxa valga has been observed in several affected individuals. Clubfoot was described in nine individuals [ Scoliosis has also been described. Cleft palate, reported in nine individuals. Small oral cavity, high arched palate, and bifid uvula have also been described. Brachycephaly Torticollis of a muscular origin in some individuals Congenital structural malformations or polyhydramnios may be detected on prenatal ultrasound examination. Intrauterine growth restriction is not a major feature, and most affected pregnancies have an uncomplicated course. However, about 40% of individuals have been small for gestational age [ Affected infants are usually born at term with borderline low or normal birth weight. Abnormal fetal lie has been described, probably reflecting hypotonia. It is not possible to draw conclusions regarding genotype-phenotype correlations until more individuals are reported. Prior to the identification of causative biallelic Blepharophimosis-ptosis-intellectual disability (BPID) syndrome Phenotype seen in a subset of individuals clinically diagnosed with Toriello-Carey syndrome [ Phenotype described by The prevalence of KOS is unknown. To date, 36 individuals (from 25 families) with KOS and biallelic • Postnatal microcephaly is frequently present and more than 60% of affected children have prenatal microcephaly or a small occipitofrontal circumference (OFC) at birth (<10 • Hypotonia and delayed motor milestones are universal findings. • The onset of independent ambulation varies; in most it is achieved by age four to five years. Gait is frequently described as unsteady. • Intellectual disability is severe to profound in the individuals reported to date; rare, affected individuals develop limited speech. • Seizures are reported in approximately 20% of individuals and are usually fever related. • Abnormal brain MRI was reported in 19/26 individuals. Anomalies included corpus callosum hypoplasia or agenesis (13 individuals), dilated ventricles (3 individuals), Chiari 1 malformation (2), small pituitary (2), ectopic pituitary gland and hypoplastic vermis (1) [ • Significant behavior problems do not appear to be prominent; six individuals were described as having a cheerful disposition [ • Growth deficiency is common during infancy and most affected children have poor weight gain and short stature [ • Stature is usually below the 10 • Feeding difficulties are a main complication and manifest as poor weight gain, generalized hypotonia, poor suck, poor swallowing, small oral cavity, palate defects, gastroesophageal reflux, and poor dietary intake. Feeding by nasogastric tube or gastrostomy is needed in some individuals. • Constipation has been reported in several individuals. • Three individuals had intestinal malrotation. • Eyebrows: highly arched, laterally broad with flaring (medial or lateral) • Telecanthus, blepharophimosis with epicanthal folds, ptosis, upslanted palpebral fissures • Ears: often apparently low set with overfolded helices and small lobes; variably seen: cupped ears, underdeveloped crus helix, preauricular tags • Narrow nasal bridge, wide nasal base, anteverted nares • Flat zygomata • Long, flat philtrum • Narrow mouth, thin vermilion of the upper lip with absent Cupid's bow • Micrognathia • Prominent cheeks • Structural abnormalities (microcornea or microphthalmia, coloboma, optic nerve hypoplasia, spherophakia); • Refractive errors (myopia with or without astigmatism, hyperopia); • Abnormal alignment of the eyes (strabismus); • Entropion (inward turning of the lower eyelid); • Epibulbar dermoid in one individual [ • Hearing impairment is common. Both conductive and sensorineural hearing loss have been reported as well as mixed conductive-sensorineural hearing loss of variable severity. • Ear anomalies include stenotic auditory canals, dysplastic ears, and cupped ears; ear tags are present in about 30%-40% of individuals. • Two affected individuals had cholesteatoma [ • Breathing problems are quite common leading to a complicated course with prolonged hospitalization after birth in more than half of individuals. Breathing problems include a spectrum of abnormalities including laryngomalacia, micrognathia, stridor or noisy breathing at the mild end to subglottic stenosis, tracheomalacia, and tracheostomy with or without mechanical ventilation at the severe end. • A severe respiratory course was described in at least seven individuals including mechanical ventilation (in 2 individuals), tracheostomy placements (in 4 individuals), laryngeal reconstruction (in 3), and mandibular advancement (in 3) [ • Obstructive sleep apnea is noted in some individuals. • Sparse scalp hair, thin skin, dry skin, and hyperkeratosis are noted in some infants. The appearance of the scalp hair improves with age. • Small teeth and nail dysplasia or hypoplasia have also been described [ • Pulmonary artery stenosis; • Atrial septal defect; • Ventricular septal defect; • Aortic coarctation, supravalvular or subvalvular aortic stenosis; • Dysplastic mitral valve; • Hypertrophic cardiomyopathy (may be obstructive, may involve the left ventricle or the septum only). • Genital abnormalities are more frequent in females than males and include hypoplastic labia majora and/or minora or clitoromegaly. • Micropenis was described in some males. • Renal abnormalities are not common and include vesicoureteral reflux (grade V reflux has been reported) and duplicated renal pelvis. Small kidneys with borderline function were reported in one individual. • Chest is abnormal in shape (bell-shaped thorax, pectus carinatum). • Fingers and toes are long and slender, and fingers may be tapering. Other findings include bilateral postaxial polydactyly, fifth finger clinodactyly, and metatarsus adductus. Absent or hypoplastic distal phalanges of the fingers are probably rare but a valuable diagnostic clue. • Congenital hip dysplasia or coxa valga has been observed in several affected individuals. • Clubfoot was described in nine individuals [ • Scoliosis has also been described. • Cleft palate, reported in nine individuals. Small oral cavity, high arched palate, and bifid uvula have also been described. • Brachycephaly • Torticollis of a muscular origin in some individuals • Congenital structural malformations or polyhydramnios may be detected on prenatal ultrasound examination. • Intrauterine growth restriction is not a major feature, and most affected pregnancies have an uncomplicated course. However, about 40% of individuals have been small for gestational age [ • Affected infants are usually born at term with borderline low or normal birth weight. • Abnormal fetal lie has been described, probably reflecting hypotonia. • Blepharophimosis-ptosis-intellectual disability (BPID) syndrome • Phenotype seen in a subset of individuals clinically diagnosed with Toriello-Carey syndrome [ • Phenotype described by ## Clinical Description Kaufman oculocerebrofacial syndrome (KOS) is characterized by prenatal-onset microcephaly, growth deficiency, developmental delay, severe intellectual disability, and distinct facial features. To date, 36 individuals have been identified with biallelic pathogenic variants in Kaufman Oculocerebrofacial Syndrome: Frequency of Select Features Postnatal microcephaly is frequently present and more than 60% of affected children have prenatal microcephaly or a small occipitofrontal circumference (OFC) at birth (<10 Hypotonia and delayed motor milestones are universal findings. The onset of independent ambulation varies; in most it is achieved by age four to five years. Gait is frequently described as unsteady. Intellectual disability is severe to profound in the individuals reported to date; rare, affected individuals develop limited speech. Seizures are reported in approximately 20% of individuals and are usually fever related. Abnormal brain MRI was reported in 19/26 individuals. Anomalies included corpus callosum hypoplasia or agenesis (13 individuals), dilated ventricles (3 individuals), Chiari 1 malformation (2), small pituitary (2), ectopic pituitary gland and hypoplastic vermis (1) [ Significant behavior problems do not appear to be prominent; six individuals were described as having a cheerful disposition [ Growth deficiency is common during infancy and most affected children have poor weight gain and short stature [ Stature is usually below the 10 Feeding difficulties are a main complication and manifest as poor weight gain, generalized hypotonia, poor suck, poor swallowing, small oral cavity, palate defects, gastroesophageal reflux, and poor dietary intake. Feeding by nasogastric tube or gastrostomy is needed in some individuals. Constipation has been reported in several individuals. Three individuals had intestinal malrotation. Eyebrows: highly arched, laterally broad with flaring (medial or lateral) Telecanthus, blepharophimosis with epicanthal folds, ptosis, upslanted palpebral fissures Ears: often apparently low set with overfolded helices and small lobes; variably seen: cupped ears, underdeveloped crus helix, preauricular tags Narrow nasal bridge, wide nasal base, anteverted nares Flat zygomata Long, flat philtrum Narrow mouth, thin vermilion of the upper lip with absent Cupid's bow Micrognathia Prominent cheeks Structural abnormalities (microcornea or microphthalmia, coloboma, optic nerve hypoplasia, spherophakia); Refractive errors (myopia with or without astigmatism, hyperopia); Abnormal alignment of the eyes (strabismus); Entropion (inward turning of the lower eyelid); Epibulbar dermoid in one individual [ Hearing impairment is common. Both conductive and sensorineural hearing loss have been reported as well as mixed conductive-sensorineural hearing loss of variable severity. Ear anomalies include stenotic auditory canals, dysplastic ears, and cupped ears; ear tags are present in about 30%-40% of individuals. Two affected individuals had cholesteatoma [ Breathing problems are quite common leading to a complicated course with prolonged hospitalization after birth in more than half of individuals. Breathing problems include a spectrum of abnormalities including laryngomalacia, micrognathia, stridor or noisy breathing at the mild end to subglottic stenosis, tracheomalacia, and tracheostomy with or without mechanical ventilation at the severe end. A severe respiratory course was described in at least seven individuals including mechanical ventilation (in 2 individuals), tracheostomy placements (in 4 individuals), laryngeal reconstruction (in 3), and mandibular advancement (in 3) [ Obstructive sleep apnea is noted in some individuals. Sparse scalp hair, thin skin, dry skin, and hyperkeratosis are noted in some infants. The appearance of the scalp hair improves with age. Small teeth and nail dysplasia or hypoplasia have also been described [ Pulmonary artery stenosis; Atrial septal defect; Ventricular septal defect; Aortic coarctation, supravalvular or subvalvular aortic stenosis; Dysplastic mitral valve; Hypertrophic cardiomyopathy (may be obstructive, may involve the left ventricle or the septum only). Genital abnormalities are more frequent in females than males and include hypoplastic labia majora and/or minora or clitoromegaly. Micropenis was described in some males. Renal abnormalities are not common and include vesicoureteral reflux (grade V reflux has been reported) and duplicated renal pelvis. Small kidneys with borderline function were reported in one individual. Chest is abnormal in shape (bell-shaped thorax, pectus carinatum). Fingers and toes are long and slender, and fingers may be tapering. Other findings include bilateral postaxial polydactyly, fifth finger clinodactyly, and metatarsus adductus. Absent or hypoplastic distal phalanges of the fingers are probably rare but a valuable diagnostic clue. Congenital hip dysplasia or coxa valga has been observed in several affected individuals. Clubfoot was described in nine individuals [ Scoliosis has also been described. Cleft palate, reported in nine individuals. Small oral cavity, high arched palate, and bifid uvula have also been described. Brachycephaly Torticollis of a muscular origin in some individuals Congenital structural malformations or polyhydramnios may be detected on prenatal ultrasound examination. Intrauterine growth restriction is not a major feature, and most affected pregnancies have an uncomplicated course. However, about 40% of individuals have been small for gestational age [ Affected infants are usually born at term with borderline low or normal birth weight. Abnormal fetal lie has been described, probably reflecting hypotonia. • Postnatal microcephaly is frequently present and more than 60% of affected children have prenatal microcephaly or a small occipitofrontal circumference (OFC) at birth (<10 • Hypotonia and delayed motor milestones are universal findings. • The onset of independent ambulation varies; in most it is achieved by age four to five years. Gait is frequently described as unsteady. • Intellectual disability is severe to profound in the individuals reported to date; rare, affected individuals develop limited speech. • Seizures are reported in approximately 20% of individuals and are usually fever related. • Abnormal brain MRI was reported in 19/26 individuals. Anomalies included corpus callosum hypoplasia or agenesis (13 individuals), dilated ventricles (3 individuals), Chiari 1 malformation (2), small pituitary (2), ectopic pituitary gland and hypoplastic vermis (1) [ • Significant behavior problems do not appear to be prominent; six individuals were described as having a cheerful disposition [ • Growth deficiency is common during infancy and most affected children have poor weight gain and short stature [ • Stature is usually below the 10 • Feeding difficulties are a main complication and manifest as poor weight gain, generalized hypotonia, poor suck, poor swallowing, small oral cavity, palate defects, gastroesophageal reflux, and poor dietary intake. Feeding by nasogastric tube or gastrostomy is needed in some individuals. • Constipation has been reported in several individuals. • Three individuals had intestinal malrotation. • Eyebrows: highly arched, laterally broad with flaring (medial or lateral) • Telecanthus, blepharophimosis with epicanthal folds, ptosis, upslanted palpebral fissures • Ears: often apparently low set with overfolded helices and small lobes; variably seen: cupped ears, underdeveloped crus helix, preauricular tags • Narrow nasal bridge, wide nasal base, anteverted nares • Flat zygomata • Long, flat philtrum • Narrow mouth, thin vermilion of the upper lip with absent Cupid's bow • Micrognathia • Prominent cheeks • Structural abnormalities (microcornea or microphthalmia, coloboma, optic nerve hypoplasia, spherophakia); • Refractive errors (myopia with or without astigmatism, hyperopia); • Abnormal alignment of the eyes (strabismus); • Entropion (inward turning of the lower eyelid); • Epibulbar dermoid in one individual [ • Hearing impairment is common. Both conductive and sensorineural hearing loss have been reported as well as mixed conductive-sensorineural hearing loss of variable severity. • Ear anomalies include stenotic auditory canals, dysplastic ears, and cupped ears; ear tags are present in about 30%-40% of individuals. • Two affected individuals had cholesteatoma [ • Breathing problems are quite common leading to a complicated course with prolonged hospitalization after birth in more than half of individuals. Breathing problems include a spectrum of abnormalities including laryngomalacia, micrognathia, stridor or noisy breathing at the mild end to subglottic stenosis, tracheomalacia, and tracheostomy with or without mechanical ventilation at the severe end. • A severe respiratory course was described in at least seven individuals including mechanical ventilation (in 2 individuals), tracheostomy placements (in 4 individuals), laryngeal reconstruction (in 3), and mandibular advancement (in 3) [ • Obstructive sleep apnea is noted in some individuals. • Sparse scalp hair, thin skin, dry skin, and hyperkeratosis are noted in some infants. The appearance of the scalp hair improves with age. • Small teeth and nail dysplasia or hypoplasia have also been described [ • Pulmonary artery stenosis; • Atrial septal defect; • Ventricular septal defect; • Aortic coarctation, supravalvular or subvalvular aortic stenosis; • Dysplastic mitral valve; • Hypertrophic cardiomyopathy (may be obstructive, may involve the left ventricle or the septum only). • Genital abnormalities are more frequent in females than males and include hypoplastic labia majora and/or minora or clitoromegaly. • Micropenis was described in some males. • Renal abnormalities are not common and include vesicoureteral reflux (grade V reflux has been reported) and duplicated renal pelvis. Small kidneys with borderline function were reported in one individual. • Chest is abnormal in shape (bell-shaped thorax, pectus carinatum). • Fingers and toes are long and slender, and fingers may be tapering. Other findings include bilateral postaxial polydactyly, fifth finger clinodactyly, and metatarsus adductus. Absent or hypoplastic distal phalanges of the fingers are probably rare but a valuable diagnostic clue. • Congenital hip dysplasia or coxa valga has been observed in several affected individuals. • Clubfoot was described in nine individuals [ • Scoliosis has also been described. • Cleft palate, reported in nine individuals. Small oral cavity, high arched palate, and bifid uvula have also been described. • Brachycephaly • Torticollis of a muscular origin in some individuals • Congenital structural malformations or polyhydramnios may be detected on prenatal ultrasound examination. • Intrauterine growth restriction is not a major feature, and most affected pregnancies have an uncomplicated course. However, about 40% of individuals have been small for gestational age [ • Affected infants are usually born at term with borderline low or normal birth weight. • Abnormal fetal lie has been described, probably reflecting hypotonia. ## Genotype-Phenotype Correlations It is not possible to draw conclusions regarding genotype-phenotype correlations until more individuals are reported. ## Nomenclature Prior to the identification of causative biallelic Blepharophimosis-ptosis-intellectual disability (BPID) syndrome Phenotype seen in a subset of individuals clinically diagnosed with Toriello-Carey syndrome [ Phenotype described by • Blepharophimosis-ptosis-intellectual disability (BPID) syndrome • Phenotype seen in a subset of individuals clinically diagnosed with Toriello-Carey syndrome [ • Phenotype described by ## Prevalence The prevalence of KOS is unknown. To date, 36 individuals (from 25 families) with KOS and biallelic ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Kaufman oculocerebrofacial syndrome (KOS) has a relatively uniform, clinically recognizable phenotype mainly due to the characteristic dysmorphic features combined with severe intellectual disability [ Disorders of Interest in the Differential Diagnosis of Kaufman Oculocerebrofacial Syndrome (KOS) AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; DiffDx = differential diagnosis; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked Typically caused by a ## Management No clinical practice guidelines for Kaufman oculocerebrofacial syndrome (KOS) have been published. To establish the extent of disease and needs in an individual diagnosed with KOS, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Kaufman Oculocerebrofacial Syndrome To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Gastroenterology / nutrition / feeding team eval Eval for GERD; bowel malrotation (if indicated); cleft palate incl submucosal type To incl eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in those w/dysphagia & aspiration risk. Referral for ENT Referral to pulmonologist To evaluate for subglottic stenosis, laryngomalacia, tracheomalacia if respiratory issues or obstructive sleep apnea are present Evaluate for recurrent respiratory infections. Eval for genital anomalies Renal ultrasound exam for structural renal abnormalities & vesicoureteral reflux Hip ultrasound exam to evaluate for femoral head dislocation Eval of torticollis, clubfoot, & hand malformations or contractures Referral to orthopedist & PT Eval of thyroid function Eval of other hormone levels if clinically indicated Community or Social work involvement for parental support; Home nursing referral. GERD = gastroesophageal reflux disease; KOS = Kaufman oculocerebrofacial syndrome; MOI = mode of inheritance; PT = physical therapist Medical geneticist, certified genetic counselor, certified advanced genetic nurse Treatment of Manifestations in Individuals with Kaufman Oculocerebrofacial Syndrome Many ASMs may be effective; none has been demonstrated effective specifically for KOS. Education of parents/caregivers Cataract & ptosis surgery if indicated Treatment of refractive errors &/or strabismus Children: through early intervention programs &/or school district Adults: referral to low vision clinic &/or community vision services Tracheostomy placement if needed, laryngeal reconstruction, mandibular advancement, mechanical ventilation support if needed, mechanical aids for obstructive sleep apnea. Aggressive treatment of respiratory infections to prevent deterioration of respiratory function Referral to orthopedist if joint dislocations, clubfoot, hand contractures or scoliosis is present Early referral to PT ASM = anti-seizure medication; KOS = Kaufman oculocerebrofacial syndrome; PT = physical therapy The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. Individualized education plan (IEP) services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. Physical therapy, occupational therapy, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). Recommended Surveillance for Individuals with Kaufman Oculocerebrofacial Syndrome Monitor those w/seizures as clinically indicated. Assess for new manifestations incl seizures, changes in tone, mvmt disorders. Measure growth parameters. Evaluate nutritional status & safety of oral intake. Monitor for constipation. See Search • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Gastroenterology / nutrition / feeding team eval • Eval for GERD; bowel malrotation (if indicated); cleft palate incl submucosal type • To incl eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in those w/dysphagia & aspiration risk. • Referral for ENT • Referral to pulmonologist • To evaluate for subglottic stenosis, laryngomalacia, tracheomalacia if respiratory issues or obstructive sleep apnea are present • Evaluate for recurrent respiratory infections. • Eval for genital anomalies • Renal ultrasound exam for structural renal abnormalities & vesicoureteral reflux • Hip ultrasound exam to evaluate for femoral head dislocation • Eval of torticollis, clubfoot, & hand malformations or contractures • Referral to orthopedist & PT • Eval of thyroid function • Eval of other hormone levels if clinically indicated • Community or • Social work involvement for parental support; • Home nursing referral. • Many ASMs may be effective; none has been demonstrated effective specifically for KOS. • Education of parents/caregivers • Cataract & ptosis surgery if indicated • Treatment of refractive errors &/or strabismus • Children: through early intervention programs &/or school district • Adults: referral to low vision clinic &/or community vision services • Tracheostomy placement if needed, laryngeal reconstruction, mandibular advancement, mechanical ventilation support if needed, mechanical aids for obstructive sleep apnea. • Aggressive treatment of respiratory infections to prevent deterioration of respiratory function • Referral to orthopedist if joint dislocations, clubfoot, hand contractures or scoliosis is present • Early referral to PT • 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. • Physical therapy, occupational therapy, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • Physical therapy, occupational therapy, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • Physical therapy, occupational therapy, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • Monitor those w/seizures as clinically indicated. • Assess for new manifestations incl seizures, changes in tone, mvmt disorders. • Measure growth parameters. • Evaluate nutritional status & safety of oral intake. • Monitor for constipation. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with KOS, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Kaufman Oculocerebrofacial Syndrome To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Gastroenterology / nutrition / feeding team eval Eval for GERD; bowel malrotation (if indicated); cleft palate incl submucosal type To incl eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in those w/dysphagia & aspiration risk. Referral for ENT Referral to pulmonologist To evaluate for subglottic stenosis, laryngomalacia, tracheomalacia if respiratory issues or obstructive sleep apnea are present Evaluate for recurrent respiratory infections. Eval for genital anomalies Renal ultrasound exam for structural renal abnormalities & vesicoureteral reflux Hip ultrasound exam to evaluate for femoral head dislocation Eval of torticollis, clubfoot, & hand malformations or contractures Referral to orthopedist & PT Eval of thyroid function Eval of other hormone levels if clinically indicated Community or Social work involvement for parental support; Home nursing referral. GERD = gastroesophageal reflux disease; KOS = Kaufman oculocerebrofacial syndrome; MOI = mode of inheritance; PT = physical therapist Medical geneticist, certified genetic counselor, certified advanced genetic nurse • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Gastroenterology / nutrition / feeding team eval • Eval for GERD; bowel malrotation (if indicated); cleft palate incl submucosal type • To incl eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in those w/dysphagia & aspiration risk. • Referral for ENT • Referral to pulmonologist • To evaluate for subglottic stenosis, laryngomalacia, tracheomalacia if respiratory issues or obstructive sleep apnea are present • Evaluate for recurrent respiratory infections. • Eval for genital anomalies • Renal ultrasound exam for structural renal abnormalities & vesicoureteral reflux • Hip ultrasound exam to evaluate for femoral head dislocation • Eval of torticollis, clubfoot, & hand malformations or contractures • Referral to orthopedist & PT • Eval of thyroid function • Eval of other hormone levels if clinically indicated • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Treatment of Manifestations in Individuals with Kaufman Oculocerebrofacial Syndrome Many ASMs may be effective; none has been demonstrated effective specifically for KOS. Education of parents/caregivers Cataract & ptosis surgery if indicated Treatment of refractive errors &/or strabismus Children: through early intervention programs &/or school district Adults: referral to low vision clinic &/or community vision services Tracheostomy placement if needed, laryngeal reconstruction, mandibular advancement, mechanical ventilation support if needed, mechanical aids for obstructive sleep apnea. Aggressive treatment of respiratory infections to prevent deterioration of respiratory function Referral to orthopedist if joint dislocations, clubfoot, hand contractures or scoliosis is present Early referral to PT ASM = anti-seizure medication; KOS = Kaufman oculocerebrofacial syndrome; PT = physical therapy The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. Individualized education plan (IEP) services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. Physical therapy, occupational therapy, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • Many ASMs may be effective; none has been demonstrated effective specifically for KOS. • Education of parents/caregivers • Cataract & ptosis surgery if indicated • Treatment of refractive errors &/or strabismus • Children: through early intervention programs &/or school district • Adults: referral to low vision clinic &/or community vision services • Tracheostomy placement if needed, laryngeal reconstruction, mandibular advancement, mechanical ventilation support if needed, mechanical aids for obstructive sleep apnea. • Aggressive treatment of respiratory infections to prevent deterioration of respiratory function • Referral to orthopedist if joint dislocations, clubfoot, hand contractures or scoliosis is present • Early referral to PT • 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. • Physical therapy, occupational therapy, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • Physical therapy, occupational therapy, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • Physical therapy, occupational therapy, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## 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. Physical therapy, occupational therapy, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • 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. • Physical therapy, occupational therapy, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • Physical therapy, occupational therapy, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • Physical therapy, occupational therapy, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Motor Dysfunction Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • Physical therapy is recommended to 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 Kaufman Oculocerebrofacial Syndrome Monitor those w/seizures as clinically indicated. Assess for new manifestations incl seizures, changes in tone, mvmt disorders. Measure growth parameters. Evaluate nutritional status & safety of oral intake. Monitor for constipation. • Monitor those w/seizures as clinically indicated. • Assess for new manifestations incl seizures, changes in tone, mvmt disorders. • Measure growth parameters. • Evaluate nutritional status & safety of oral intake. • Monitor for constipation. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Kaufman oculocerebrofacial syndrome (KOS) 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 Some intrafamilial clinical variability has been observed between affected sibs; reported phenotypic differences involved seizures, respiratory issues, the severity and extent of hearing impairment, and congenital malformations [ 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 • Some intrafamilial clinical variability has been observed between affected sibs; reported phenotypic differences involved seizures, respiratory issues, the severity and extent of hearing impairment, and congenital malformations [ • 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 Kaufman oculocerebrofacial syndrome (KOS) 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 Some intrafamilial clinical variability has been observed between affected sibs; reported phenotypic differences involved seizures, respiratory issues, the severity and extent of hearing impairment, and congenital malformations [ 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 • Some intrafamilial clinical variability has been observed between affected sibs; reported phenotypic differences involved seizures, respiratory issues, the severity and extent of hearing impairment, and congenital malformations [ • 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 Speaking out for People with Intellectual and Developmental Disabilities • • • • • • Speaking out for People with Intellectual and Developmental Disabilities • ## Molecular Genetics Kaufman Oculocerebrofacial Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Kaufman Oculocerebrofacial Syndrome ( UBE3B is highly expressed in the central nervous system, digestive tract, and respiratory system as well as in multiple cell lineages of skin and other soft tissues. In the brain UBE3B associates with postsynaptic density fractions and regulates dendritic branching in a cell-autonomous manner [ ## Molecular Pathogenesis UBE3B is highly expressed in the central nervous system, digestive tract, and respiratory system as well as in multiple cell lineages of skin and other soft tissues. In the brain UBE3B associates with postsynaptic density fractions and regulates dendritic branching in a cell-autonomous manner [ ## Chapter Notes We would like to thank Dr Guntram Borck, who unfortunately passed away on 12-7-2021, for his valuable contribution in writing the first version of this Lina Basel-Salmon, MD, PhD (2016-present)Dana Brabbing-Goldstein, MD (2022-present)Guntram Borck, MD, PhD; University of Ulm (2016-2022) 28 July 2022 (sw) Comprehensive update posted live 20 October 2016 (bp) Review posted live 25 January 2016 (lbv) Original submission • 28 July 2022 (sw) Comprehensive update posted live • 20 October 2016 (bp) Review posted live • 25 January 2016 (lbv) Original submission ## Acknowledgments We would like to thank Dr Guntram Borck, who unfortunately passed away on 12-7-2021, for his valuable contribution in writing the first version of this ## Author History Lina Basel-Salmon, MD, PhD (2016-present)Dana Brabbing-Goldstein, MD (2022-present)Guntram Borck, MD, PhD; University of Ulm (2016-2022) ## Revision History 28 July 2022 (sw) Comprehensive update posted live 20 October 2016 (bp) Review posted live 25 January 2016 (lbv) Original submission • 28 July 2022 (sw) Comprehensive update posted live • 20 October 2016 (bp) Review posted live • 25 January 2016 (lbv) Original submission ## References ## Literature Cited Facial dysmorphism associated with KOS caused by biallelic Photographs published with permission of the families	[ "MC Ambrozkiewicz, KJ Cuthill, D Harnett, H Kawabe, V Tarabykin. Molecular evolution, neurodevelopmental roles and clinical significance of HECT-type UBE3 E3 ubiquitin ligases.. Cells. 2020;9:2455", "L Basel-Vanagaite, B Dallapiccola, R Ramirez-Solis, A Segref, H Thiele, A Edwards, MJ Arends, X Miró, JK White, J Désir, M Abramowicz, ML Dentici, F Lepri, K Hofmann, A Har-Zahav, E Ryder, NA Karp, J Estabel, AK Gerdin, C Podrini, NJ Ingham, J Altmüller, G Nürnberg, P Frommolt, S Abdelhak, M Pasmanik-Chor, O Konen, RI Kelley, M Shohat, P Nürnberg, J Flint, KP Steel, T Hoppe, C Kubisch, DJ Adams, G Borck. Deficiency for the ubiquitin ligase UBE3B in a blepharophimosis-ptosis-intellectual-disability syndrome.. Am J Hum Genet. 2012;91:998-1010", "L Basel-Vanagaite, R Yilmaz, S Tang, MS Reuter, N Rahner, DK Grange, M Mortenson, P Koty, H Feenstra, KD Farwell Gonzalez, H Sticht, N Boddaert, J Désir, K Anyane-Yeboa, C Zweier, A Reis, C Kubisch, T Jewett, W Zeng, G Borck. Expanding the clinical and mutational spectrum of Kaufman oculocerebrofacial syndrome with biallelic UBE3B mutations.. Hum Genet. 2014;133:939-49", "I Buntinx, F Majewski. Blepharophimosis, iris coloboma, microgenia, hearing loss, postaxial polydactyly, aplasia of corpus callosum, hydroureter, and developmental delay.. Am J Med Genet 1990;36:273-4", "G Cappuccio, C Sayou, PL Tanno, E Tisserant, AL Bruel, SE Kennani, J Sá, KJ Low, C Dias, M Havlovicová, M Hančárová, EE Eichler, F Devillard, S Moutton, J Van-Gils, C Dubourg, S Odent, B Gerard, A Piton, T Yamamoto, N Okamoto, H Firth, K Metcalfe, A Moh, KA Chapman, E Aref-Eshghi, J Kerkhof, A Torella, V Nigro, L Perrin, J Piard, G Le Guyader, T Jouan, C Thauvin-Robinet, Y Duffourd, JK George-Abraham, CA Buchanan, D Williams, U Kini, K Wilson, SB Sousa, RCM Hennekam, B Sadikovic, J Thevenon, J Govin, A Vitobello, N Brunetti-Pierri. De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome.. Genet Med. 2020;22:1838-50", "LE Figuera, D García-Cruz, ML Ramírez-Dueñas, V Rivera-Robles, JM Cantù. Kaufman oculocerebrofacial syndrome: report of two new cases and further delineation.. Clin Genet. 1993;44:98-101", "E Flex, A Ciolfi, V Caputo, V Fodale, C Leoni, D Melis, MF Bedeschi, L Mazzanti, A Pizzuti, M Tartaglia, G Zampino. Loss of function of the E3 ubiquitin-protein ligase UBE3B causes Kaufman oculocerebrofacial syndrome.. J Med Genet. 2013;50:493-9", "CI Galarreta, KM Wigby, MC Jones. Further phenotypic characterization of Kaufman oculocerebrofacial syndrome: report of five new cases and literature review.. Clin Dysmorphol. 2019;28:175-83", "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", "SB Jurenka, J Evans. Kaufman oculocerebrofacial syndrome: case report.. Am J Med Genet. 1979;3:15-9", "A Kariminejad, NF Ajeawung, B Bozorgmehr, A Dionne-Laporte, S Molidperee, K Najafi, RA Gibbs, BH Lee, RC Hennekam, PM Campeau. Kaufman oculo-cerebro-facial syndrome in a child with small and absent terminal phalanges and absent nails.. J Hum Genet. 2017;62:465-71", "RL Kaufman, DL Rimoin, AL Prensky, WS Sly. An oculocerebrofacial syndrome.. Birth Defects Orig Artic Ser. 1971;7:135-8", "CR Pedurupillay, T Barøy, A Holmgren, A Blomhoff, MD Vigeland, Y Sheng, E Frengen, P Strømme, D Misceo. Kaufman oculocerebrofacial syndrome in sisters with novel compound heterozygous mutation in UBE3B.. Am J Med Genet A. 2015;167A:657-63", "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", "HV Toriello, JC Carey, MC Addor, W Allen, L Burke, N Chun, W Dobyns, E Elias, R Gallagher, R Hordijk, G Hoyme, M Irons, T Jewett, M LeMerrer, M Lubinsky, R Martin, D McDonald-McGinn, L Neumann, W Newman, R Pauli, L Seaver, A Tsai, D Wargowsky, M Williams, E Zackai. Toriello-Carey syndrome: delineation and review.. Am J Med Genet A. 2003;123A:84-90", "G Ürel-Demir, B Aydın, B Karaosmanoğlu, Ö Akgün-Doğan, EZ Taşkıran, PÖ Şimşek-Kiper, GE Utine, K Boduroğlu. Two siblings with Kaufman oculocerebrofacial syndrome resembling oculoauriculovertebral spectrum.. Mol Syndromol. 2021;12:106-11", "R Yilmaz, K Szakszon, A Altmann, U Altunoglu, L Senturk, M McGuire, O Calabrese, S Madan-Khetarpal, L Basel-Vanagaite, G. Borck. Kaufman oculocerebrofacial syndrome: Novel UBE3B mutations and clinical features in four unrelated patients.. Am J Med Genet A. 2018;176:187-93", "MS Zaki, GA Otaify, S Ismail, MY Issa, MO El-Ruby, AA Sadek, EA Ashaat, SA El Saeidi, MS Aglan, S Temtamy, MS Abdel-Hamid. Blepharophimosis-ptosis-intellectual disability syndrome: A report of nine Egyptian patients with further expansion of phenotypic and mutational spectrum.. Am J Med Genet A. 2020;182:2857-66" ]	20/10/2016	28/7/2022		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
kptn-dis	kptn-dis	[ "Macrocephaly, Autistic Features, Seizures, Developmental Delay (MASD) Syndrome", "Macrocephaly, Autistic Features, Seizures, Developmental Delay (MASD) Syndrome", "KICSTOR complex protein kaptin", "KPTN", "KPTN-Related Disorder" ]		Lettie E Rawlins, Peter B Crino, Philip H Iffland, Andrew H Crosby, Emma L Baple	Summary The diagnosis of	## Diagnosis Mild-to-profound intellectual disability Developmental delay Postnatal and progressive macrocephaly (onset usually within the first year of life) Neurobehavioral/psychiatric manifestations associated with autism spectrum disorder (anxiety, stereotypies, hyperactivity, repetitive speech, impaired social communication) Neonatal/childhood hypotonia Seizures (generalized tonic-clonic, absence, focal, tonic seizures) Recurrent infections (lower respiratory tract infections, otitis media) Characteristic facial features in some individuals (frontal bossing, short downslanted palpebral fissures, hypertelorism, depressed nasal bridge, broad nasal tip, tall, broad chin, thick vermilion of the lower lip; 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: Targeted analysis for the Single-gene testing (sequence analysis of An For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. To date, no large intragenic deletions/duplications have been reported in individuals with • Mild-to-profound intellectual disability • Developmental delay • Postnatal and progressive macrocephaly (onset usually within the first year of life) • Neurobehavioral/psychiatric manifestations associated with autism spectrum disorder (anxiety, stereotypies, hyperactivity, repetitive speech, impaired social communication) • Neonatal/childhood hypotonia • Seizures (generalized tonic-clonic, absence, focal, tonic seizures) • Recurrent infections (lower respiratory tract infections, otitis media) • Characteristic facial features in some individuals (frontal bossing, short downslanted palpebral fissures, hypertelorism, depressed nasal bridge, broad nasal tip, tall, broad chin, thick vermilion of the lower lip; see ## Suggestive Findings Mild-to-profound intellectual disability Developmental delay Postnatal and progressive macrocephaly (onset usually within the first year of life) Neurobehavioral/psychiatric manifestations associated with autism spectrum disorder (anxiety, stereotypies, hyperactivity, repetitive speech, impaired social communication) Neonatal/childhood hypotonia Seizures (generalized tonic-clonic, absence, focal, tonic seizures) Recurrent infections (lower respiratory tract infections, otitis media) Characteristic facial features in some individuals (frontal bossing, short downslanted palpebral fissures, hypertelorism, depressed nasal bridge, broad nasal tip, tall, broad chin, thick vermilion of the lower lip; see • Mild-to-profound intellectual disability • Developmental delay • Postnatal and progressive macrocephaly (onset usually within the first year of life) • Neurobehavioral/psychiatric manifestations associated with autism spectrum disorder (anxiety, stereotypies, hyperactivity, repetitive speech, impaired social communication) • Neonatal/childhood hypotonia • Seizures (generalized tonic-clonic, absence, focal, tonic seizures) • Recurrent infections (lower respiratory tract infections, otitis media) • Characteristic facial features in some individuals (frontal bossing, short downslanted palpebral fissures, hypertelorism, depressed nasal bridge, broad nasal tip, tall, broad chin, thick vermilion of the lower lip; see ## Establishing the Diagnosis The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Note: Targeted analysis for the Single-gene testing (sequence analysis of An For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. To date, no large intragenic deletions/duplications have been reported in individuals with ## Option 1 An For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. To date, no large intragenic deletions/duplications have been reported in individuals with ## Clinical Characteristics Hepatosplenomegaly (2 individuals) Hepatomegaly (1 individual) Splenomegaly (1 individual) Although no specific genotype-phenotype correlations have been conclusively identified, biallelic predicted loss-of-function variants (e.g., frameshift, nonsense) appear to have a greater degree of severity of ID and increased frequency of seizures when compared with biallelic protein-altering variants (e.g., missense, inframe indels). Two founder Pathogenic variant Pathogenic variant • Hepatosplenomegaly (2 individuals) • Hepatomegaly (1 individual) • Splenomegaly (1 individual) ## Clinical Description Hepatosplenomegaly (2 individuals) Hepatomegaly (1 individual) Splenomegaly (1 individual) • Hepatosplenomegaly (2 individuals) • Hepatomegaly (1 individual) • Splenomegaly (1 individual) ## Genotype-Phenotype Correlations Although no specific genotype-phenotype correlations have been conclusively identified, biallelic predicted loss-of-function variants (e.g., frameshift, nonsense) appear to have a greater degree of severity of ID and increased frequency of seizures when compared with biallelic protein-altering variants (e.g., missense, inframe indels). ## Prevalence Two founder Pathogenic variant Pathogenic variant ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Disorders Associated with Macrocephaly and Intellectual Disability / Developmental Delay in the Differential Diagnosis of ASD Downslanted palpebral fissures Seizures GI issues (e.g., recurrent constipation ± periods of diarrhea) Developmental regression of social, speech, &/or motor skills in infancy & early childhood ASD Behavioral issues (e.g., hyperactivity) Frontal bossing Prominent jaw Seizures Macroorchidism Mitral valve prolapse Facial features (frontal bossing, hypertelorism, downslanted palpebral fissures) Hypotonia Seizures Behavioral issues Facial features (frontal bossing, pointed chin, downslanted palpebral fissures) Hypotonia Seizures Ocular issues (incl strabismus & nystagmus) Behavioral issues Ventriculomegaly Generalized overgrowth Additional syndromic features incl congenital heart disease, renal anomalies, & scoliosis Behavioral issues (incl a specific anxious profile & ADHD) Downslanted palpebral fissures Hypotonia Ocular issues (incl strabismus & nystagmus) Ventriculomegaly ASD Hypertelorism Seizures Tone abnormalities ASD Scoliosis Pectus excavatum Cancer predisposition Dermatologic features incl skin tags/papules Hamartomatous tumors ASD Depressed nasal bridge Frontal bossing Hepatomegaly/splenomegaly Recurrent infections Anxiety ASD Downslanted palpebral fissures Hypotonia Seizures Ventriculomegaly Chiari I malformation & syringomyelia Polycystic ovarian syndrome Facial features: frontal bossing, prominent chin, hypertelorism Hypotonia Seizures Strabismus Ventriculomegaly Facial features: frontal bossing, hypertelorism, downslanted palpebral fissures, high-arched palate Hypotonia Persistent cavum septum pellucidum Seizures Ventriculomegaly ASD Downslanted palpebral fissures Frontal bossing Seizures Stereotypies AD = autosomal dominant; ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; DD = developmental delay; ID = intellectual disability; GI = gastrointestinal; MOI = mode of inheritance; XL = X-linked Fragile X syndrome is associated with a large occipitofrontal head circumference (>50th percentile). • ASD • Downslanted palpebral fissures • Seizures • GI issues (e.g., recurrent constipation ± periods of diarrhea) • Developmental regression of social, speech, &/or motor skills in infancy & early childhood • ASD • Behavioral issues (e.g., hyperactivity) • Frontal bossing • Prominent jaw • Seizures • Macroorchidism • Mitral valve prolapse • Facial features (frontal bossing, hypertelorism, downslanted palpebral fissures) • Hypotonia • Seizures • Behavioral issues • Facial features (frontal bossing, pointed chin, downslanted palpebral fissures) • Hypotonia • Seizures • Ocular issues (incl strabismus & nystagmus) • Behavioral issues • Ventriculomegaly • Generalized overgrowth • Additional syndromic features incl congenital heart disease, renal anomalies, & scoliosis • Behavioral issues (incl a specific anxious profile & ADHD) • Downslanted palpebral fissures • Hypotonia • Ocular issues (incl strabismus & nystagmus) • Ventriculomegaly • ASD • Hypertelorism • Seizures • Tone abnormalities • ASD • Scoliosis • Pectus excavatum • Cancer predisposition • Dermatologic features incl skin tags/papules • Hamartomatous tumors • ASD • Depressed nasal bridge • Frontal bossing • Hepatomegaly/splenomegaly • Recurrent infections • Anxiety • ASD • Downslanted palpebral fissures • Hypotonia • Seizures • Ventriculomegaly • Chiari I malformation & syringomyelia • Polycystic ovarian syndrome • Facial features: frontal bossing, prominent chin, hypertelorism • Hypotonia • Seizures • Strabismus • Ventriculomegaly • Facial features: frontal bossing, hypertelorism, downslanted palpebral fissures, high-arched palate • Hypotonia • Persistent cavum septum pellucidum • Seizures • Ventriculomegaly • ASD • Downslanted palpebral fissures • Frontal bossing • Seizures • Stereotypies ## 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 To incl assessment for balance problems & oral apraxia Eval for early intervention / special education Assessment for hypoglycemia in neonatal period, in infancy, & w/intercurrent illness Assessment for hypo- & hyperthyroidism & hyperprolactinemia Community or Social work involvement for parental support Home nursing referral MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse There is currently no cure for 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 The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about 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 Monitoring of developmental progress & educational needs Physical medicine, OT/PT assessment of mobility, self-help skills Monitor those w/seizures as clinically indicated. Assess for new manifestations such as seizures, balance problems, & oral apraxia. Monitor in neonatal period & then at each visit & during intercurrent illness. Education on symptoms of hypoglycemia for parents/caregivers OT = occupational therapy; PT = physical therapy; TSH = thyroid-stimulating hormone See Current studies of the efficacy of mTOR inhibitors are under way in • To incl motor, adaptive, cognitive, & speech-language eval • To incl assessment for balance problems & oral apraxia • Eval for early intervention / special education • Assessment for hypoglycemia in neonatal period, in infancy, & w/intercurrent illness • Assessment for hypo- & hyperthyroidism & hyperprolactinemia • Community or • Social work involvement for parental support • Home nursing referral • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • Monitoring of developmental progress & educational needs • Physical medicine, OT/PT assessment of mobility, self-help skills • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as seizures, balance problems, & oral apraxia. • Monitor in neonatal period & then at each visit & during intercurrent illness. • Education on symptoms of hypoglycemia for parents/caregivers ## 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 To incl assessment for balance problems & oral apraxia Eval for early intervention / special education Assessment for hypoglycemia in neonatal period, in infancy, & w/intercurrent illness Assessment for hypo- & hyperthyroidism & hyperprolactinemia Community or Social work involvement for parental support Home nursing referral MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse • To incl motor, adaptive, cognitive, & speech-language eval • To incl assessment for balance problems & oral apraxia • Eval for early intervention / special education • Assessment for hypoglycemia in neonatal period, in infancy, & w/intercurrent illness • Assessment for hypo- & hyperthyroidism & hyperprolactinemia • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations There is currently no cure for 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 The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about destructive behavior can be addressed by a pediatric psychiatrist. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Motor Dysfunction Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## Neurobehavioral/Psychiatric Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, 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 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 Monitoring of developmental progress & educational needs Physical medicine, OT/PT assessment of mobility, self-help skills Monitor those w/seizures as clinically indicated. Assess for new manifestations such as seizures, balance problems, & oral apraxia. Monitor in neonatal period & then at each visit & during intercurrent illness. Education on symptoms of hypoglycemia for parents/caregivers OT = occupational therapy; PT = physical therapy; TSH = thyroid-stimulating hormone • Monitoring of developmental progress & educational needs • Physical medicine, OT/PT assessment of mobility, self-help skills • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as seizures, balance problems, & oral apraxia. • Monitor in neonatal period & then at each visit & during intercurrent illness. • Education on symptoms of hypoglycemia for parents/caregivers ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Current studies of the efficacy of mTOR inhibitors are under way in ## Genetic Counseling The parents of an affected child are presumed to be heterozygous for a Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a 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, although increased head circumference (above the mean for age and sex) is commonly observed. If both parents are known to be heterozygous for a Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder, although increased head circumference (above the mean for age and sex) is commonly observed. Carrier testing for at-risk relatives requires prior identification of the The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. Carrier testing should be considered for the reproductive partners of known carriers, particularly if both partners are of the same ancestry. Founder variants have been identified in the Ohio Amish community (see Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected child are presumed to be heterozygous for a • Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a • 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, although increased head circumference (above the mean for age and sex) is commonly observed. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual 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, although increased head circumference (above the mean for age and sex) is commonly observed. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. • Carrier testing should be considered for the reproductive partners of known carriers, particularly if both partners are of the same ancestry. Founder variants have been identified in the Ohio Amish community (see ## Mode of Inheritance ## Risk to Family Members The parents of an affected child are presumed to be heterozygous for a Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a 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, although increased head circumference (above the mean for age and sex) is commonly observed. If both parents are known to be heterozygous for a Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder, although increased head circumference (above the mean for age and sex) is commonly observed. • The parents of an affected child are presumed to be heterozygous for a • Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a • If a 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, although increased head circumference (above the mean for age and sex) is commonly observed. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual 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, although increased head circumference (above the mean for age and sex) is commonly observed. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. Carrier testing should be considered for the reproductive partners of known carriers, particularly if both partners are of the same ancestry. Founder variants have been identified in the Ohio Amish community (see • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. • Carrier testing should be considered for the reproductive partners of known carriers, particularly if both partners are of the same ancestry. Founder variants have been identified in the Ohio Amish community (see ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • ## Molecular Genetics KPTN-Related Disorder: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for KPTN-Related Disorder ( Further studies of Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis Further studies of Variants listed in the table have been provided by the authors. ## Chapter Notes Further information on our work with the Amish and Mennonite communities can be found at Prof Emma Baple and Dr Lettie Rawlins continue to be involved in clinical studies of The authors would like to thank the patients and their families as well as the collaborators who have been involved in describing This work was supported by the Medical Research Council (MRC), Medical Research Foundation (MRF), National Institutes of Health Javits Award (NIH), Newlife Foundation for Disabled Children (16-17/12), and the National Institute for Health and Care Research Exeter Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. 1 August 2024 (sw) Review posted live 18 December 2023 (eb) Original submission • 1 August 2024 (sw) Review posted live • 18 December 2023 (eb) Original submission ## Author Notes Further information on our work with the Amish and Mennonite communities can be found at Prof Emma Baple and Dr Lettie Rawlins continue to be involved in clinical studies of ## Acknowledgments The authors would like to thank the patients and their families as well as the collaborators who have been involved in describing This work was supported by the Medical Research Council (MRC), Medical Research Foundation (MRF), National Institutes of Health Javits Award (NIH), Newlife Foundation for Disabled Children (16-17/12), and the National Institute for Health and Care Research Exeter Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. ## Revision History 1 August 2024 (sw) Review posted live 18 December 2023 (eb) Original submission • 1 August 2024 (sw) Review posted live • 18 December 2023 (eb) Original submission ## References ## Literature Cited Photographs of individuals with Reprinted with permission from	[]	1/8/2024			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
krabbe	krabbe	[ "Galactocerebrosidase Deficiency", "GALC Deficiency", "Globoid Cell Leukodystrophy", "GALC Deficiency", "Galactosylceramidase Deficiency", "Globoid Cell Leukodystrophy", "Galactosylcerebrosidase Deficiency", "ß-Galactocerebrosidase Deficiency", "Galactocerebrosidase", "GALC", "Krabbe Disease" ]	Krabbe Disease	Joseph J Orsini, Maria L Escolar, Melissa P Wasserstein, Michele Caggana	Summary Krabbe disease comprises a spectrum ranging from infantile-onset disease (i.e., onset of extreme irritability, spasticity, and developmental delay before age 12 months) to later-onset disease (i.e., onset of manifestations after age 12 months and as late as the seventh decade). Although historically 85%-90% of symptomatic individuals with Krabbe disease diagnosed by enzyme activity alone have infantile-onset Krabbe disease and 10%-15% have later-onset Krabbe disease, the experience with newborn screening (NBS) suggests that the proportion of individuals with possible later-onset Krabbe disease is higher than previously thought. Infantile-onset Krabbe disease is characterized by normal development in the first few months followed by rapid severe neurologic deterioration; the average age of death is 24 months (range 8 months to 9 years). Later-onset Krabbe disease is much more variable in its presentation and disease course. The two diagnostic scenarios are the following: Scenario 1. The diagnosis of Krabbe disease, suspected in a symptomatic proband based on clinical findings (by age) and other supportive laboratory, neuroimaging, and electrophysiologic findings, is established by detection of deficient GALC enzyme activity in leukocytes. Abnormal results require follow-up molecular genetic testing of Scenario 2. In an asymptomatic newborn with low GALC enzyme activity on dried blood spot specimens on NBS urgent time-critical measurement of blood psychosine levels and Krabbe disease 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 Krabbe disease (also known as galactocerebrosidase [GALC] deficiency) has two major phenotypes that constitute a continuum: Infantile-onset Krabbe disease (onset <12 months), characterized by progressive neurologic deterioration in infancy and death before age two years (85%-90% of affected individuals) Later-onset Krabbe disease (onset >12 months), with slower disease progression (10%-15%) The two different scenarios in which Krabbe disease could be suspected in a proband: Krabbe disease Excessive crying to extreme irritability Feeding difficulties, gastroesophageal reflux disease Spasticity of lower extremities and fisting, with axial hypotonia Loss of acquired milestones (smiling, cooing, and head control) Staring episodes Peripheral neuropathy Slow development of motor milestones or loss of milestones (e.g., sitting without support, walking), slurred speech Spasticity of extremities with truncal hypotonia Vision loss, esotropia Seizures Peripheral neuropathy Increased cerebrospinal fluid (CSF) protein concentration. Ranges vary by age and laboratory, normal infant range reported at 48-72 mg/dL [ Note: CSF protein concentration is already increased in Stage I infantile-onset Krabbe disease (see MRI (infantile-onset Krabbe disease) observed within the first few months of age Abnormal brain MRI, consistent with demyelination. T Abnormal spine MRI (enhancement of spinal nerve roots) Abnormal electrophysiologic studies (nerve conduction velocity, brain stem auditory evoked response, visual evoked potentials) Krabbe disease Currently, seven states (Illinois, Kentucky, Missouri, New York, Ohio, Pennsylvania, and Tennessee) perform NBS for GALC deficiency using dried blood spots. While the approaches to testing and cut-off values indicating a positive newborn screen vary by state, all results suggesting GALC deficiency require immediate follow-up studies (see Establishing the Diagnosis, Very low GALC enzyme activity (0%-5% of normal activityl) is observed in all individuals with Krabbe disease who are symptomatic. Note: Low GALC activity can result from pseudodeficiency alleles (benign If GALC enzyme activity in leukocytes is completely normal, no additional biochemical testing is required to exclude Krabbe disease. However, if psychosine was elevated in such cases, a diagnosis of saposin A deficiency should be considered. Molecular Genetic Testing Used in Krabbe Disease (Galactosylcerebrosidase 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 This large deletion accounts for approximately 35% of the pathogenic variants in individuals with Krabbe disease of Mexican heritage [D.Wenger, personal experience] and 45% of the pathogenic variants in individuals with Krabbe disease of European ancestry [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single exon deletions or duplications. Deletions involving single exons and multiple exons, other than the common 30-kb deletion, are rare but have been reported [ Note that regardless of the method used to assay GALC enzyme activity, low GALC activity in dried blood spots and/or leukocytes in asymptomatic newborns is not sufficiently specific to diagnose Krabbe disease, let alone to distinguish between infantile-onset and later-onset Krabbe disease. In addition to certain environmental factors, low GALC activity can result from pseudodeficiency alleles (benign Sequence analysis of Gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications including the common 30kb deletion ( Identification of biallelic Of note, the vast majority of infants identified through the New York State NBS program who have low GALC enzyme activity and two presumptive pathogenic • Infantile-onset Krabbe disease (onset <12 months), characterized by progressive neurologic deterioration in infancy and death before age two years (85%-90% of affected individuals) • Later-onset Krabbe disease (onset >12 months), with slower disease progression (10%-15%) • Excessive crying to extreme irritability • Feeding difficulties, gastroesophageal reflux disease • Spasticity of lower extremities and fisting, with axial hypotonia • Loss of acquired milestones (smiling, cooing, and head control) • Staring episodes • Peripheral neuropathy • Slow development of motor milestones or loss of milestones (e.g., sitting without support, walking), slurred speech • Spasticity of extremities with truncal hypotonia • Vision loss, esotropia • Seizures • Peripheral neuropathy • Increased cerebrospinal fluid (CSF) protein concentration. Ranges vary by age and laboratory, normal infant range reported at 48-72 mg/dL [ • Note: CSF protein concentration is already increased in Stage I infantile-onset Krabbe disease (see • MRI (infantile-onset Krabbe disease) observed within the first few months of age • Abnormal brain MRI, consistent with demyelination. T • Abnormal spine MRI (enhancement of spinal nerve roots) • Abnormal electrophysiologic studies (nerve conduction velocity, brain stem auditory evoked response, visual evoked potentials) • Very low GALC enzyme activity (0%-5% of normal activityl) is observed in all individuals with Krabbe disease who are symptomatic. Note: Low GALC activity can result from pseudodeficiency alleles (benign • If GALC enzyme activity in leukocytes is completely normal, no additional biochemical testing is required to exclude Krabbe disease. However, if psychosine was elevated in such cases, a diagnosis of saposin A deficiency should be considered. • • Sequence analysis of • Gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications including the common 30kb deletion ( • Sequence analysis of • Gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications including the common 30kb deletion ( • Sequence analysis of • Gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications including the common 30kb deletion ( ## Suggestive Findings The two different scenarios in which Krabbe disease could be suspected in a proband: Krabbe disease Excessive crying to extreme irritability Feeding difficulties, gastroesophageal reflux disease Spasticity of lower extremities and fisting, with axial hypotonia Loss of acquired milestones (smiling, cooing, and head control) Staring episodes Peripheral neuropathy Slow development of motor milestones or loss of milestones (e.g., sitting without support, walking), slurred speech Spasticity of extremities with truncal hypotonia Vision loss, esotropia Seizures Peripheral neuropathy Increased cerebrospinal fluid (CSF) protein concentration. Ranges vary by age and laboratory, normal infant range reported at 48-72 mg/dL [ Note: CSF protein concentration is already increased in Stage I infantile-onset Krabbe disease (see MRI (infantile-onset Krabbe disease) observed within the first few months of age Abnormal brain MRI, consistent with demyelination. T Abnormal spine MRI (enhancement of spinal nerve roots) Abnormal electrophysiologic studies (nerve conduction velocity, brain stem auditory evoked response, visual evoked potentials) Krabbe disease Currently, seven states (Illinois, Kentucky, Missouri, New York, Ohio, Pennsylvania, and Tennessee) perform NBS for GALC deficiency using dried blood spots. While the approaches to testing and cut-off values indicating a positive newborn screen vary by state, all results suggesting GALC deficiency require immediate follow-up studies (see Establishing the Diagnosis, • Excessive crying to extreme irritability • Feeding difficulties, gastroesophageal reflux disease • Spasticity of lower extremities and fisting, with axial hypotonia • Loss of acquired milestones (smiling, cooing, and head control) • Staring episodes • Peripheral neuropathy • Slow development of motor milestones or loss of milestones (e.g., sitting without support, walking), slurred speech • Spasticity of extremities with truncal hypotonia • Vision loss, esotropia • Seizures • Peripheral neuropathy • Increased cerebrospinal fluid (CSF) protein concentration. Ranges vary by age and laboratory, normal infant range reported at 48-72 mg/dL [ • Note: CSF protein concentration is already increased in Stage I infantile-onset Krabbe disease (see • MRI (infantile-onset Krabbe disease) observed within the first few months of age • Abnormal brain MRI, consistent with demyelination. T • Abnormal spine MRI (enhancement of spinal nerve roots) • Abnormal electrophysiologic studies (nerve conduction velocity, brain stem auditory evoked response, visual evoked potentials) ## Scenario 1 Krabbe disease Excessive crying to extreme irritability Feeding difficulties, gastroesophageal reflux disease Spasticity of lower extremities and fisting, with axial hypotonia Loss of acquired milestones (smiling, cooing, and head control) Staring episodes Peripheral neuropathy Slow development of motor milestones or loss of milestones (e.g., sitting without support, walking), slurred speech Spasticity of extremities with truncal hypotonia Vision loss, esotropia Seizures Peripheral neuropathy Increased cerebrospinal fluid (CSF) protein concentration. Ranges vary by age and laboratory, normal infant range reported at 48-72 mg/dL [ Note: CSF protein concentration is already increased in Stage I infantile-onset Krabbe disease (see MRI (infantile-onset Krabbe disease) observed within the first few months of age Abnormal brain MRI, consistent with demyelination. T Abnormal spine MRI (enhancement of spinal nerve roots) Abnormal electrophysiologic studies (nerve conduction velocity, brain stem auditory evoked response, visual evoked potentials) • Excessive crying to extreme irritability • Feeding difficulties, gastroesophageal reflux disease • Spasticity of lower extremities and fisting, with axial hypotonia • Loss of acquired milestones (smiling, cooing, and head control) • Staring episodes • Peripheral neuropathy • Slow development of motor milestones or loss of milestones (e.g., sitting without support, walking), slurred speech • Spasticity of extremities with truncal hypotonia • Vision loss, esotropia • Seizures • Peripheral neuropathy • Increased cerebrospinal fluid (CSF) protein concentration. Ranges vary by age and laboratory, normal infant range reported at 48-72 mg/dL [ • Note: CSF protein concentration is already increased in Stage I infantile-onset Krabbe disease (see • MRI (infantile-onset Krabbe disease) observed within the first few months of age • Abnormal brain MRI, consistent with demyelination. T • Abnormal spine MRI (enhancement of spinal nerve roots) • Abnormal electrophysiologic studies (nerve conduction velocity, brain stem auditory evoked response, visual evoked potentials) ## Scenario 2 Krabbe disease Currently, seven states (Illinois, Kentucky, Missouri, New York, Ohio, Pennsylvania, and Tennessee) perform NBS for GALC deficiency using dried blood spots. While the approaches to testing and cut-off values indicating a positive newborn screen vary by state, all results suggesting GALC deficiency require immediate follow-up studies (see Establishing the Diagnosis, ## Establishing the Diagnosis Very low GALC enzyme activity (0%-5% of normal activityl) is observed in all individuals with Krabbe disease who are symptomatic. Note: Low GALC activity can result from pseudodeficiency alleles (benign If GALC enzyme activity in leukocytes is completely normal, no additional biochemical testing is required to exclude Krabbe disease. However, if psychosine was elevated in such cases, a diagnosis of saposin A deficiency should be considered. Molecular Genetic Testing Used in Krabbe Disease (Galactosylcerebrosidase 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 This large deletion accounts for approximately 35% of the pathogenic variants in individuals with Krabbe disease of Mexican heritage [D.Wenger, personal experience] and 45% of the pathogenic variants in individuals with Krabbe disease of European ancestry [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single exon deletions or duplications. Deletions involving single exons and multiple exons, other than the common 30-kb deletion, are rare but have been reported [ Note that regardless of the method used to assay GALC enzyme activity, low GALC activity in dried blood spots and/or leukocytes in asymptomatic newborns is not sufficiently specific to diagnose Krabbe disease, let alone to distinguish between infantile-onset and later-onset Krabbe disease. In addition to certain environmental factors, low GALC activity can result from pseudodeficiency alleles (benign Sequence analysis of Gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications including the common 30kb deletion ( Identification of biallelic Of note, the vast majority of infants identified through the New York State NBS program who have low GALC enzyme activity and two presumptive pathogenic • Very low GALC enzyme activity (0%-5% of normal activityl) is observed in all individuals with Krabbe disease who are symptomatic. Note: Low GALC activity can result from pseudodeficiency alleles (benign • If GALC enzyme activity in leukocytes is completely normal, no additional biochemical testing is required to exclude Krabbe disease. However, if psychosine was elevated in such cases, a diagnosis of saposin A deficiency should be considered. • • Sequence analysis of • Gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications including the common 30kb deletion ( • Sequence analysis of • Gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications including the common 30kb deletion ( • Sequence analysis of • Gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications including the common 30kb deletion ( ## Scenario 1 Very low GALC enzyme activity (0%-5% of normal activityl) is observed in all individuals with Krabbe disease who are symptomatic. Note: Low GALC activity can result from pseudodeficiency alleles (benign If GALC enzyme activity in leukocytes is completely normal, no additional biochemical testing is required to exclude Krabbe disease. However, if psychosine was elevated in such cases, a diagnosis of saposin A deficiency should be considered. Molecular Genetic Testing Used in Krabbe Disease (Galactosylcerebrosidase 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 This large deletion accounts for approximately 35% of the pathogenic variants in individuals with Krabbe disease of Mexican heritage [D.Wenger, personal experience] and 45% of the pathogenic variants in individuals with Krabbe disease of European ancestry [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single exon deletions or duplications. Deletions involving single exons and multiple exons, other than the common 30-kb deletion, are rare but have been reported [ • Very low GALC enzyme activity (0%-5% of normal activityl) is observed in all individuals with Krabbe disease who are symptomatic. Note: Low GALC activity can result from pseudodeficiency alleles (benign • If GALC enzyme activity in leukocytes is completely normal, no additional biochemical testing is required to exclude Krabbe disease. However, if psychosine was elevated in such cases, a diagnosis of saposin A deficiency should be considered. ## Scenario 2 Note that regardless of the method used to assay GALC enzyme activity, low GALC activity in dried blood spots and/or leukocytes in asymptomatic newborns is not sufficiently specific to diagnose Krabbe disease, let alone to distinguish between infantile-onset and later-onset Krabbe disease. In addition to certain environmental factors, low GALC activity can result from pseudodeficiency alleles (benign Sequence analysis of Gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications including the common 30kb deletion ( Identification of biallelic Of note, the vast majority of infants identified through the New York State NBS program who have low GALC enzyme activity and two presumptive pathogenic • • Sequence analysis of • Gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications including the common 30kb deletion ( • Sequence analysis of • Gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications including the common 30kb deletion ( • Sequence analysis of • Gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications including the common 30kb deletion ( ## Clinical Characteristics Historically, 85%-90% of symptomatic individuals with Krabbe disease diagnosed by enzyme activity alone had infantile-onset Krabbe disease (i.e., onset of extreme irritability, spasticity, and developmental delay before age 12 months) and 10%-15% had later-onset Krabbe disease (i.e., onset of manifestations after age 12 months and as late as the seventh decade). In contrast, the vast majority of infants identified through the New York State newborn screening (NBS) program who have low GALC enzyme activity and two presumptive pathogenic Infantile-onset Krabbe disease typically has four stages: The average age of death in children with infantile-onset Krabbe disease is 24 months; however, some succumb by age eight months from infections and respiratory failure, while others live up to age nine years. Symptoms and signs are confined to the nervous system. No visceromegaly is present. Head size may be large or small; hydrocephalus with increased intracranial pressure has been observed. Macular cherry-red spots were described in one individual. One infant, diagnosed with GALC deficiency Some infants with a positive NBS (and subsequently confirmed to have infantile-onset Krabbe disease) had at least one of the following in the first weeks of life: clonus in the lower extremities, difficulty feeding, abnormal nerve conduction velocity, elevated CSF protein, abnormal brain MRI. Children with onset between ages 12 months and three years can be clinically normal until they manifest gait changes, hemiplegia/diplegia, visual impairment, febrile seizures, and/or tremors. Because myelination occurs very rapidly between birth and age two years, symptoms develop more rapidly at this age than after age two years. Children with disease onset between ages 24 months and four years can initially manifest loss of milestones and vision (including rapid loss of vision) or gait changes and seizures. Although disease progression is variable, children who develop symptoms between ages nine months and four years may have rapid worsening of symptoms shortly after presentation. In most instances death occurs approximately four to six years after onset [M Escolar, personal communication]. Initial manifestations in children older than age six years may be behavioral difficulties (attention-deficit/hyperactivity disorder and mood disorders) followed by motor difficulty. They often decline rapidly soon after disease onset [ Some individuals with onset in adolescence and adulthood present with loss of manual dexterity, burning paresthesias in their extremities, and weakness without intellectual deterioration; others become bedridden and continue to deteriorate mentally and physically [ The adult-onset group includes individuals in whom the diagnosis was first made in adulthood (because the subtle symptoms present earlier in life did not prompt biochemical testing) as well as individuals considered completely normal until manifestations began after age 20 years [ Peripheral neuropathy is less common in later-onset disease (affecting about half of affected individuals) than in infantile-onset disease (affecting nearly all affected individuals) [ Survival varies widely among persons with later-onset disease; the median age is eight years after symptom onset [ Homozygosity for the common Compound heterozygosity for either the common p.Gly286Asp + another severe allele The Note that although p.Gly286Asp has been observed in individuals with a milder phenotype, to date it is not possible to predict the clinical course in a given individual. The protein encoded by Galactosylceramidase deficiency Galactosylcerebrosidase deficiency β-galactocerebrosidase deficiency Krabbe disease occurs in approximately one in 250,000 births in the United States [ A very high incidence of Krabbe disease is found in a Druze community in northern Israel and two Muslim Arab villages located near Jerusalem where the carrier rate is estimated at one in six [ No phenotypes other than those discussed in this • Homozygosity for the common • Compound heterozygosity for either the common • p.Gly286Asp + another severe allele • Galactosylceramidase deficiency • Galactosylcerebrosidase deficiency • β-galactocerebrosidase deficiency ## Clinical Description Historically, 85%-90% of symptomatic individuals with Krabbe disease diagnosed by enzyme activity alone had infantile-onset Krabbe disease (i.e., onset of extreme irritability, spasticity, and developmental delay before age 12 months) and 10%-15% had later-onset Krabbe disease (i.e., onset of manifestations after age 12 months and as late as the seventh decade). In contrast, the vast majority of infants identified through the New York State newborn screening (NBS) program who have low GALC enzyme activity and two presumptive pathogenic Infantile-onset Krabbe disease typically has four stages: The average age of death in children with infantile-onset Krabbe disease is 24 months; however, some succumb by age eight months from infections and respiratory failure, while others live up to age nine years. Symptoms and signs are confined to the nervous system. No visceromegaly is present. Head size may be large or small; hydrocephalus with increased intracranial pressure has been observed. Macular cherry-red spots were described in one individual. One infant, diagnosed with GALC deficiency Some infants with a positive NBS (and subsequently confirmed to have infantile-onset Krabbe disease) had at least one of the following in the first weeks of life: clonus in the lower extremities, difficulty feeding, abnormal nerve conduction velocity, elevated CSF protein, abnormal brain MRI. Children with onset between ages 12 months and three years can be clinically normal until they manifest gait changes, hemiplegia/diplegia, visual impairment, febrile seizures, and/or tremors. Because myelination occurs very rapidly between birth and age two years, symptoms develop more rapidly at this age than after age two years. Children with disease onset between ages 24 months and four years can initially manifest loss of milestones and vision (including rapid loss of vision) or gait changes and seizures. Although disease progression is variable, children who develop symptoms between ages nine months and four years may have rapid worsening of symptoms shortly after presentation. In most instances death occurs approximately four to six years after onset [M Escolar, personal communication]. Initial manifestations in children older than age six years may be behavioral difficulties (attention-deficit/hyperactivity disorder and mood disorders) followed by motor difficulty. They often decline rapidly soon after disease onset [ Some individuals with onset in adolescence and adulthood present with loss of manual dexterity, burning paresthesias in their extremities, and weakness without intellectual deterioration; others become bedridden and continue to deteriorate mentally and physically [ The adult-onset group includes individuals in whom the diagnosis was first made in adulthood (because the subtle symptoms present earlier in life did not prompt biochemical testing) as well as individuals considered completely normal until manifestations began after age 20 years [ Peripheral neuropathy is less common in later-onset disease (affecting about half of affected individuals) than in infantile-onset disease (affecting nearly all affected individuals) [ Survival varies widely among persons with later-onset disease; the median age is eight years after symptom onset [ ## Infantile-Onset Krabbe Disease Infantile-onset Krabbe disease typically has four stages: The average age of death in children with infantile-onset Krabbe disease is 24 months; however, some succumb by age eight months from infections and respiratory failure, while others live up to age nine years. Symptoms and signs are confined to the nervous system. No visceromegaly is present. Head size may be large or small; hydrocephalus with increased intracranial pressure has been observed. Macular cherry-red spots were described in one individual. One infant, diagnosed with GALC deficiency Some infants with a positive NBS (and subsequently confirmed to have infantile-onset Krabbe disease) had at least one of the following in the first weeks of life: clonus in the lower extremities, difficulty feeding, abnormal nerve conduction velocity, elevated CSF protein, abnormal brain MRI. ## Later-Onset Krabbe Disease Children with onset between ages 12 months and three years can be clinically normal until they manifest gait changes, hemiplegia/diplegia, visual impairment, febrile seizures, and/or tremors. Because myelination occurs very rapidly between birth and age two years, symptoms develop more rapidly at this age than after age two years. Children with disease onset between ages 24 months and four years can initially manifest loss of milestones and vision (including rapid loss of vision) or gait changes and seizures. Although disease progression is variable, children who develop symptoms between ages nine months and four years may have rapid worsening of symptoms shortly after presentation. In most instances death occurs approximately four to six years after onset [M Escolar, personal communication]. Initial manifestations in children older than age six years may be behavioral difficulties (attention-deficit/hyperactivity disorder and mood disorders) followed by motor difficulty. They often decline rapidly soon after disease onset [ Some individuals with onset in adolescence and adulthood present with loss of manual dexterity, burning paresthesias in their extremities, and weakness without intellectual deterioration; others become bedridden and continue to deteriorate mentally and physically [ The adult-onset group includes individuals in whom the diagnosis was first made in adulthood (because the subtle symptoms present earlier in life did not prompt biochemical testing) as well as individuals considered completely normal until manifestations began after age 20 years [ Peripheral neuropathy is less common in later-onset disease (affecting about half of affected individuals) than in infantile-onset disease (affecting nearly all affected individuals) [ Survival varies widely among persons with later-onset disease; the median age is eight years after symptom onset [ ## Genotype-Phenotype Correlations Homozygosity for the common Compound heterozygosity for either the common p.Gly286Asp + another severe allele The Note that although p.Gly286Asp has been observed in individuals with a milder phenotype, to date it is not possible to predict the clinical course in a given individual. • Homozygosity for the common • Compound heterozygosity for either the common • p.Gly286Asp + another severe allele ## Nomenclature The protein encoded by Galactosylceramidase deficiency Galactosylcerebrosidase deficiency β-galactocerebrosidase deficiency • Galactosylceramidase deficiency • Galactosylcerebrosidase deficiency • β-galactocerebrosidase deficiency ## Prevalence Krabbe disease occurs in approximately one in 250,000 births in the United States [ A very high incidence of Krabbe disease is found in a Druze community in northern Israel and two Muslim Arab villages located near Jerusalem where the carrier rate is estimated at one in six [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Although a history of normal development for the first few months after birth followed by psychomotor deterioration differentiates Krabbe disease from non-progressive CNS disorders of congenital or perinatal origin, it is nonetheless often difficult to differentiate Krabbe disease from other degenerative diseases. Individuals of any age with progressive deterioration of the central or peripheral nervous system should be evaluated for galactocerebrosidase (GALC) deficiency. The following disorders, ordered by mode of inheritance, should be considered in the differential diagnosis. Late-infantile MLD (50%-60% of individuals) with onset between age one and three years Juvenile MLD (~20%-30%) with onset between age four years and sexual maturity (12-14 years) Adult MLD (~15%-20%) with onset after sexual maturity Biallelic pathogenic variants in • Late-infantile MLD (50%-60% of individuals) with onset between age one and three years • Juvenile MLD (~20%-30%) with onset between age four years and sexual maturity (12-14 years) • Adult MLD (~15%-20%) with onset after sexual maturity ## Autosomal Recessive Late-infantile MLD (50%-60% of individuals) with onset between age one and three years Juvenile MLD (~20%-30%) with onset between age four years and sexual maturity (12-14 years) Adult MLD (~15%-20%) with onset after sexual maturity Biallelic pathogenic variants in • Late-infantile MLD (50%-60% of individuals) with onset between age one and three years • Juvenile MLD (~20%-30%) with onset between age four years and sexual maturity (12-14 years) • Adult MLD (~15%-20%) with onset after sexual maturity ## X-Linked ## Autosomal Dominant ## Management To establish the extent of disease and needs of Neurologic and developmental examination Brain stem auditory evoked response to assess hearing and auditory neuropathy Brain MRI (DTI preferred) to understand disease progression and anticipate care needs (e.g., atrophy of brain stem is likely associated with apnea and temperature instability). Nerve conduction velocity to help understand the peripheral nerve involvement and development of muscle weakness Visual evoked potential to help understand the best approach to visual and developmental therapy Consultation with a clinical geneticist and/or genetic counselor Treatment of Manifestations in Individuals with Krabbe Disease Who Have NOT Undergone Hematopoietic Stem Cell Transplantation (HSCT) Maintainence of upright positioning during & after feeding Consideration of proton pump inhibitors in those age >1 yr Nissen fundoplication w/gastrostomy tube (G-tube) placement. Modifying texture & thickness of foods using commercial thickening agents can help w/swallowing difficulties. Swallowing ability may be improved by providing tiny tastes of food or juice several times per day in non-feeders. Consideration of nasogastric tube or gastric tube placement Maintain appropriate fluid intake. Consideration of osmotic laxatives &/or use of stimulant medication in those w/refractory constipation Baclofen & clonazepam may improve global spasticity Botox injections at specific sites may be considered; spasticity typically decreases for 3-5 mos after each injection. Standard anti-seizure medications; monotherapy is preferred, if possible. Gabapentin may decrease neuropathic pain & can be used for control of seizures in some. Positioning devices (wedges, rolls, and cushions) to decrease spasticity & prevent contractures Physical therapy Chest physiotherapy Postural drainage Suctioning device Bladder massage (Crede maneuver) to encourage complete bladder emptying Intermittent catheterization Dark glasses to help reduce photophobia Eye lubricants or protective ointments Table adapted from Physical therapy can improve strength, mobility, flexibility, and function. Erythromycin may be useful as a prophylactic antibiotic and may also improve gastrointestinal motility. Annual influenza vaccination is recommended [ Monitor for development of: Hydrocephalus and need for VP shunt Scoliosis, hip subluxation, and osteopenia (via dual-energy x-ray absorptiometry [DXA] scan) Decreased vision and corneal ulcerations Swallowing difficulties and chronic microaspiration (via modified barium swallow) Atypical antipsychotics and multiple medications for seizures [Author, personal experience], which can: overly sedate patients, further affecting cognition; affect respiratory drive; and accelerate the neurodegenerative cascade Routine childhood vaccinations, including live virus vaccines, as the resulting immune response may accelerate disease progression [ Prolonged indwelling catheters for urinary retention due to the high risk of infection Couples who have had one child with molecularly confirmed infantile-onset Krabbe disease may choose prenatal molecular genetic testing in subsequent pregnancies so that newborns with biallelic Note that because of intrafamilial variability, sibs of an individual with later-onset Krabbe disease may develop the disease at a much earlier age. See Studies are being conducted using well-characterized animal models to investigate other treatment options including enzyme replacement therapy, neural stem cell transplantation, substrate reduction therapy, and chemical chaperone therapy. To date experimental "combination therapies" (HSCT together with gene therapy) in the GALC-deficient murine model have demonstrated the potential to further advance treatment of GALC deficiency by synergistically increasing the life span of the treated mice [ Search • Neurologic and developmental examination • Brain stem auditory evoked response to assess hearing and auditory neuropathy • Brain MRI (DTI preferred) to understand disease progression and anticipate care needs (e.g., atrophy of brain stem is likely associated with apnea and temperature instability). • Nerve conduction velocity to help understand the peripheral nerve involvement and development of muscle weakness • Visual evoked potential to help understand the best approach to visual and developmental therapy • Consultation with a clinical geneticist and/or genetic counselor • Maintainence of upright positioning during & after feeding • Consideration of proton pump inhibitors in those age >1 yr • Nissen fundoplication w/gastrostomy tube (G-tube) placement. • Modifying texture & thickness of foods using commercial thickening agents can help w/swallowing difficulties. • Swallowing ability may be improved by providing tiny tastes of food or juice several times per day in non-feeders. • Consideration of nasogastric tube or gastric tube placement • Maintain appropriate fluid intake. • Consideration of osmotic laxatives &/or use of stimulant medication in those w/refractory constipation • Baclofen & clonazepam may improve global spasticity • Botox injections at specific sites may be considered; spasticity typically decreases for 3-5 mos after each injection. • Standard anti-seizure medications; monotherapy is preferred, if possible. • Gabapentin may decrease neuropathic pain & can be used for control of seizures in some. • Positioning devices (wedges, rolls, and cushions) to decrease spasticity & prevent contractures • Physical therapy • Chest physiotherapy • Postural drainage • Suctioning device • Bladder massage (Crede maneuver) to encourage complete bladder emptying • Intermittent catheterization • Dark glasses to help reduce photophobia • Eye lubricants or protective ointments • Physical therapy can improve strength, mobility, flexibility, and function. • Erythromycin may be useful as a prophylactic antibiotic and may also improve gastrointestinal motility. • Annual influenza vaccination is recommended [ • Hydrocephalus and need for VP shunt • Scoliosis, hip subluxation, and osteopenia (via dual-energy x-ray absorptiometry [DXA] scan) • Decreased vision and corneal ulcerations • Swallowing difficulties and chronic microaspiration (via modified barium swallow) • Atypical antipsychotics and multiple medications for seizures [Author, personal experience], which can: overly sedate patients, further affecting cognition; affect respiratory drive; and accelerate the neurodegenerative cascade • Routine childhood vaccinations, including live virus vaccines, as the resulting immune response may accelerate disease progression [ • Prolonged indwelling catheters for urinary retention due to the high risk of infection ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs of Neurologic and developmental examination Brain stem auditory evoked response to assess hearing and auditory neuropathy Brain MRI (DTI preferred) to understand disease progression and anticipate care needs (e.g., atrophy of brain stem is likely associated with apnea and temperature instability). Nerve conduction velocity to help understand the peripheral nerve involvement and development of muscle weakness Visual evoked potential to help understand the best approach to visual and developmental therapy Consultation with a clinical geneticist and/or genetic counselor • Neurologic and developmental examination • Brain stem auditory evoked response to assess hearing and auditory neuropathy • Brain MRI (DTI preferred) to understand disease progression and anticipate care needs (e.g., atrophy of brain stem is likely associated with apnea and temperature instability). • Nerve conduction velocity to help understand the peripheral nerve involvement and development of muscle weakness • Visual evoked potential to help understand the best approach to visual and developmental therapy • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations Treatment of Manifestations in Individuals with Krabbe Disease Who Have NOT Undergone Hematopoietic Stem Cell Transplantation (HSCT) Maintainence of upright positioning during & after feeding Consideration of proton pump inhibitors in those age >1 yr Nissen fundoplication w/gastrostomy tube (G-tube) placement. Modifying texture & thickness of foods using commercial thickening agents can help w/swallowing difficulties. Swallowing ability may be improved by providing tiny tastes of food or juice several times per day in non-feeders. Consideration of nasogastric tube or gastric tube placement Maintain appropriate fluid intake. Consideration of osmotic laxatives &/or use of stimulant medication in those w/refractory constipation Baclofen & clonazepam may improve global spasticity Botox injections at specific sites may be considered; spasticity typically decreases for 3-5 mos after each injection. Standard anti-seizure medications; monotherapy is preferred, if possible. Gabapentin may decrease neuropathic pain & can be used for control of seizures in some. Positioning devices (wedges, rolls, and cushions) to decrease spasticity & prevent contractures Physical therapy Chest physiotherapy Postural drainage Suctioning device Bladder massage (Crede maneuver) to encourage complete bladder emptying Intermittent catheterization Dark glasses to help reduce photophobia Eye lubricants or protective ointments Table adapted from • Maintainence of upright positioning during & after feeding • Consideration of proton pump inhibitors in those age >1 yr • Nissen fundoplication w/gastrostomy tube (G-tube) placement. • Modifying texture & thickness of foods using commercial thickening agents can help w/swallowing difficulties. • Swallowing ability may be improved by providing tiny tastes of food or juice several times per day in non-feeders. • Consideration of nasogastric tube or gastric tube placement • Maintain appropriate fluid intake. • Consideration of osmotic laxatives &/or use of stimulant medication in those w/refractory constipation • Baclofen & clonazepam may improve global spasticity • Botox injections at specific sites may be considered; spasticity typically decreases for 3-5 mos after each injection. • Standard anti-seizure medications; monotherapy is preferred, if possible. • Gabapentin may decrease neuropathic pain & can be used for control of seizures in some. • Positioning devices (wedges, rolls, and cushions) to decrease spasticity & prevent contractures • Physical therapy • Chest physiotherapy • Postural drainage • Suctioning device • Bladder massage (Crede maneuver) to encourage complete bladder emptying • Intermittent catheterization • Dark glasses to help reduce photophobia • Eye lubricants or protective ointments ## Prevention of Primary Manifestations ## Prevention of Secondary Complications Physical therapy can improve strength, mobility, flexibility, and function. Erythromycin may be useful as a prophylactic antibiotic and may also improve gastrointestinal motility. Annual influenza vaccination is recommended [ • Physical therapy can improve strength, mobility, flexibility, and function. • Erythromycin may be useful as a prophylactic antibiotic and may also improve gastrointestinal motility. • Annual influenza vaccination is recommended [ ## Surveillance Monitor for development of: Hydrocephalus and need for VP shunt Scoliosis, hip subluxation, and osteopenia (via dual-energy x-ray absorptiometry [DXA] scan) Decreased vision and corneal ulcerations Swallowing difficulties and chronic microaspiration (via modified barium swallow) • Hydrocephalus and need for VP shunt • Scoliosis, hip subluxation, and osteopenia (via dual-energy x-ray absorptiometry [DXA] scan) • Decreased vision and corneal ulcerations • Swallowing difficulties and chronic microaspiration (via modified barium swallow) ## Agents/Circumstances to Avoid Atypical antipsychotics and multiple medications for seizures [Author, personal experience], which can: overly sedate patients, further affecting cognition; affect respiratory drive; and accelerate the neurodegenerative cascade Routine childhood vaccinations, including live virus vaccines, as the resulting immune response may accelerate disease progression [ Prolonged indwelling catheters for urinary retention due to the high risk of infection • Atypical antipsychotics and multiple medications for seizures [Author, personal experience], which can: overly sedate patients, further affecting cognition; affect respiratory drive; and accelerate the neurodegenerative cascade • Routine childhood vaccinations, including live virus vaccines, as the resulting immune response may accelerate disease progression [ • Prolonged indwelling catheters for urinary retention due to the high risk of infection ## Evaluation of Relatives at Risk Couples who have had one child with molecularly confirmed infantile-onset Krabbe disease may choose prenatal molecular genetic testing in subsequent pregnancies so that newborns with biallelic Note that because of intrafamilial variability, sibs of an individual with later-onset Krabbe disease may develop the disease at a much earlier age. See ## Therapies Under Investigation Studies are being conducted using well-characterized animal models to investigate other treatment options including enzyme replacement therapy, neural stem cell transplantation, substrate reduction therapy, and chemical chaperone therapy. To date experimental "combination therapies" (HSCT together with gene therapy) in the GALC-deficient murine model have demonstrated the potential to further advance treatment of GALC deficiency by synergistically increasing the life span of the treated mice [ Search ## Genetic Counseling Krabbe disease is inherited in an autosomal recessive manner. The parents of an affected individual are obligate heterozygotes (i.e., carriers of one Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. See Management, The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The parents of an affected individual are obligate heterozygotes (i.e., carriers of one • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including 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 Krabbe disease is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected individual are obligate heterozygotes (i.e., carriers of one Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The parents of an affected individual are obligate heterozygotes (i.e., carriers of one • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Carrier 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 ## Resources Health Resources & Services Administration • • • • Health Resources & Services Administration • • • • • • • • • ## Molecular Genetics Krabbe Disease: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Krabbe Disease ( The 30-kb deletion, the most common pathogenic variant, which begins within the large intron 10 and extends beyond the end of the gene, accounts for approximately 45% of pathogenic variants in persons of European ancestry. This deletion comprises a significant proportion of pathogenic variants in individuals of Mexican, Pakistani, and Indian heritage. When in the homozygous state or in the compound heterozygous state with another severe pathogenic variant this deletion results in infantile-onset Krabbe disease. Thus far, all individuals with Krabbe disease identified through newborn screening have a least one copy of the deletion. Several other pathogenic variants associated with infantile-onset Krabbe disease (p.Thr529Met, p.Tyr567Ser, and c.1472delA) make up another 15% of the abnormal alleles in individuals of European ancestry [ A 7.4-kb deletion has also been observed in multiple patients. The pathogenic variant p.Gly286Asp results in the later-onset form of GALC deficiency, even when present with the 30-kb deletion as the second allele. A founder variant common in Catania, Italy, p.Gly57Ser, is associated with later-onset Krabbe disease in both the homozygous and compound heterozygous states [ When variants of unknown significance are identified, elevated psychosine (within reference range for infantile-onset Krabbe disease) and low GALC activity are suggestive findings of infantile-onset Krabbe disease. A more complete catalog of reported Common See Historical variant designations that do not conform to current naming conventions. In this instance, the variant designations conform to the cDNA reference sequence in the HGMD database (see Begins in intron 10 and deletes the remainder of the gene and additional contiguous sequences One copy of this allele together with another pathogenic variant results in late-onset disease. One copy of this allele together with another severe allele in the homozygous state is associated with late-onset disease [ ## Chapter Notes The Program for Neurodevelopment in Rare Disorders Registry4401 Penn Ave, Plaza building 4th FloorPittsburgh, PA 15224 Michele Caggana, ScD (2018-present)Stephanie Coppola, BS; Thomas Jefferson University, Pennsylvania (2004-2006)Maria L Escolar, MD (2018-present)Joseph J Orsini, PhD (2018-present)Melissa P Wasserstein, MD (2018-present)David A Wenger, PhD; Thomas Jefferson University, Pennsylvania (2000-2018) 11 October 2018 (bp) Comprehensive update posted live 31 March 2011 (me) Comprehensive update posted live 5 August 2008 (cd) Revision: deletion/duplication analysis available clinically for 3 January 2007 (me) Comprehensive update posted live 27 September 2004 (me) Comprehensive update posted live 25 November 2002 (me) Comprehensive update posted live 19 June 2000 (me) Review posted live February 2000 (dw) Original submission • 11 October 2018 (bp) Comprehensive update posted live • 31 March 2011 (me) Comprehensive update posted live • 5 August 2008 (cd) Revision: deletion/duplication analysis available clinically for • 3 January 2007 (me) Comprehensive update posted live • 27 September 2004 (me) Comprehensive update posted live • 25 November 2002 (me) Comprehensive update posted live • 19 June 2000 (me) Review posted live • February 2000 (dw) Original submission ## Author Notes The Program for Neurodevelopment in Rare Disorders Registry4401 Penn Ave, Plaza building 4th FloorPittsburgh, PA 15224 ## Author History Michele Caggana, ScD (2018-present)Stephanie Coppola, BS; Thomas Jefferson University, Pennsylvania (2004-2006)Maria L Escolar, MD (2018-present)Joseph J Orsini, PhD (2018-present)Melissa P Wasserstein, MD (2018-present)David A Wenger, PhD; Thomas Jefferson University, Pennsylvania (2000-2018) ## Revision History 11 October 2018 (bp) Comprehensive update posted live 31 March 2011 (me) Comprehensive update posted live 5 August 2008 (cd) Revision: deletion/duplication analysis available clinically for 3 January 2007 (me) Comprehensive update posted live 27 September 2004 (me) Comprehensive update posted live 25 November 2002 (me) Comprehensive update posted live 19 June 2000 (me) Review posted live February 2000 (dw) Original submission • 11 October 2018 (bp) Comprehensive update posted live • 31 March 2011 (me) Comprehensive update posted live • 5 August 2008 (cd) Revision: deletion/duplication analysis available clinically for • 3 January 2007 (me) Comprehensive update posted live • 27 September 2004 (me) Comprehensive update posted live • 25 November 2002 (me) Comprehensive update posted live • 19 June 2000 (me) Review posted live • February 2000 (dw) Original submission ## References ## Literature Cited	[]	19/6/2000	11/10/2018	5/8/2008	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
kss	kss	[ "mtDNA Deletion Syndromes", "SLSMDS", "mtDNA Deletion Syndromes", "SLSMDS", "Pearson Syndrome", "Kearns-Sayre Syndrome (KSS)", "Chronic Progressive External Ophthalmoplegia (CPEO)", "Leigh Syndrome (mtDNA deletion)", "CPEO-Plus", "Kearns-Sayre Syndrome Spectrum", "Single Large-Scale Mitochondrial DNA Deletion Syndromes" ]	Single Large-Scale Mitochondrial DNA Deletion Syndromes	Amy Goldstein, Marni J Falk	Summary Single large-scale mitochondrial DNA deletion syndromes (SLSMDSs) comprise overlapping clinical phenotypes including Kearns-Sayre syndrome (KSS), KSS spectrum, Pearson syndrome (PS), chronic progressive external ophthalmoplegia (CPEO), and CPEO-plus. Rarely, an SLSMDS can manifest as The diagnosis of an SLSMDS is established in a proband with characteristic clinical features by identification of a mitochondrial DNA (mtDNA) deletion ranging in size from 1.1 to 10 kb on molecular genetic testing. SLSMDSs can be identified in DNA from blood, buccal cells, and urine in affected children; analysis of skeletal muscle tissue may be required to detect an SLSMDS in an affected adult. SLSMDSs are almost never inherited, suggesting that these disorders are typically caused by a	Single Large-Scale Mitochondrial DNA Deletion Syndromes: Phenotypic Spectrum Kearns-Sayre syndrome (KSS) KSS spectrum (includes KSS) Pearson syndrome (also referred to as Pearson marrow-pancreas syndrome) Chronic progressive external ophthalmoplegia (CPEO) CPEO-plus For other genetic causes of this phenotype, see For discussion of terminology used to describe single large-scale mitochondrial DNA deletion syndromes, see • Kearns-Sayre syndrome (KSS) • KSS spectrum (includes KSS) • Pearson syndrome (also referred to as Pearson marrow-pancreas syndrome) • Chronic progressive external ophthalmoplegia (CPEO) • CPEO-plus ## Diagnosis A diagnostic algorithm has been proposed for single large-scale mitochondrial DNA deletion syndromes (SLSMDSs) by SLSMDSs Pigmentary retinopathy (progressive vision impairment due to rod-cone dystrophy), the pivotal feature that distinguishes KSS from chronic progressive external ophthalmoplegia (CPEO) CPEO including ptosis Cardiac conduction abnormality including bundle branch block, which may progress to complete heart block Note: Individuals with Endocrinopathies: diabetes mellitus, hypoparathyroidism, hypothyroidism, adrenal insufficiency, growth hormone deficiency Myopathy: muscle weakness, exercise intolerance, and/or fatigue Dementia (cognitive decline) Learning disability Cerebellar ataxia Tremor Sensorineural hearing loss Short stature Poor weight gain, feeding intolerance, and dysphagia or achalasia (bulbar weakness) Renal impairment including chronic kidney failure and/or renal tubular acidosis (elevated urine amino acids, hypokalemia, and metabolic acidosis) Exocrine pancreatic insufficiency (reduced fecal elastase and/or increased fecal fat) Seizures (may be provoked by electrolyte disturbance or unprovoked) Cerebrospinal fluid (CSF) protein concentration exceeding 100 mg/dL (>1 g/L) Elevated lactate and pyruvate in blood and CSF; commonly elevated at rest and increased excessively in blood after moderate activity Muscle biopsy typically showing ragged red fibers (RRF) with modified Gomori trichrome stain and hyperactive fibers with succinate dehydrogenase (SDH) stain. Both RRF and some non-RRF fail to stain with histochemical reaction for cytochrome- Biochemical studies of electron transport chain enzyme activity in muscle tissue usually shows decreased activity of complexes containing mitochondrial DNA (mtDNA)-encoded subunits (I, III, IV), especially when enzyme values are corrected for the activity of citrate synthase that is used as a marker of mitochondrial content. However, depending on the proportion of mtDNA with the deletion (heteroplasmy load), biochemical studies may be unrevealing. Electroencephalogram (EEG) may show focal or generalized epileptiform features in those that have recurrent seizures (epilepsy). Pancytopenia, refractory anemia Sideroblastic anemia (ringed sideroblasts, detected by iron stains of the bone marrow), typically transfusion dependent until natural resolution that often occurs in early childhood Exocrine pancreatic dysfunction with increased fecal fat (identified qualitatively by Sudan staining of feces or quantitatively by measuring fecal fat) and reduced fecal elastase May be fatal in infancy due to neutropenia-related infections or refractory lactic acidosis Poor weight gain, short stature Ptosis Extraocular muscle paralysis (ophthalmoplegia) Proximal limb weakness (myopathy) Dysphagia Exercise intolerance Note: (1) Individuals with features of CPEO-plus and pigmentary retinopathy are classified as KSS spectrum. (2) Young adults with clinical manifestations of CPEO-plus may be better classified as KSS spectrum; see The diagnosis of an SLSMDS Molecular genetic testing approaches can include The occurrence of mtDNA heteroplasmy may result in variable tissue distribution of mtDNA with an SLSMD. An SLSMD can be identified in DNA from blood leukocytes and/or urine sediment in all reported affected children. A skeletal muscle biopsy may be necessary in adults to confirm the diagnosis [ Note: Southern blot analysis was historically used for identification of an SLSMD but is not as sensitive as next-generation sequencing in detecting low-level heteroplasmy for an SLSMD and may fail to distinguish an SLSMD from multiple mtDNA deletions in the same region. For an introduction to multigene panels click When the diagnosis of an SLSMDS has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Single Large-Scale Mitochondrial DNA Deletion Syndromes 100% KSS = Kearns-Sayre syndrome; CPEO = chronic progressive external ophthalmoplegia; PS = Pearson syndrome; SLSMD = single large-scale mitochondrial DNA deletion See More than 150 different SLSMDs have been associated with KSS [ Testing that identifies deletions/duplications not readily detectable by standard sequence analysis. Methods used may include a range of techniques including long-range PCR, quantitative PCR, and next-generation sequence analysis. Note: The mitochondrial genome has homology with regions of the nuclear genome; therefore, assays that depend on hybridization must be used with caution. The diagnosis of KSS requires identification of an SLSMD. A deletion of 4,977 bp known as m.8470_13446del4977 is the most common deletion [ Numerous pathogenic variants in either mtDNA or nuclear genes also cause CPEO that is often associated with other clinical manifestations. Identification of multiple (small- or large-scale) mtDNA deletions suggests a pathogenic variant in a nuclear gene (see An SLSMD can cause clinical and brain MRI findings consistent with Leigh syndrome. Leigh syndrome has more than 111 monogenic causes, including pathogenic variants in nuclear and mitochondrial genes (see • Pigmentary retinopathy (progressive vision impairment due to rod-cone dystrophy), the pivotal feature that distinguishes KSS from chronic progressive external ophthalmoplegia (CPEO) • CPEO including ptosis • Cardiac conduction abnormality including bundle branch block, which may progress to complete heart block • Endocrinopathies: diabetes mellitus, hypoparathyroidism, hypothyroidism, adrenal insufficiency, growth hormone deficiency • Myopathy: muscle weakness, exercise intolerance, and/or fatigue • Dementia (cognitive decline) • Learning disability • Cerebellar ataxia • Tremor • Sensorineural hearing loss • Short stature • Poor weight gain, feeding intolerance, and dysphagia or achalasia (bulbar weakness) • Renal impairment including chronic kidney failure and/or renal tubular acidosis (elevated urine amino acids, hypokalemia, and metabolic acidosis) • Exocrine pancreatic insufficiency (reduced fecal elastase and/or increased fecal fat) • Seizures (may be provoked by electrolyte disturbance or unprovoked) • Cerebrospinal fluid (CSF) protein concentration exceeding 100 mg/dL (>1 g/L) • Elevated lactate and pyruvate in blood and CSF; commonly elevated at rest and increased excessively in blood after moderate activity • Muscle biopsy typically showing ragged red fibers (RRF) with modified Gomori trichrome stain and hyperactive fibers with succinate dehydrogenase (SDH) stain. Both RRF and some non-RRF fail to stain with histochemical reaction for cytochrome- • Biochemical studies of electron transport chain enzyme activity in muscle tissue usually shows decreased activity of complexes containing mitochondrial DNA (mtDNA)-encoded subunits (I, III, IV), especially when enzyme values are corrected for the activity of citrate synthase that is used as a marker of mitochondrial content. However, depending on the proportion of mtDNA with the deletion (heteroplasmy load), biochemical studies may be unrevealing. • Electroencephalogram (EEG) may show focal or generalized epileptiform features in those that have recurrent seizures (epilepsy). • Pancytopenia, refractory anemia • Sideroblastic anemia (ringed sideroblasts, detected by iron stains of the bone marrow), typically transfusion dependent until natural resolution that often occurs in early childhood • Exocrine pancreatic dysfunction with increased fecal fat (identified qualitatively by Sudan staining of feces or quantitatively by measuring fecal fat) and reduced fecal elastase • May be fatal in infancy due to neutropenia-related infections or refractory lactic acidosis • Poor weight gain, short stature • Ptosis • Extraocular muscle paralysis (ophthalmoplegia) • Proximal limb weakness (myopathy) • Dysphagia • Exercise intolerance ## Suggestive Findings SLSMDSs Pigmentary retinopathy (progressive vision impairment due to rod-cone dystrophy), the pivotal feature that distinguishes KSS from chronic progressive external ophthalmoplegia (CPEO) CPEO including ptosis Cardiac conduction abnormality including bundle branch block, which may progress to complete heart block Note: Individuals with Endocrinopathies: diabetes mellitus, hypoparathyroidism, hypothyroidism, adrenal insufficiency, growth hormone deficiency Myopathy: muscle weakness, exercise intolerance, and/or fatigue Dementia (cognitive decline) Learning disability Cerebellar ataxia Tremor Sensorineural hearing loss Short stature Poor weight gain, feeding intolerance, and dysphagia or achalasia (bulbar weakness) Renal impairment including chronic kidney failure and/or renal tubular acidosis (elevated urine amino acids, hypokalemia, and metabolic acidosis) Exocrine pancreatic insufficiency (reduced fecal elastase and/or increased fecal fat) Seizures (may be provoked by electrolyte disturbance or unprovoked) Cerebrospinal fluid (CSF) protein concentration exceeding 100 mg/dL (>1 g/L) Elevated lactate and pyruvate in blood and CSF; commonly elevated at rest and increased excessively in blood after moderate activity Muscle biopsy typically showing ragged red fibers (RRF) with modified Gomori trichrome stain and hyperactive fibers with succinate dehydrogenase (SDH) stain. Both RRF and some non-RRF fail to stain with histochemical reaction for cytochrome- Biochemical studies of electron transport chain enzyme activity in muscle tissue usually shows decreased activity of complexes containing mitochondrial DNA (mtDNA)-encoded subunits (I, III, IV), especially when enzyme values are corrected for the activity of citrate synthase that is used as a marker of mitochondrial content. However, depending on the proportion of mtDNA with the deletion (heteroplasmy load), biochemical studies may be unrevealing. Electroencephalogram (EEG) may show focal or generalized epileptiform features in those that have recurrent seizures (epilepsy). Pancytopenia, refractory anemia Sideroblastic anemia (ringed sideroblasts, detected by iron stains of the bone marrow), typically transfusion dependent until natural resolution that often occurs in early childhood Exocrine pancreatic dysfunction with increased fecal fat (identified qualitatively by Sudan staining of feces or quantitatively by measuring fecal fat) and reduced fecal elastase May be fatal in infancy due to neutropenia-related infections or refractory lactic acidosis Poor weight gain, short stature Ptosis Extraocular muscle paralysis (ophthalmoplegia) Proximal limb weakness (myopathy) Dysphagia Exercise intolerance Note: (1) Individuals with features of CPEO-plus and pigmentary retinopathy are classified as KSS spectrum. (2) Young adults with clinical manifestations of CPEO-plus may be better classified as KSS spectrum; see • Pigmentary retinopathy (progressive vision impairment due to rod-cone dystrophy), the pivotal feature that distinguishes KSS from chronic progressive external ophthalmoplegia (CPEO) • CPEO including ptosis • Cardiac conduction abnormality including bundle branch block, which may progress to complete heart block • Endocrinopathies: diabetes mellitus, hypoparathyroidism, hypothyroidism, adrenal insufficiency, growth hormone deficiency • Myopathy: muscle weakness, exercise intolerance, and/or fatigue • Dementia (cognitive decline) • Learning disability • Cerebellar ataxia • Tremor • Sensorineural hearing loss • Short stature • Poor weight gain, feeding intolerance, and dysphagia or achalasia (bulbar weakness) • Renal impairment including chronic kidney failure and/or renal tubular acidosis (elevated urine amino acids, hypokalemia, and metabolic acidosis) • Exocrine pancreatic insufficiency (reduced fecal elastase and/or increased fecal fat) • Seizures (may be provoked by electrolyte disturbance or unprovoked) • Cerebrospinal fluid (CSF) protein concentration exceeding 100 mg/dL (>1 g/L) • Elevated lactate and pyruvate in blood and CSF; commonly elevated at rest and increased excessively in blood after moderate activity • Muscle biopsy typically showing ragged red fibers (RRF) with modified Gomori trichrome stain and hyperactive fibers with succinate dehydrogenase (SDH) stain. Both RRF and some non-RRF fail to stain with histochemical reaction for cytochrome- • Biochemical studies of electron transport chain enzyme activity in muscle tissue usually shows decreased activity of complexes containing mitochondrial DNA (mtDNA)-encoded subunits (I, III, IV), especially when enzyme values are corrected for the activity of citrate synthase that is used as a marker of mitochondrial content. However, depending on the proportion of mtDNA with the deletion (heteroplasmy load), biochemical studies may be unrevealing. • Electroencephalogram (EEG) may show focal or generalized epileptiform features in those that have recurrent seizures (epilepsy). • Pancytopenia, refractory anemia • Sideroblastic anemia (ringed sideroblasts, detected by iron stains of the bone marrow), typically transfusion dependent until natural resolution that often occurs in early childhood • Exocrine pancreatic dysfunction with increased fecal fat (identified qualitatively by Sudan staining of feces or quantitatively by measuring fecal fat) and reduced fecal elastase • May be fatal in infancy due to neutropenia-related infections or refractory lactic acidosis • Poor weight gain, short stature • Ptosis • Extraocular muscle paralysis (ophthalmoplegia) • Proximal limb weakness (myopathy) • Dysphagia • Exercise intolerance ## Kearns-Sayre Syndrome (KSS) / Kearns-Sayre Syndrome Spectrum (KSS Spectrum) Pigmentary retinopathy (progressive vision impairment due to rod-cone dystrophy), the pivotal feature that distinguishes KSS from chronic progressive external ophthalmoplegia (CPEO) CPEO including ptosis Cardiac conduction abnormality including bundle branch block, which may progress to complete heart block Note: Individuals with Endocrinopathies: diabetes mellitus, hypoparathyroidism, hypothyroidism, adrenal insufficiency, growth hormone deficiency Myopathy: muscle weakness, exercise intolerance, and/or fatigue Dementia (cognitive decline) Learning disability Cerebellar ataxia Tremor Sensorineural hearing loss Short stature Poor weight gain, feeding intolerance, and dysphagia or achalasia (bulbar weakness) Renal impairment including chronic kidney failure and/or renal tubular acidosis (elevated urine amino acids, hypokalemia, and metabolic acidosis) Exocrine pancreatic insufficiency (reduced fecal elastase and/or increased fecal fat) Seizures (may be provoked by electrolyte disturbance or unprovoked) Cerebrospinal fluid (CSF) protein concentration exceeding 100 mg/dL (>1 g/L) Elevated lactate and pyruvate in blood and CSF; commonly elevated at rest and increased excessively in blood after moderate activity Muscle biopsy typically showing ragged red fibers (RRF) with modified Gomori trichrome stain and hyperactive fibers with succinate dehydrogenase (SDH) stain. Both RRF and some non-RRF fail to stain with histochemical reaction for cytochrome- Biochemical studies of electron transport chain enzyme activity in muscle tissue usually shows decreased activity of complexes containing mitochondrial DNA (mtDNA)-encoded subunits (I, III, IV), especially when enzyme values are corrected for the activity of citrate synthase that is used as a marker of mitochondrial content. However, depending on the proportion of mtDNA with the deletion (heteroplasmy load), biochemical studies may be unrevealing. Electroencephalogram (EEG) may show focal or generalized epileptiform features in those that have recurrent seizures (epilepsy). • Pigmentary retinopathy (progressive vision impairment due to rod-cone dystrophy), the pivotal feature that distinguishes KSS from chronic progressive external ophthalmoplegia (CPEO) • CPEO including ptosis • Cardiac conduction abnormality including bundle branch block, which may progress to complete heart block • Endocrinopathies: diabetes mellitus, hypoparathyroidism, hypothyroidism, adrenal insufficiency, growth hormone deficiency • Myopathy: muscle weakness, exercise intolerance, and/or fatigue • Dementia (cognitive decline) • Learning disability • Cerebellar ataxia • Tremor • Sensorineural hearing loss • Short stature • Poor weight gain, feeding intolerance, and dysphagia or achalasia (bulbar weakness) • Renal impairment including chronic kidney failure and/or renal tubular acidosis (elevated urine amino acids, hypokalemia, and metabolic acidosis) • Exocrine pancreatic insufficiency (reduced fecal elastase and/or increased fecal fat) • Seizures (may be provoked by electrolyte disturbance or unprovoked) • Cerebrospinal fluid (CSF) protein concentration exceeding 100 mg/dL (>1 g/L) • Elevated lactate and pyruvate in blood and CSF; commonly elevated at rest and increased excessively in blood after moderate activity • Muscle biopsy typically showing ragged red fibers (RRF) with modified Gomori trichrome stain and hyperactive fibers with succinate dehydrogenase (SDH) stain. Both RRF and some non-RRF fail to stain with histochemical reaction for cytochrome- • Biochemical studies of electron transport chain enzyme activity in muscle tissue usually shows decreased activity of complexes containing mitochondrial DNA (mtDNA)-encoded subunits (I, III, IV), especially when enzyme values are corrected for the activity of citrate synthase that is used as a marker of mitochondrial content. However, depending on the proportion of mtDNA with the deletion (heteroplasmy load), biochemical studies may be unrevealing. • Electroencephalogram (EEG) may show focal or generalized epileptiform features in those that have recurrent seizures (epilepsy). ## Pearson Syndrome (PS) Pancytopenia, refractory anemia Sideroblastic anemia (ringed sideroblasts, detected by iron stains of the bone marrow), typically transfusion dependent until natural resolution that often occurs in early childhood Exocrine pancreatic dysfunction with increased fecal fat (identified qualitatively by Sudan staining of feces or quantitatively by measuring fecal fat) and reduced fecal elastase May be fatal in infancy due to neutropenia-related infections or refractory lactic acidosis Poor weight gain, short stature • Pancytopenia, refractory anemia • Sideroblastic anemia (ringed sideroblasts, detected by iron stains of the bone marrow), typically transfusion dependent until natural resolution that often occurs in early childhood • Exocrine pancreatic dysfunction with increased fecal fat (identified qualitatively by Sudan staining of feces or quantitatively by measuring fecal fat) and reduced fecal elastase • May be fatal in infancy due to neutropenia-related infections or refractory lactic acidosis • Poor weight gain, short stature ## Chronic Progressive External Ophthalmoplegia (CPEO) / CPEO-Plus Ptosis Extraocular muscle paralysis (ophthalmoplegia) Proximal limb weakness (myopathy) Dysphagia Exercise intolerance Note: (1) Individuals with features of CPEO-plus and pigmentary retinopathy are classified as KSS spectrum. (2) Young adults with clinical manifestations of CPEO-plus may be better classified as KSS spectrum; see • Ptosis • Extraocular muscle paralysis (ophthalmoplegia) • Proximal limb weakness (myopathy) • Dysphagia • Exercise intolerance ## Leigh Syndrome ## Establishing the Diagnosis The diagnosis of an SLSMDS Molecular genetic testing approaches can include The occurrence of mtDNA heteroplasmy may result in variable tissue distribution of mtDNA with an SLSMD. An SLSMD can be identified in DNA from blood leukocytes and/or urine sediment in all reported affected children. A skeletal muscle biopsy may be necessary in adults to confirm the diagnosis [ Note: Southern blot analysis was historically used for identification of an SLSMD but is not as sensitive as next-generation sequencing in detecting low-level heteroplasmy for an SLSMD and may fail to distinguish an SLSMD from multiple mtDNA deletions in the same region. For an introduction to multigene panels click When the diagnosis of an SLSMDS has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Single Large-Scale Mitochondrial DNA Deletion Syndromes 100% KSS = Kearns-Sayre syndrome; CPEO = chronic progressive external ophthalmoplegia; PS = Pearson syndrome; SLSMD = single large-scale mitochondrial DNA deletion See More than 150 different SLSMDs have been associated with KSS [ Testing that identifies deletions/duplications not readily detectable by standard sequence analysis. Methods used may include a range of techniques including long-range PCR, quantitative PCR, and next-generation sequence analysis. Note: The mitochondrial genome has homology with regions of the nuclear genome; therefore, assays that depend on hybridization must be used with caution. The diagnosis of KSS requires identification of an SLSMD. A deletion of 4,977 bp known as m.8470_13446del4977 is the most common deletion [ Numerous pathogenic variants in either mtDNA or nuclear genes also cause CPEO that is often associated with other clinical manifestations. Identification of multiple (small- or large-scale) mtDNA deletions suggests a pathogenic variant in a nuclear gene (see An SLSMD can cause clinical and brain MRI findings consistent with Leigh syndrome. Leigh syndrome has more than 111 monogenic causes, including pathogenic variants in nuclear and mitochondrial genes (see ## Deletion/Duplication Analysis of the Mitochondrial Genome The occurrence of mtDNA heteroplasmy may result in variable tissue distribution of mtDNA with an SLSMD. An SLSMD can be identified in DNA from blood leukocytes and/or urine sediment in all reported affected children. A skeletal muscle biopsy may be necessary in adults to confirm the diagnosis [ Note: Southern blot analysis was historically used for identification of an SLSMD but is not as sensitive as next-generation sequencing in detecting low-level heteroplasmy for an SLSMD and may fail to distinguish an SLSMD from multiple mtDNA deletions in the same region. ## Multigene Panel For an introduction to multigene panels click ## Comprehensive Genomic Testing When the diagnosis of an SLSMDS has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Single Large-Scale Mitochondrial DNA Deletion Syndromes 100% KSS = Kearns-Sayre syndrome; CPEO = chronic progressive external ophthalmoplegia; PS = Pearson syndrome; SLSMD = single large-scale mitochondrial DNA deletion See More than 150 different SLSMDs have been associated with KSS [ Testing that identifies deletions/duplications not readily detectable by standard sequence analysis. Methods used may include a range of techniques including long-range PCR, quantitative PCR, and next-generation sequence analysis. Note: The mitochondrial genome has homology with regions of the nuclear genome; therefore, assays that depend on hybridization must be used with caution. The diagnosis of KSS requires identification of an SLSMD. A deletion of 4,977 bp known as m.8470_13446del4977 is the most common deletion [ Numerous pathogenic variants in either mtDNA or nuclear genes also cause CPEO that is often associated with other clinical manifestations. Identification of multiple (small- or large-scale) mtDNA deletions suggests a pathogenic variant in a nuclear gene (see An SLSMD can cause clinical and brain MRI findings consistent with Leigh syndrome. Leigh syndrome has more than 111 monogenic causes, including pathogenic variants in nuclear and mitochondrial genes (see ## Clinical Characteristics Single large-scale mitochondrial DNA deletion syndromes (SLSMDSs) predominantly comprise overlapping phenotypes including Kearns-Sayre syndrome (KSS), KSS spectrum, Pearson syndrome (PS), chronic progressive external ophthalmoplegia (CPEO), and CPEO-plus (see Single Large-Scale Mitochondrial DNA Deletion Syndromes: Frequency of Phenotypes CPEO = chronic progressive external ophthalmoplegia; KSS = Kearns-Sayre syndrome; PS = Pearson syndrome Using classic criteria for CPEO (ptosis, ophthalmoplegia, dysphagia, proximal limb weakness, exercise intolerance), 57% met criteria for CPEO. Although individuals with an SLSMDS may be assigned a clinical diagnosis based on features at the time of presentation, the phenotypes comprise a continuous spectrum of disease, and features evolve with time (see Single Large-Scale Mitochondrial DNA Deletion Syndromes: Frequency of Select Features CK = creatine kinase; SLSMDSs = single large-scale mitochondrial DNA deletion syndromes KSS is a multisystem disorder with onset before age 20 years, defined by a classic clinical triad of pigmentary retinopathy (sometimes referred to as retinitis pigmentosa), CPEO, and cardiac conduction defect. KSS predominantly affects the central nervous system, skeletal muscle, and heart. Onset is usually in childhood, with ptosis, ophthalmoplegia, or both. Exercise intolerance and impaired night vision (nyctalopia) may be early symptoms. Additional findings may include cerebellar ataxia, tremor, elevated cerebrospinal fluid protein, dysphagia, cricopharyngeal achalasia, sensorineural hearing loss, endocrinopathies (diabetes mellitus, growth hormone deficiency, hypoparathyroidism, adrenal insufficiency), renal involvement, learning disability, cognitive decline/dementia, abnormal brain MRI, poor weight gain, short stature, and cardiomyopathy. KSS may progress to death by young adulthood. Note: Individuals with Brain MRI may show leukoencephalopathy often associated with cerebral and cerebellar atrophy, basal ganglia lesions (typically involving the globus pallidus), and midbrain / brain stem lesions, similar to those seen in individuals with Compared to other mitochondrial encephalomyopathies (e.g., PS manifests clinically with bone marrow failure resulting in pancytopenia, severe refractory, transfusion-dependent sideroblastic anemia, and variable exocrine pancreatic insufficiency. In one study, age of onset for PS was 0.3 ± 0.8 years [ CPEO is predominantly a myopathic disorder characterized by progressive ptosis and extraocular muscle paralysis (ophthalmoplegia) typically presenting in adulthood. The mean age of onset is 26 years. CPEO variably also includes severe oropharyngeal and proximal limb weakness. The disorder is compatible with a normal life span. Individuals with CPEO-plus who do not meet clinical criteria for KSS or KSS spectrum can have the following additional multisystemic features: neuropathy, diabetes mellitus, migraine headaches, hypothyroidism, psychiatric involvement, and optic neuropathy. Brain MRI is typically normal. Note: (1) Those with cardiac conduction defect and/or pigmentary retinopathy are instead diagnosed with KSS or KSS spectrum. (2) Childhood onset of progressive ptosis and ophthalmoplegia is more typical of KSS spectrum. Leigh syndrome typically begins in infancy or early childhood and is characterized by psychomotor regression or delay (especially with stressors such as infection) with disease manifestations involving the brain stem, basal ganglia, or both. Leigh syndrome involves regression of developmental milestones and lactic acidosis, which are less common in other SLSMDSs. The brain MRI is typically abnormal in SLSMDSs, showing characteristic T For all mitochondrial DNA (mtDNA) pathogenic variants, including SLSMDs, clinical expressivity depends on three factors: Relative abundance of mtDNA with the deletion ( Tissue distribution of mtDNA with the deletion Tissue vulnerability to impaired oxidative metabolism ( Tissue vulnerability thresholds likely do not vary substantially among affected individuals, whereas variable proportions of the mtDNA deletion and their tissue distribution may account for the wide spectrum of clinical findings in individuals with KSS. The SLSMD is present in all tissues in individuals with KSS, is predominantly present in hematopoietic cells of individuals with PS, and is confined to skeletal muscle in individuals with CPEO, explaining the variability in phenotype. Infants with PS may develop KSS later in life due to the gradual decrease in SLSMDs in rapidly dividing blood cells and the gradual increase in SLSMDs in postmitotic tissues. In some reported cohorts, disease severity and progression correlate with mtDNA heteroplasmy levels as well as mtDNA deletion size and location [ In a study of 228 individuals with SLSMDs, deletion length was greater in those with KSS spectrum compared to those with CPEO, and the percentage of heteroplasmy was inversely related to age of onset of manifestations [ Thus, the genotype-phenotype correlations in SLSMDSs remains controversial, with some cohorts reporting a correlation between age of onset and deletion size or inclusion of Penetrance is a function of the proportion of mtDNA with the deletion. However, the authors are not aware of any non-penetrant individuals. To date, individuals with low-level heteroplasmy (e.g., 25%-33% in muscle) are symptomatic [ The terms "KSS spectrum" and "CPEO-plus" were introduced by Pearson syndrome may also be referred to as "Pearson marrow-pancreas syndrome." (Of note, the term "sideroblastic anemia and exocrine pancreatic dysfunction" is not currently used.) Leigh syndrome has also been described as "subacute necrotizing encephalomyelopathy." An epidemiologic study of an adult population in northeast England estimated the prevalence of SLSMDs at 1.2 in 100,000 [ • Relative abundance of mtDNA with the deletion ( • Tissue distribution of mtDNA with the deletion • Tissue vulnerability to impaired oxidative metabolism ( ## Clinical Description Single large-scale mitochondrial DNA deletion syndromes (SLSMDSs) predominantly comprise overlapping phenotypes including Kearns-Sayre syndrome (KSS), KSS spectrum, Pearson syndrome (PS), chronic progressive external ophthalmoplegia (CPEO), and CPEO-plus (see Single Large-Scale Mitochondrial DNA Deletion Syndromes: Frequency of Phenotypes CPEO = chronic progressive external ophthalmoplegia; KSS = Kearns-Sayre syndrome; PS = Pearson syndrome Using classic criteria for CPEO (ptosis, ophthalmoplegia, dysphagia, proximal limb weakness, exercise intolerance), 57% met criteria for CPEO. Although individuals with an SLSMDS may be assigned a clinical diagnosis based on features at the time of presentation, the phenotypes comprise a continuous spectrum of disease, and features evolve with time (see Single Large-Scale Mitochondrial DNA Deletion Syndromes: Frequency of Select Features CK = creatine kinase; SLSMDSs = single large-scale mitochondrial DNA deletion syndromes KSS is a multisystem disorder with onset before age 20 years, defined by a classic clinical triad of pigmentary retinopathy (sometimes referred to as retinitis pigmentosa), CPEO, and cardiac conduction defect. KSS predominantly affects the central nervous system, skeletal muscle, and heart. Onset is usually in childhood, with ptosis, ophthalmoplegia, or both. Exercise intolerance and impaired night vision (nyctalopia) may be early symptoms. Additional findings may include cerebellar ataxia, tremor, elevated cerebrospinal fluid protein, dysphagia, cricopharyngeal achalasia, sensorineural hearing loss, endocrinopathies (diabetes mellitus, growth hormone deficiency, hypoparathyroidism, adrenal insufficiency), renal involvement, learning disability, cognitive decline/dementia, abnormal brain MRI, poor weight gain, short stature, and cardiomyopathy. KSS may progress to death by young adulthood. Note: Individuals with Brain MRI may show leukoencephalopathy often associated with cerebral and cerebellar atrophy, basal ganglia lesions (typically involving the globus pallidus), and midbrain / brain stem lesions, similar to those seen in individuals with Compared to other mitochondrial encephalomyopathies (e.g., PS manifests clinically with bone marrow failure resulting in pancytopenia, severe refractory, transfusion-dependent sideroblastic anemia, and variable exocrine pancreatic insufficiency. In one study, age of onset for PS was 0.3 ± 0.8 years [ CPEO is predominantly a myopathic disorder characterized by progressive ptosis and extraocular muscle paralysis (ophthalmoplegia) typically presenting in adulthood. The mean age of onset is 26 years. CPEO variably also includes severe oropharyngeal and proximal limb weakness. The disorder is compatible with a normal life span. Individuals with CPEO-plus who do not meet clinical criteria for KSS or KSS spectrum can have the following additional multisystemic features: neuropathy, diabetes mellitus, migraine headaches, hypothyroidism, psychiatric involvement, and optic neuropathy. Brain MRI is typically normal. Note: (1) Those with cardiac conduction defect and/or pigmentary retinopathy are instead diagnosed with KSS or KSS spectrum. (2) Childhood onset of progressive ptosis and ophthalmoplegia is more typical of KSS spectrum. Leigh syndrome typically begins in infancy or early childhood and is characterized by psychomotor regression or delay (especially with stressors such as infection) with disease manifestations involving the brain stem, basal ganglia, or both. Leigh syndrome involves regression of developmental milestones and lactic acidosis, which are less common in other SLSMDSs. The brain MRI is typically abnormal in SLSMDSs, showing characteristic T ## Kearns-Sayre Syndrome (KSS) and KSS Spectrum KSS is a multisystem disorder with onset before age 20 years, defined by a classic clinical triad of pigmentary retinopathy (sometimes referred to as retinitis pigmentosa), CPEO, and cardiac conduction defect. KSS predominantly affects the central nervous system, skeletal muscle, and heart. Onset is usually in childhood, with ptosis, ophthalmoplegia, or both. Exercise intolerance and impaired night vision (nyctalopia) may be early symptoms. Additional findings may include cerebellar ataxia, tremor, elevated cerebrospinal fluid protein, dysphagia, cricopharyngeal achalasia, sensorineural hearing loss, endocrinopathies (diabetes mellitus, growth hormone deficiency, hypoparathyroidism, adrenal insufficiency), renal involvement, learning disability, cognitive decline/dementia, abnormal brain MRI, poor weight gain, short stature, and cardiomyopathy. KSS may progress to death by young adulthood. Note: Individuals with Brain MRI may show leukoencephalopathy often associated with cerebral and cerebellar atrophy, basal ganglia lesions (typically involving the globus pallidus), and midbrain / brain stem lesions, similar to those seen in individuals with Compared to other mitochondrial encephalomyopathies (e.g., ## Pearson Syndrome (PS) PS manifests clinically with bone marrow failure resulting in pancytopenia, severe refractory, transfusion-dependent sideroblastic anemia, and variable exocrine pancreatic insufficiency. In one study, age of onset for PS was 0.3 ± 0.8 years [ ## Chronic Progressive External Ophthalmoplegia (CPEO) and CPEO-Plus CPEO is predominantly a myopathic disorder characterized by progressive ptosis and extraocular muscle paralysis (ophthalmoplegia) typically presenting in adulthood. The mean age of onset is 26 years. CPEO variably also includes severe oropharyngeal and proximal limb weakness. The disorder is compatible with a normal life span. Individuals with CPEO-plus who do not meet clinical criteria for KSS or KSS spectrum can have the following additional multisystemic features: neuropathy, diabetes mellitus, migraine headaches, hypothyroidism, psychiatric involvement, and optic neuropathy. Brain MRI is typically normal. Note: (1) Those with cardiac conduction defect and/or pigmentary retinopathy are instead diagnosed with KSS or KSS spectrum. (2) Childhood onset of progressive ptosis and ophthalmoplegia is more typical of KSS spectrum. ## Leigh Syndrome Leigh syndrome typically begins in infancy or early childhood and is characterized by psychomotor regression or delay (especially with stressors such as infection) with disease manifestations involving the brain stem, basal ganglia, or both. Leigh syndrome involves regression of developmental milestones and lactic acidosis, which are less common in other SLSMDSs. The brain MRI is typically abnormal in SLSMDSs, showing characteristic T ## Genotype-Phenotype Correlations For all mitochondrial DNA (mtDNA) pathogenic variants, including SLSMDs, clinical expressivity depends on three factors: Relative abundance of mtDNA with the deletion ( Tissue distribution of mtDNA with the deletion Tissue vulnerability to impaired oxidative metabolism ( Tissue vulnerability thresholds likely do not vary substantially among affected individuals, whereas variable proportions of the mtDNA deletion and their tissue distribution may account for the wide spectrum of clinical findings in individuals with KSS. The SLSMD is present in all tissues in individuals with KSS, is predominantly present in hematopoietic cells of individuals with PS, and is confined to skeletal muscle in individuals with CPEO, explaining the variability in phenotype. Infants with PS may develop KSS later in life due to the gradual decrease in SLSMDs in rapidly dividing blood cells and the gradual increase in SLSMDs in postmitotic tissues. In some reported cohorts, disease severity and progression correlate with mtDNA heteroplasmy levels as well as mtDNA deletion size and location [ In a study of 228 individuals with SLSMDs, deletion length was greater in those with KSS spectrum compared to those with CPEO, and the percentage of heteroplasmy was inversely related to age of onset of manifestations [ Thus, the genotype-phenotype correlations in SLSMDSs remains controversial, with some cohorts reporting a correlation between age of onset and deletion size or inclusion of • Relative abundance of mtDNA with the deletion ( • Tissue distribution of mtDNA with the deletion • Tissue vulnerability to impaired oxidative metabolism ( ## Penetrance Penetrance is a function of the proportion of mtDNA with the deletion. However, the authors are not aware of any non-penetrant individuals. To date, individuals with low-level heteroplasmy (e.g., 25%-33% in muscle) are symptomatic [ ## Nomenclature The terms "KSS spectrum" and "CPEO-plus" were introduced by Pearson syndrome may also be referred to as "Pearson marrow-pancreas syndrome." (Of note, the term "sideroblastic anemia and exocrine pancreatic dysfunction" is not currently used.) Leigh syndrome has also been described as "subacute necrotizing encephalomyelopathy." ## Prevalence An epidemiologic study of an adult population in northeast England estimated the prevalence of SLSMDs at 1.2 in 100,000 [ ## Genetically Related Disorders No other phenotypes are known to be associated with single large-scale mitochondrial DNA deletions. See ## Differential Diagnosis Disorders with Progressive External Ophthalmoplegia to Consider in the Differential Diagnosis of KSS and CPEO Primary muscle disorders Do not involve cardiac muscle Not multisystemic in nature PEO w/variable, slowly progressive features; onset: childhood to adulthood Slender build Facial muscle weakness; exertional dyspnea; obstructive sleep apnea; myopathy w/weakness, atrophy, exercise intolerance, myalgia, & cramps; gait disturbance ↑ CK Onset in early adulthood Distal limb weakness Frequent respiratory muscle weakness Stroke-like episodes Typically large maternal family history of multiple persons w/deafness & diabetes Childhood-onset myopathy Generalized & extraocular muscle weakness Minor progression (i.e., slowly progressive or nonprogressive) Not multisystemic Late onset Ptosis w/mild ophthalmoparesis Severe dysphagia Abnormal EMG/NCV Highly variable phenotypes adPEO presentation: generalized myopathy, sensorineural hearing loss, axonal neuropathy, ataxia, depression, parkinsonism, hypogonadism, cataracts, premature ovarian/testicular failure arPEO presentation: PEO may be initial feature; however, additional manifestations may appear years later (as for adPEO) Mitochondrial DNA depletion Typically adult onset AR form may be multisystemic severe disorder w/marked progressive weakness due to skeletal myopathy. AD form incl CPEO & variable manifestations: hearing loss, dysphagia, dysmotility, myopathy (exercise intolerance, fatigue, weakness), COX-deficient fibers & RRF on muscle biopsy, dysarthria, ataxic gait, peripheral neuropathy, & mood disorders. Adult onset (age 20-40 yrs) Progressive hearing loss, cataracts, cardiomyopathy, dysphagia Skeletal myopathy w/exercise intolerance, fatigue, progressive muscle weakness, myopathic EMG, & RRF & ↓ COX levels on muscle biopsy DD, parkinsonism, gait difficulties, sensory ataxia Cognitive decline, cerebral atrophy, peripheral neuropathy Endocrinopathies (diabetes, infertility) Mood disorders Peripheral neuropathy & GI dysmotility ↓ thymidine phosphorylase & ↑ thymidine in blood AD = autosomal dominant; AR = autosomal recessive; adPEO = autosomal dominant PEO; arPEO = autosomal recessive PEO; CPEO = chronic progressive external ophthalmoplegia; DD = developmental delay; CK = creatine kinase; COX = cytochrome- Congenital myasthenic syndrome (CMS) is typically inherited in an autosomal recessive manner. Less commonly, CMS is inherited in an autosomal dominant manner. Disorders in the Differential Diagnosis of Pearson Syndrome Inherited blood disorder assoc w/anemia & variable congenital abnormalities In a cohort of 362 individuals clinically (but not genetically confirmed) diagnosed w/DBA, 2.2% had an SLSMD identified, consistent w/PS. AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; mtDNA = mitochondrial DNA; PS = Pearson syndrome; SLSMD = single large-scale mitochondrial DNA deletion; XL = X-linked • Primary muscle disorders • Do not involve cardiac muscle • Not multisystemic in nature • PEO w/variable, slowly progressive features; onset: childhood to adulthood • Slender build • Facial muscle weakness; exertional dyspnea; obstructive sleep apnea; myopathy w/weakness, atrophy, exercise intolerance, myalgia, & cramps; gait disturbance • ↑ CK • Onset in early adulthood • Distal limb weakness • Frequent respiratory muscle weakness • Stroke-like episodes • Typically large maternal family history of multiple persons w/deafness & diabetes • Childhood-onset myopathy • Generalized & extraocular muscle weakness • Minor progression (i.e., slowly progressive or nonprogressive) • Not multisystemic • Late onset • Ptosis w/mild ophthalmoparesis • Severe dysphagia • Abnormal EMG/NCV • Highly variable phenotypes • adPEO presentation: generalized myopathy, sensorineural hearing loss, axonal neuropathy, ataxia, depression, parkinsonism, hypogonadism, cataracts, premature ovarian/testicular failure • arPEO presentation: PEO may be initial feature; however, additional manifestations may appear years later (as for adPEO) • Mitochondrial DNA depletion • Typically adult onset • AR form may be multisystemic severe disorder w/marked progressive weakness due to skeletal myopathy. • AD form incl CPEO & variable manifestations: hearing loss, dysphagia, dysmotility, myopathy (exercise intolerance, fatigue, weakness), COX-deficient fibers & RRF on muscle biopsy, dysarthria, ataxic gait, peripheral neuropathy, & mood disorders. • Adult onset (age 20-40 yrs) • Progressive hearing loss, cataracts, cardiomyopathy, dysphagia • Skeletal myopathy w/exercise intolerance, fatigue, progressive muscle weakness, myopathic EMG, & RRF & ↓ COX levels on muscle biopsy • DD, parkinsonism, gait difficulties, sensory ataxia • Cognitive decline, cerebral atrophy, peripheral neuropathy • Endocrinopathies (diabetes, infertility) • Mood disorders • Peripheral neuropathy & GI dysmotility • ↓ thymidine phosphorylase & ↑ thymidine in blood • Inherited blood disorder assoc w/anemia & variable congenital abnormalities • In a cohort of 362 individuals clinically (but not genetically confirmed) diagnosed w/DBA, 2.2% had an SLSMD identified, consistent w/PS. ## Management To establish the extent of disease in an individual diagnosed with a single large-scale mitochondrial DNA deletion syndrome (SLSMDS), the evaluations summarized in Single Large-Scale Mitochondrial DNA Deletion Syndromes: Recommended Evaluations Following Initial Diagnosis To consider brain MRI (esp before cochlear implants or pacemaker are indicated) Consider EEG if seizures are a concern in the setting of normal electrolytes (i.e., unprovoked seizures). To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education in children To incl assessment of weight, eval of nutritional status, & aspiration risk Consider eval for gastrostomy tube placement in persons w/dysphagia, poor weight gain, &/or aspiration risk. Ophthalmologic eval for retinal dystrophy Consider oculoplastics for ptosis, neuro-ophthalmology for prisms. 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) EKG Echocardiogram Assessment of growth, thyroid, parathyroid, diabetes mellitus, adrenal insufficiency TSH, free T Referral to endocrinologist BUN:Cr ratio, GFR, NAG, cystatin C Urine amino acids, urine electrolytes Assessment for poor weight gain, poor growth, greasy stools Fecal fat, fecal elastase Pulmonary eval for airway clearance & maintenance (e.g., assessment of need for drying agents for hypersalivation to prevent aspiration) Pulmonary function studies Community or Social work involvement for parental support; Home nursing referral. ADL = activities of daily living; BUN = blood urea nitrogen; CBC = complete blood count; CPEO = chronic progressive external ophthalmoplegia; Cr = creatinine; EKG = electrocardiography; GFR = glomerular filtration rate; KSS = Kearns-Sayre syndrome; MOI = mode of inheritance; NAG = acetyl-3-glucosaminidase; OSA = obstructive sleep apnea; OT = occupational therapy; PS = Pearson syndrome; PT = physical therapy; SLSMDSs = single large-scale mitochondrial DNA deletion syndromes; T Medical geneticist, certified genetic counselor, certified advanced genetic nurse Single Large-Scale Mitochondrial DNA Deletion Syndromes: Treatment of Manifestations Consider mitochondrial supplement therapies such as coenzyme Q Optimize nutrition & exercise regimen to prevent acute decompensations. Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers Feeding therapy Gastrostomy tube placement may improve nutritional intake for those w/persistent feeding issues, choking, or aspiration risk due to dysphagia. Mgmt per cardiologist & cardiac electrophysiologist Prophylactic placement of cardiac pacemaker in persons w/cardiac conduction block, w/consideration of implantable cardioverter defibrillator Acute changes may be provoked by stressors (fever, vomiting) & require sudden increase in dosing needs. Renal dosing of medications Dialysis may be necessary in those w/end-stage kidney failure. Placement of eyelid slings &/or ptosis repair for severe ptosis Standard treatments incl eye ointment for dry eyes Eyeglass prisms for diplopia Lutein & NAC has been used for retinopathy. Mgmt of cataracts per ophthalmologist 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; KSS = Kearns-Sayre syndrome; NAC = N-acetylcysteine; OT = occupational therapy; PS = Pearson syndrome; PT = physical therapy; RBC = red blood cell; SNHL = sensorineural hearing loss 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 Mitochondrial Medicine Society (MMS) published surveillance standards (summarized in Single Large-Scale Mitochondrial DNA Deletion Syndromes: Recommended Surveillance Measurement of growth parameters Eval of nutritional status & safety of oral intake Assessment w/endocrinologist Fructosamine may more accurately measure blood glucose. BUN:Cr ratio Consider cystatin C in those w/low muscle mass In those w/PS, CBC to assess transfusion needs; additional labs per hematologist In those w/PS needing recurrent transfusions, ferritin to assess need for chelation BUN = blood urea nitrogen; CBC = complete blood count; CPEO = chronic progressive external ophthalmoplegia; Cr = creatinine; EKG = electrocardiography; OT = occupational therapy; PS = Pearson syndrome; PT = physical therapy; SLSMDSs = single large-scale mitochondrial DNA deletion syndromes Volatile anesthetic hypersensitivity may occur. Avoid prolonged treatment with propofol (>30-60 minutes) [ Note: Previously, avoidance of numerous medications was recommended in individuals with primary mitochondrial disorders including SLSMDSs. However, a recent expert review panel utilizing a Delphi consensus method updated the recommendations on medication safety and advised affected individuals to consult with the physician managing their mitochondrial disease. See Search • To consider brain MRI (esp before cochlear implants or pacemaker are indicated) • Consider EEG if seizures are a concern in the setting of normal electrolytes (i.e., unprovoked seizures). • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education in children • To incl assessment of weight, eval of nutritional status, & aspiration risk • Consider eval for gastrostomy tube placement in persons w/dysphagia, poor weight gain, &/or aspiration risk. • Ophthalmologic eval for retinal dystrophy • Consider oculoplastics for ptosis, neuro-ophthalmology for prisms. • 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) • EKG • Echocardiogram • Assessment of growth, thyroid, parathyroid, diabetes mellitus, adrenal insufficiency • TSH, free T • Referral to endocrinologist • BUN:Cr ratio, GFR, NAG, cystatin C • Urine amino acids, urine electrolytes • Assessment for poor weight gain, poor growth, greasy stools • Fecal fat, fecal elastase • Pulmonary eval for airway clearance & maintenance (e.g., assessment of need for drying agents for hypersalivation to prevent aspiration) • Pulmonary function studies • Community or • Social work involvement for parental support; • Home nursing referral. • Consider mitochondrial supplement therapies such as coenzyme Q • Optimize nutrition & exercise regimen to prevent acute decompensations. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Feeding therapy • Gastrostomy tube placement may improve nutritional intake for those w/persistent feeding issues, choking, or aspiration risk due to dysphagia. • Mgmt per cardiologist & cardiac electrophysiologist • Prophylactic placement of cardiac pacemaker in persons w/cardiac conduction block, w/consideration of implantable cardioverter defibrillator • Acute changes may be provoked by stressors (fever, vomiting) & require sudden increase in dosing needs. • Renal dosing of medications • Dialysis may be necessary in those w/end-stage kidney failure. • Placement of eyelid slings &/or ptosis repair for severe ptosis • Standard treatments incl eye ointment for dry eyes • Eyeglass prisms for diplopia • Lutein & NAC has been used for retinopathy. • Mgmt of cataracts per ophthalmologist • 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 • Assessment w/endocrinologist • Fructosamine may more accurately measure blood glucose. • BUN:Cr ratio • Consider cystatin C in those w/low muscle mass • In those w/PS, CBC to assess transfusion needs; additional labs per hematologist • In those w/PS needing recurrent transfusions, ferritin to assess need for chelation ## Evaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with a single large-scale mitochondrial DNA deletion syndrome (SLSMDS), the evaluations summarized in Single Large-Scale Mitochondrial DNA Deletion Syndromes: Recommended Evaluations Following Initial Diagnosis To consider brain MRI (esp before cochlear implants or pacemaker are indicated) Consider EEG if seizures are a concern in the setting of normal electrolytes (i.e., unprovoked seizures). To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education in children To incl assessment of weight, eval of nutritional status, & aspiration risk Consider eval for gastrostomy tube placement in persons w/dysphagia, poor weight gain, &/or aspiration risk. Ophthalmologic eval for retinal dystrophy Consider oculoplastics for ptosis, neuro-ophthalmology for prisms. 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) EKG Echocardiogram Assessment of growth, thyroid, parathyroid, diabetes mellitus, adrenal insufficiency TSH, free T Referral to endocrinologist BUN:Cr ratio, GFR, NAG, cystatin C Urine amino acids, urine electrolytes Assessment for poor weight gain, poor growth, greasy stools Fecal fat, fecal elastase Pulmonary eval for airway clearance & maintenance (e.g., assessment of need for drying agents for hypersalivation to prevent aspiration) Pulmonary function studies Community or Social work involvement for parental support; Home nursing referral. ADL = activities of daily living; BUN = blood urea nitrogen; CBC = complete blood count; CPEO = chronic progressive external ophthalmoplegia; Cr = creatinine; EKG = electrocardiography; GFR = glomerular filtration rate; KSS = Kearns-Sayre syndrome; MOI = mode of inheritance; NAG = acetyl-3-glucosaminidase; OSA = obstructive sleep apnea; OT = occupational therapy; PS = Pearson syndrome; PT = physical therapy; SLSMDSs = single large-scale mitochondrial DNA deletion syndromes; T Medical geneticist, certified genetic counselor, certified advanced genetic nurse • To consider brain MRI (esp before cochlear implants or pacemaker are indicated) • Consider EEG if seizures are a concern in the setting of normal electrolytes (i.e., unprovoked seizures). • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education in children • To incl assessment of weight, eval of nutritional status, & aspiration risk • Consider eval for gastrostomy tube placement in persons w/dysphagia, poor weight gain, &/or aspiration risk. • Ophthalmologic eval for retinal dystrophy • Consider oculoplastics for ptosis, neuro-ophthalmology for prisms. • 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) • EKG • Echocardiogram • Assessment of growth, thyroid, parathyroid, diabetes mellitus, adrenal insufficiency • TSH, free T • Referral to endocrinologist • BUN:Cr ratio, GFR, NAG, cystatin C • Urine amino acids, urine electrolytes • Assessment for poor weight gain, poor growth, greasy stools • Fecal fat, fecal elastase • Pulmonary eval for airway clearance & maintenance (e.g., assessment of need for drying agents for hypersalivation to prevent aspiration) • Pulmonary function studies • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Single Large-Scale Mitochondrial DNA Deletion Syndromes: Treatment of Manifestations Consider mitochondrial supplement therapies such as coenzyme Q Optimize nutrition & exercise regimen to prevent acute decompensations. Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers Feeding therapy Gastrostomy tube placement may improve nutritional intake for those w/persistent feeding issues, choking, or aspiration risk due to dysphagia. Mgmt per cardiologist & cardiac electrophysiologist Prophylactic placement of cardiac pacemaker in persons w/cardiac conduction block, w/consideration of implantable cardioverter defibrillator Acute changes may be provoked by stressors (fever, vomiting) & require sudden increase in dosing needs. Renal dosing of medications Dialysis may be necessary in those w/end-stage kidney failure. Placement of eyelid slings &/or ptosis repair for severe ptosis Standard treatments incl eye ointment for dry eyes Eyeglass prisms for diplopia Lutein & NAC has been used for retinopathy. Mgmt of cataracts per ophthalmologist 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; KSS = Kearns-Sayre syndrome; NAC = N-acetylcysteine; OT = occupational therapy; PS = Pearson syndrome; PT = physical therapy; RBC = red blood cell; SNHL = sensorineural hearing loss 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 • Consider mitochondrial supplement therapies such as coenzyme Q • Optimize nutrition & exercise regimen to prevent acute decompensations. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Feeding therapy • Gastrostomy tube placement may improve nutritional intake for those w/persistent feeding issues, choking, or aspiration risk due to dysphagia. • Mgmt per cardiologist & cardiac electrophysiologist • Prophylactic placement of cardiac pacemaker in persons w/cardiac conduction block, w/consideration of implantable cardioverter defibrillator • Acute changes may be provoked by stressors (fever, vomiting) & require sudden increase in dosing needs. • Renal dosing of medications • Dialysis may be necessary in those w/end-stage kidney failure. • Placement of eyelid slings &/or ptosis repair for severe ptosis • Standard treatments incl eye ointment for dry eyes • Eyeglass prisms for diplopia • Lutein & NAC has been used for retinopathy. • Mgmt of cataracts per ophthalmologist • 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 ## Targeted Therapy ## Supportive Care Single Large-Scale Mitochondrial DNA Deletion Syndromes: Treatment of Manifestations Consider mitochondrial supplement therapies such as coenzyme Q Optimize nutrition & exercise regimen to prevent acute decompensations. Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers Feeding therapy Gastrostomy tube placement may improve nutritional intake for those w/persistent feeding issues, choking, or aspiration risk due to dysphagia. Mgmt per cardiologist & cardiac electrophysiologist Prophylactic placement of cardiac pacemaker in persons w/cardiac conduction block, w/consideration of implantable cardioverter defibrillator Acute changes may be provoked by stressors (fever, vomiting) & require sudden increase in dosing needs. Renal dosing of medications Dialysis may be necessary in those w/end-stage kidney failure. Placement of eyelid slings &/or ptosis repair for severe ptosis Standard treatments incl eye ointment for dry eyes Eyeglass prisms for diplopia Lutein & NAC has been used for retinopathy. Mgmt of cataracts per ophthalmologist 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; KSS = Kearns-Sayre syndrome; NAC = N-acetylcysteine; OT = occupational therapy; PS = Pearson syndrome; PT = physical therapy; RBC = red blood cell; SNHL = sensorineural hearing loss 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 • Consider mitochondrial supplement therapies such as coenzyme Q • Optimize nutrition & exercise regimen to prevent acute decompensations. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Feeding therapy • Gastrostomy tube placement may improve nutritional intake for those w/persistent feeding issues, choking, or aspiration risk due to dysphagia. • Mgmt per cardiologist & cardiac electrophysiologist • Prophylactic placement of cardiac pacemaker in persons w/cardiac conduction block, w/consideration of implantable cardioverter defibrillator • Acute changes may be provoked by stressors (fever, vomiting) & require sudden increase in dosing needs. • Renal dosing of medications • Dialysis may be necessary in those w/end-stage kidney failure. • Placement of eyelid slings &/or ptosis repair for severe ptosis • Standard treatments incl eye ointment for dry eyes • Eyeglass prisms for diplopia • Lutein & NAC has been used for retinopathy. • Mgmt of cataracts per ophthalmologist • 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 The Mitochondrial Medicine Society (MMS) published surveillance standards (summarized in Single Large-Scale Mitochondrial DNA Deletion Syndromes: Recommended Surveillance Measurement of growth parameters Eval of nutritional status & safety of oral intake Assessment w/endocrinologist Fructosamine may more accurately measure blood glucose. BUN:Cr ratio Consider cystatin C in those w/low muscle mass In those w/PS, CBC to assess transfusion needs; additional labs per hematologist In those w/PS needing recurrent transfusions, ferritin to assess need for chelation BUN = blood urea nitrogen; CBC = complete blood count; CPEO = chronic progressive external ophthalmoplegia; Cr = creatinine; EKG = electrocardiography; OT = occupational therapy; PS = Pearson syndrome; PT = physical therapy; SLSMDSs = single large-scale mitochondrial DNA deletion syndromes • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Assessment w/endocrinologist • Fructosamine may more accurately measure blood glucose. • BUN:Cr ratio • Consider cystatin C in those w/low muscle mass • In those w/PS, CBC to assess transfusion needs; additional labs per hematologist • In those w/PS needing recurrent transfusions, ferritin to assess need for chelation ## Agents/Circumstances to Avoid Volatile anesthetic hypersensitivity may occur. Avoid prolonged treatment with propofol (>30-60 minutes) [ Note: Previously, avoidance of numerous medications was recommended in individuals with primary mitochondrial disorders including SLSMDSs. However, a recent expert review panel utilizing a Delphi consensus method updated the recommendations on medication safety and advised affected individuals to consult with the physician managing their mitochondrial disease. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Single large-scale mitochondrial DNA deletion syndromes (SLSMDSs) are almost never inherited, suggesting that these disorders are typically caused by a The father of a proband is not at risk of having the SLSMDS. The mother of a proband with an SLSMDS is usually unaffected. Typically, testing of maternal somatic tissues does not detect the SLSMD, although the mother of the proband may have the SLSMD in a population of her oocytes (i.e., maternal germline mosaicism). The SLSMD is almost always If the mother is clinically unaffected and the proband represents a simplex case (i.e., a single affected family member), the empiric risk to the sibs of a proband is very low (at or below 1%). If the mother is affected, the recurrence risk to sibs is estimated to be approximately 4% (one in 24 births) [ The likelihood that an affected woman will have an affected child is estimated to be approximately 4% (one in 24 births) [ Offspring of a male proband with an SLSMD are not at risk. The optimal time for determination of genetic risk is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. Once the SLSMD has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are scientifically possible but technically prohibitive as next-generation sequencing methodology does not accurately quantify the heteroplasmy level of an SLSMD and droplet digital quantitative PCR cannot reliably detect less than 10% heteroplasmy levels of an SLSMD. Further, prenatal testing is not clinically available due to the inability to accurately interpret the clinical prognosis based on prenatal diagnostic results of an SLSMD. Due to mitotic segregation of mtDNA during cell division, the proportion of abnormal mtDNA in amniocytes and chorionic villi is unlikely to correspond to heteroplasmy levels in other fetal or adult tissues. Differences in perspective may exist among medical professionals and within families regarding the use 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 a proband is not at risk of having the SLSMDS. • The mother of a proband with an SLSMDS is usually unaffected. Typically, testing of maternal somatic tissues does not detect the SLSMD, although the mother of the proband may have the SLSMD in a population of her oocytes (i.e., maternal germline mosaicism). • The SLSMD is almost always • If the mother is clinically unaffected and the proband represents a simplex case (i.e., a single affected family member), the empiric risk to the sibs of a proband is very low (at or below 1%). • If the mother is affected, the recurrence risk to sibs is estimated to be approximately 4% (one in 24 births) [ • The likelihood that an affected woman will have an affected child is estimated to be approximately 4% (one in 24 births) [ • Offspring of a male proband with an SLSMD are not at risk. • The optimal time for determination of genetic risk is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. ## Mode of Inheritance Single large-scale mitochondrial DNA deletion syndromes (SLSMDSs) are almost never inherited, suggesting that these disorders are typically caused by a ## Risk to Family Members The father of a proband is not at risk of having the SLSMDS. The mother of a proband with an SLSMDS is usually unaffected. Typically, testing of maternal somatic tissues does not detect the SLSMD, although the mother of the proband may have the SLSMD in a population of her oocytes (i.e., maternal germline mosaicism). The SLSMD is almost always If the mother is clinically unaffected and the proband represents a simplex case (i.e., a single affected family member), the empiric risk to the sibs of a proband is very low (at or below 1%). If the mother is affected, the recurrence risk to sibs is estimated to be approximately 4% (one in 24 births) [ The likelihood that an affected woman will have an affected child is estimated to be approximately 4% (one in 24 births) [ Offspring of a male proband with an SLSMD are not at risk. • The father of a proband is not at risk of having the SLSMDS. • The mother of a proband with an SLSMDS is usually unaffected. Typically, testing of maternal somatic tissues does not detect the SLSMD, although the mother of the proband may have the SLSMD in a population of her oocytes (i.e., maternal germline mosaicism). • The SLSMD is almost always • If the mother is clinically unaffected and the proband represents a simplex case (i.e., a single affected family member), the empiric risk to the sibs of a proband is very low (at or below 1%). • If the mother is affected, the recurrence risk to sibs is estimated to be approximately 4% (one in 24 births) [ • The likelihood that an affected woman will have an affected child is estimated to be approximately 4% (one in 24 births) [ • Offspring of a male proband with an SLSMD are not at risk. ## Related Genetic Counseling Issues The optimal time for determination of genetic risk is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. • The optimal time for determination of genetic risk is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. ## Prenatal Testing and Preimplantation Genetic Testing Once the SLSMD has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are scientifically possible but technically prohibitive as next-generation sequencing methodology does not accurately quantify the heteroplasmy level of an SLSMD and droplet digital quantitative PCR cannot reliably detect less than 10% heteroplasmy levels of an SLSMD. Further, prenatal testing is not clinically available due to the inability to accurately interpret the clinical prognosis based on prenatal diagnostic results of an SLSMD. Due to mitotic segregation of mtDNA during cell division, the proportion of abnormal mtDNA in amniocytes and chorionic villi is unlikely to correspond to heteroplasmy levels in other fetal or adult tissues. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources Australia United Kingdom United Kingdom • • • • • • • • • Australia • • • • • • • United Kingdom • • • United Kingdom • • • • • • • • ## Molecular Genetics OMIM Entries for Mitochondrial DNA Deletion Syndromes ( The origin of large-scale mitochondrial DNA (mtDNA) deletions is uncertain. However, it has been noted that deletions fall into two classes [ Class I: Mitochondrial DNA deletion is flanked by perfect direct repeats that may be a result of homologous recombination or slipped mispairing. Class II: Mitochondrial DNA deletion is not flanked by any homologous sequences and the cause of the deletion is unknown. Deletions vary in size, heteroplasmy load, and tissue distribution among affected individuals. However, the size of the mtDNA deletion is uniform in an affected individual, implying that the population of mtDNA molecules with the deletion is a result of clonal expansion of a single mtDNA molecule with the deletion early in oogenesis or in embryogenesis [ Single large-scale mtDNA deletions (SLSMDs) encompass several tRNA genes. Thus, mtDNA with an SLSMD are transcribed into RNA, but the processed transcript encoding polypeptides is not translated because the SLSMD removed the essential tRNAs needed for protein synthesis [ The most common SLSMD, m.8470_13446del4977 ( • Class I: Mitochondrial DNA deletion is flanked by perfect direct repeats that may be a result of homologous recombination or slipped mispairing. • Class II: Mitochondrial DNA deletion is not flanked by any homologous sequences and the cause of the deletion is unknown. ## Molecular Pathogenesis The origin of large-scale mitochondrial DNA (mtDNA) deletions is uncertain. However, it has been noted that deletions fall into two classes [ Class I: Mitochondrial DNA deletion is flanked by perfect direct repeats that may be a result of homologous recombination or slipped mispairing. Class II: Mitochondrial DNA deletion is not flanked by any homologous sequences and the cause of the deletion is unknown. Deletions vary in size, heteroplasmy load, and tissue distribution among affected individuals. However, the size of the mtDNA deletion is uniform in an affected individual, implying that the population of mtDNA molecules with the deletion is a result of clonal expansion of a single mtDNA molecule with the deletion early in oogenesis or in embryogenesis [ Single large-scale mtDNA deletions (SLSMDs) encompass several tRNA genes. Thus, mtDNA with an SLSMD are transcribed into RNA, but the processed transcript encoding polypeptides is not translated because the SLSMD removed the essential tRNAs needed for protein synthesis [ The most common SLSMD, m.8470_13446del4977 ( • Class I: Mitochondrial DNA deletion is flanked by perfect direct repeats that may be a result of homologous recombination or slipped mispairing. • Class II: Mitochondrial DNA deletion is not flanked by any homologous sequences and the cause of the deletion is unknown. ## Chapter Notes Salvatore DiMauro, MD; Columbia University Medical Center (2003-2019)Marni J Falk, MD (2019-present)Amy Goldstein, MD (2019-present)Michio Hirano, MD; Columbia University Medical Center (2003-2019) 28 September 2023 (sw) Comprehensive update posted live 31 January 2019 (sw) Comprehensive update posted live 3 May 2011 (me) Comprehensive update posted live 8 February 2006 (me) Comprehensive update posted live 17 December 2003 (me) Review posted live 17 July 2003 (sdm) Original submission • 28 September 2023 (sw) Comprehensive update posted live • 31 January 2019 (sw) Comprehensive update posted live • 3 May 2011 (me) Comprehensive update posted live • 8 February 2006 (me) Comprehensive update posted live • 17 December 2003 (me) Review posted live • 17 July 2003 (sdm) Original submission ## Author Notes ## Author History Salvatore DiMauro, MD; Columbia University Medical Center (2003-2019)Marni J Falk, MD (2019-present)Amy Goldstein, MD (2019-present)Michio Hirano, MD; Columbia University Medical Center (2003-2019) ## Revision History 28 September 2023 (sw) Comprehensive update posted live 31 January 2019 (sw) Comprehensive update posted live 3 May 2011 (me) Comprehensive update posted live 8 February 2006 (me) Comprehensive update posted live 17 December 2003 (me) Review posted live 17 July 2003 (sdm) Original submission • 28 September 2023 (sw) Comprehensive update posted live • 31 January 2019 (sw) Comprehensive update posted live • 3 May 2011 (me) Comprehensive update posted live • 8 February 2006 (me) Comprehensive update posted live • 17 December 2003 (me) Review posted live • 17 July 2003 (sdm) Original submission ## Key Sections in this ## References ## Literature Cited	[]	17/12/2003	28/9/2023		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
l1cam	l1cam	[ "L1 Disease", "L1 Disease", "X-Linked Hydrocephalus with Stenosis of the Aqueduct of Sylvius (HSAS)", "MASA (Mental Retardation, Adducted Thumbs, Shuffling Gait, Aphasia) Syndrome, Including SPG1 (X-Linked Complicated Hereditary Spastic Paraplegia Type 1)", "X-Linked Complicated Corpus Callosum Agenesis", "Neural cell adhesion molecule L1", "L1CAM", "L1 Syndrome" ]	L1 Syndrome	Connie Stumpel, Yvonne J Vos	Summary L1 syndrome involves a phenotypic spectrum ranging from severe to mild and includes three clinical phenotypes: X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS) MASA ( X-linked complicated corpus callosum agenesis Males with HSAS are born with severe hydrocephalus, adducted thumbs, and spasticity; intellectual disability is severe. In less severely affected males, hydrocephalus may be subclinically present and documented only because of developmental delay; intellectual disability ranges from mild (IQ: 50-70) to moderate (IQ: 30-50). It is important to note that all phenotypes can be observed in affected individuals within the same family. The diagnosis of L1 syndrome is established in a male proband with suggestive findings and a hemizygous pathogenic variant in L1 syndrome is inherited in an X-linked manner. If the mother of the proband is heterozygous for an	X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS) MASA ( X-linked complicated corpus callosum agenesis For other genetic causes of these phenotypes see • X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS) • MASA ( • X-linked complicated corpus callosum agenesis ## Diagnosis L1 syndrome involves a phenotypic spectrum ranging from severe to mild. L1 syndrome Severe hydrocephalus, often of prenatal onset. Clinical criteria for hydrocephalus: Increased intraventricular fluid volume evidenced by increased occipital-frontal circumference (OFC) and imaging findings including increased ventricular size, loss of cerebral sulci, and transependymal resorption of cerebrospinal fluid Increased intraventricular pressure based on: specific clinical signs and symptoms depending on age including progressive increase of OFC, headache, nausea and vomiting, and irritability; and/or ultrasound and/or brain imaging Adducted (clasped) thumbs caused by a developmental defect of the extensor pollicus longis and/or brevis muscles (>50% of males) [ Spasticity evidenced by brisk tendon reflexes and extensor plantar responses Moderate-to-severe intellectual disability Mild-to-moderate intellectual disability Delayed onset of speech Hypotonia progressing to spastic paraplegia Possible adducted (clasped) thumbs caused by a developmental defect of the extensor pollicis longis and/or brevis muscles Variable abnormalities on brain MRI Variable spastic paraplegia Mild-to-moderate intellectual disability Corpus callosum dysplasia, hypoplasia, or aplasia Hydrocephalus with or without stenosis of the aqueduct of Sylvius is found in combination with corpus callosum agenesis/hypogenesis and/or cerebellar hypoplasia, small brain stem, and agenesis of the pyramids (corticospinal tracts) [ Bilateral absence of the pyramids detected by MRI or autopsy is an almost pathognomonic finding [ Aqueductal stenosis is not a constant feature of L1 syndrome [ Family history is consistent with X-linked inheritance (e.g., no male-to-male transmission). Absence of a known family history does not preclude the diagnosis. Note: Identification of a hemizygous or heterozygous Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in L1 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. Large deletions or duplications (including one deletion of the entire gene) have been described [ • Severe hydrocephalus, often of prenatal onset. Clinical criteria for hydrocephalus: • Increased intraventricular fluid volume evidenced by increased occipital-frontal circumference (OFC) and imaging findings including increased ventricular size, loss of cerebral sulci, and transependymal resorption of cerebrospinal fluid • Increased intraventricular pressure based on: specific clinical signs and symptoms depending on age including progressive increase of OFC, headache, nausea and vomiting, and irritability; and/or ultrasound and/or brain imaging • Increased intraventricular fluid volume evidenced by increased occipital-frontal circumference (OFC) and imaging findings including increased ventricular size, loss of cerebral sulci, and transependymal resorption of cerebrospinal fluid • Increased intraventricular pressure based on: specific clinical signs and symptoms depending on age including progressive increase of OFC, headache, nausea and vomiting, and irritability; and/or ultrasound and/or brain imaging • Adducted (clasped) thumbs caused by a developmental defect of the extensor pollicus longis and/or brevis muscles (>50% of males) [ • Spasticity evidenced by brisk tendon reflexes and extensor plantar responses • Moderate-to-severe intellectual disability • Increased intraventricular fluid volume evidenced by increased occipital-frontal circumference (OFC) and imaging findings including increased ventricular size, loss of cerebral sulci, and transependymal resorption of cerebrospinal fluid • Increased intraventricular pressure based on: specific clinical signs and symptoms depending on age including progressive increase of OFC, headache, nausea and vomiting, and irritability; and/or ultrasound and/or brain imaging • Mild-to-moderate intellectual disability • Delayed onset of speech • Hypotonia progressing to spastic paraplegia • Possible adducted (clasped) thumbs caused by a developmental defect of the extensor pollicis longis and/or brevis muscles • Variable abnormalities on brain MRI • Variable spastic paraplegia • Mild-to-moderate intellectual disability • Corpus callosum dysplasia, hypoplasia, or aplasia ## Suggestive Findings L1 syndrome involves a phenotypic spectrum ranging from severe to mild. L1 syndrome Severe hydrocephalus, often of prenatal onset. Clinical criteria for hydrocephalus: Increased intraventricular fluid volume evidenced by increased occipital-frontal circumference (OFC) and imaging findings including increased ventricular size, loss of cerebral sulci, and transependymal resorption of cerebrospinal fluid Increased intraventricular pressure based on: specific clinical signs and symptoms depending on age including progressive increase of OFC, headache, nausea and vomiting, and irritability; and/or ultrasound and/or brain imaging Adducted (clasped) thumbs caused by a developmental defect of the extensor pollicus longis and/or brevis muscles (>50% of males) [ Spasticity evidenced by brisk tendon reflexes and extensor plantar responses Moderate-to-severe intellectual disability Mild-to-moderate intellectual disability Delayed onset of speech Hypotonia progressing to spastic paraplegia Possible adducted (clasped) thumbs caused by a developmental defect of the extensor pollicis longis and/or brevis muscles Variable abnormalities on brain MRI Variable spastic paraplegia Mild-to-moderate intellectual disability Corpus callosum dysplasia, hypoplasia, or aplasia Hydrocephalus with or without stenosis of the aqueduct of Sylvius is found in combination with corpus callosum agenesis/hypogenesis and/or cerebellar hypoplasia, small brain stem, and agenesis of the pyramids (corticospinal tracts) [ Bilateral absence of the pyramids detected by MRI or autopsy is an almost pathognomonic finding [ Aqueductal stenosis is not a constant feature of L1 syndrome [ Family history is consistent with X-linked inheritance (e.g., no male-to-male transmission). Absence of a known family history does not preclude the diagnosis. • Severe hydrocephalus, often of prenatal onset. Clinical criteria for hydrocephalus: • Increased intraventricular fluid volume evidenced by increased occipital-frontal circumference (OFC) and imaging findings including increased ventricular size, loss of cerebral sulci, and transependymal resorption of cerebrospinal fluid • Increased intraventricular pressure based on: specific clinical signs and symptoms depending on age including progressive increase of OFC, headache, nausea and vomiting, and irritability; and/or ultrasound and/or brain imaging • Increased intraventricular fluid volume evidenced by increased occipital-frontal circumference (OFC) and imaging findings including increased ventricular size, loss of cerebral sulci, and transependymal resorption of cerebrospinal fluid • Increased intraventricular pressure based on: specific clinical signs and symptoms depending on age including progressive increase of OFC, headache, nausea and vomiting, and irritability; and/or ultrasound and/or brain imaging • Adducted (clasped) thumbs caused by a developmental defect of the extensor pollicus longis and/or brevis muscles (>50% of males) [ • Spasticity evidenced by brisk tendon reflexes and extensor plantar responses • Moderate-to-severe intellectual disability • Increased intraventricular fluid volume evidenced by increased occipital-frontal circumference (OFC) and imaging findings including increased ventricular size, loss of cerebral sulci, and transependymal resorption of cerebrospinal fluid • Increased intraventricular pressure based on: specific clinical signs and symptoms depending on age including progressive increase of OFC, headache, nausea and vomiting, and irritability; and/or ultrasound and/or brain imaging • Mild-to-moderate intellectual disability • Delayed onset of speech • Hypotonia progressing to spastic paraplegia • Possible adducted (clasped) thumbs caused by a developmental defect of the extensor pollicis longis and/or brevis muscles • Variable abnormalities on brain MRI • Variable spastic paraplegia • Mild-to-moderate intellectual disability • Corpus callosum dysplasia, hypoplasia, or aplasia ## Clinical Phenotypes Severe hydrocephalus, often of prenatal onset. Clinical criteria for hydrocephalus: Increased intraventricular fluid volume evidenced by increased occipital-frontal circumference (OFC) and imaging findings including increased ventricular size, loss of cerebral sulci, and transependymal resorption of cerebrospinal fluid Increased intraventricular pressure based on: specific clinical signs and symptoms depending on age including progressive increase of OFC, headache, nausea and vomiting, and irritability; and/or ultrasound and/or brain imaging Adducted (clasped) thumbs caused by a developmental defect of the extensor pollicus longis and/or brevis muscles (>50% of males) [ Spasticity evidenced by brisk tendon reflexes and extensor plantar responses Moderate-to-severe intellectual disability Mild-to-moderate intellectual disability Delayed onset of speech Hypotonia progressing to spastic paraplegia Possible adducted (clasped) thumbs caused by a developmental defect of the extensor pollicis longis and/or brevis muscles Variable abnormalities on brain MRI Variable spastic paraplegia Mild-to-moderate intellectual disability Corpus callosum dysplasia, hypoplasia, or aplasia • Severe hydrocephalus, often of prenatal onset. Clinical criteria for hydrocephalus: • Increased intraventricular fluid volume evidenced by increased occipital-frontal circumference (OFC) and imaging findings including increased ventricular size, loss of cerebral sulci, and transependymal resorption of cerebrospinal fluid • Increased intraventricular pressure based on: specific clinical signs and symptoms depending on age including progressive increase of OFC, headache, nausea and vomiting, and irritability; and/or ultrasound and/or brain imaging • Increased intraventricular fluid volume evidenced by increased occipital-frontal circumference (OFC) and imaging findings including increased ventricular size, loss of cerebral sulci, and transependymal resorption of cerebrospinal fluid • Increased intraventricular pressure based on: specific clinical signs and symptoms depending on age including progressive increase of OFC, headache, nausea and vomiting, and irritability; and/or ultrasound and/or brain imaging • Adducted (clasped) thumbs caused by a developmental defect of the extensor pollicus longis and/or brevis muscles (>50% of males) [ • Spasticity evidenced by brisk tendon reflexes and extensor plantar responses • Moderate-to-severe intellectual disability • Increased intraventricular fluid volume evidenced by increased occipital-frontal circumference (OFC) and imaging findings including increased ventricular size, loss of cerebral sulci, and transependymal resorption of cerebrospinal fluid • Increased intraventricular pressure based on: specific clinical signs and symptoms depending on age including progressive increase of OFC, headache, nausea and vomiting, and irritability; and/or ultrasound and/or brain imaging • Mild-to-moderate intellectual disability • Delayed onset of speech • Hypotonia progressing to spastic paraplegia • Possible adducted (clasped) thumbs caused by a developmental defect of the extensor pollicis longis and/or brevis muscles • Variable abnormalities on brain MRI • Variable spastic paraplegia • Mild-to-moderate intellectual disability • Corpus callosum dysplasia, hypoplasia, or aplasia ## Neuroimaging Findings Hydrocephalus with or without stenosis of the aqueduct of Sylvius is found in combination with corpus callosum agenesis/hypogenesis and/or cerebellar hypoplasia, small brain stem, and agenesis of the pyramids (corticospinal tracts) [ Bilateral absence of the pyramids detected by MRI or autopsy is an almost pathognomonic finding [ Aqueductal stenosis is not a constant feature of L1 syndrome [ ## Family History Family history is consistent with X-linked inheritance (e.g., no male-to-male transmission). Absence of a known family history does not preclude the diagnosis. ## Establishing the Diagnosis Note: Identification of a hemizygous or heterozygous Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in L1 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. Large deletions or duplications (including one deletion of the entire gene) have been described [ ## Option 1 For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in L1 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. Large deletions or duplications (including one deletion of the entire gene) have been described [ ## Clinical Characteristics L1 syndrome is seen almost exclusively in males. L1 syndrome comprises three clinical phenotypes ranging from severe to mild; its major features are hydrocephalus, intellectual disability, spasticity of the legs, and adducted thumbs. To date, more than 280 individuals have been identified with a pathogenic variant in L1 Syndrome: Comparison of Phenotypes in Male Probands by Select Features CC = corpus callosum; HSAS = X-linked hydrocephalus with stenosis of aqueduct of Sylvius; MASA = Males with hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS) are born with severe hydrocephalus and adducted thumbs. Seizures may occur. In less severely affected males, hydrocephalus may be subclinically present and documented only because of developmental delay. Mild-to-moderate ventricular enlargement is compatible with long survival. The degree of intellectual impairment does not necessarily correlate with head size or severity of hydrocephalus; males with severe intellectual disability and a normal head circumference have been reported. In HSAS, intellectual disability is usually severe and is independent of shunting procedures in individuals with severe hydrocephalus. In MASA ( Boys initially exhibit hypotonia of the legs, which evolves into spasticity during the first years of life. In adult males, the spasticity tends to be somewhat progressive, although this finding has not been documented in a large group. Spasticity usually results in atrophy of the muscles of the legs and contractures that together cause the shuffling gait. Females heterozygous for an In their review, Pathogenic missense variants that affect "key amino acid residues" are most likely to result in a severe phenotype. Key amino acid residues are those crucial for the structure of the immunoglobulin or fibronectin type III-like domains of the L1 protein [ A statistical analysis was performed on 33 individuals with L1 syndrome in whom a pathogenic variant was identified to detect any possible genotype-phenotype correlation. Children harboring a pathogenic truncating variant were more likely to die before age three years (52%) than children with a pathogenic missense variant (8%), indicating a relationship between the seriousness of the disease and the type of pathogenic variant. These results are statistically significant (Fisher exact p=0.02) [ The above generalizations about genotype-phenotype correlations notwithstanding, clinical findings in L1 syndrome can range from mild to severe even within a family, indicating that other factors must influence the clinical presentation [ HSAS is the most common genetic form of congenital hydrocephalus, with an estimated prevalence of 1:30,000. It accounts for approximately 5%-10% of males with nonsyndromic congenital hydrocephalus [ In males with complicated spastic paraplegia, the prevalence of L1 syndrome is unknown. • Males with hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS) are born with severe hydrocephalus and adducted thumbs. • Seizures may occur. • In less severely affected males, hydrocephalus may be subclinically present and documented only because of developmental delay. • Mild-to-moderate ventricular enlargement is compatible with long survival. • The degree of intellectual impairment does not necessarily correlate with head size or severity of hydrocephalus; males with severe intellectual disability and a normal head circumference have been reported. • In HSAS, intellectual disability is usually severe and is independent of shunting procedures in individuals with severe hydrocephalus. • In MASA ( • Boys initially exhibit hypotonia of the legs, which evolves into spasticity during the first years of life. • In adult males, the spasticity tends to be somewhat progressive, although this finding has not been documented in a large group. • Spasticity usually results in atrophy of the muscles of the legs and contractures that together cause the shuffling gait. ## Clinical Description L1 syndrome is seen almost exclusively in males. L1 syndrome comprises three clinical phenotypes ranging from severe to mild; its major features are hydrocephalus, intellectual disability, spasticity of the legs, and adducted thumbs. To date, more than 280 individuals have been identified with a pathogenic variant in L1 Syndrome: Comparison of Phenotypes in Male Probands by Select Features CC = corpus callosum; HSAS = X-linked hydrocephalus with stenosis of aqueduct of Sylvius; MASA = Males with hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS) are born with severe hydrocephalus and adducted thumbs. Seizures may occur. In less severely affected males, hydrocephalus may be subclinically present and documented only because of developmental delay. Mild-to-moderate ventricular enlargement is compatible with long survival. The degree of intellectual impairment does not necessarily correlate with head size or severity of hydrocephalus; males with severe intellectual disability and a normal head circumference have been reported. In HSAS, intellectual disability is usually severe and is independent of shunting procedures in individuals with severe hydrocephalus. In MASA ( Boys initially exhibit hypotonia of the legs, which evolves into spasticity during the first years of life. In adult males, the spasticity tends to be somewhat progressive, although this finding has not been documented in a large group. Spasticity usually results in atrophy of the muscles of the legs and contractures that together cause the shuffling gait. Females heterozygous for an • Males with hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS) are born with severe hydrocephalus and adducted thumbs. • Seizures may occur. • In less severely affected males, hydrocephalus may be subclinically present and documented only because of developmental delay. • Mild-to-moderate ventricular enlargement is compatible with long survival. • The degree of intellectual impairment does not necessarily correlate with head size or severity of hydrocephalus; males with severe intellectual disability and a normal head circumference have been reported. • In HSAS, intellectual disability is usually severe and is independent of shunting procedures in individuals with severe hydrocephalus. • In MASA ( • Boys initially exhibit hypotonia of the legs, which evolves into spasticity during the first years of life. • In adult males, the spasticity tends to be somewhat progressive, although this finding has not been documented in a large group. • Spasticity usually results in atrophy of the muscles of the legs and contractures that together cause the shuffling gait. ## Affected Males L1 syndrome comprises three clinical phenotypes ranging from severe to mild; its major features are hydrocephalus, intellectual disability, spasticity of the legs, and adducted thumbs. To date, more than 280 individuals have been identified with a pathogenic variant in L1 Syndrome: Comparison of Phenotypes in Male Probands by Select Features CC = corpus callosum; HSAS = X-linked hydrocephalus with stenosis of aqueduct of Sylvius; MASA = Males with hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS) are born with severe hydrocephalus and adducted thumbs. Seizures may occur. In less severely affected males, hydrocephalus may be subclinically present and documented only because of developmental delay. Mild-to-moderate ventricular enlargement is compatible with long survival. The degree of intellectual impairment does not necessarily correlate with head size or severity of hydrocephalus; males with severe intellectual disability and a normal head circumference have been reported. In HSAS, intellectual disability is usually severe and is independent of shunting procedures in individuals with severe hydrocephalus. In MASA ( Boys initially exhibit hypotonia of the legs, which evolves into spasticity during the first years of life. In adult males, the spasticity tends to be somewhat progressive, although this finding has not been documented in a large group. Spasticity usually results in atrophy of the muscles of the legs and contractures that together cause the shuffling gait. • Males with hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS) are born with severe hydrocephalus and adducted thumbs. • Seizures may occur. • In less severely affected males, hydrocephalus may be subclinically present and documented only because of developmental delay. • Mild-to-moderate ventricular enlargement is compatible with long survival. • The degree of intellectual impairment does not necessarily correlate with head size or severity of hydrocephalus; males with severe intellectual disability and a normal head circumference have been reported. • In HSAS, intellectual disability is usually severe and is independent of shunting procedures in individuals with severe hydrocephalus. • In MASA ( • Boys initially exhibit hypotonia of the legs, which evolves into spasticity during the first years of life. • In adult males, the spasticity tends to be somewhat progressive, although this finding has not been documented in a large group. • Spasticity usually results in atrophy of the muscles of the legs and contractures that together cause the shuffling gait. ## Heterozygous Females Females heterozygous for an ## Genotype-Phenotype Correlations In their review, Pathogenic missense variants that affect "key amino acid residues" are most likely to result in a severe phenotype. Key amino acid residues are those crucial for the structure of the immunoglobulin or fibronectin type III-like domains of the L1 protein [ A statistical analysis was performed on 33 individuals with L1 syndrome in whom a pathogenic variant was identified to detect any possible genotype-phenotype correlation. Children harboring a pathogenic truncating variant were more likely to die before age three years (52%) than children with a pathogenic missense variant (8%), indicating a relationship between the seriousness of the disease and the type of pathogenic variant. These results are statistically significant (Fisher exact p=0.02) [ The above generalizations about genotype-phenotype correlations notwithstanding, clinical findings in L1 syndrome can range from mild to severe even within a family, indicating that other factors must influence the clinical presentation [ ## Prevalence HSAS is the most common genetic form of congenital hydrocephalus, with an estimated prevalence of 1:30,000. It accounts for approximately 5%-10% of males with nonsyndromic congenital hydrocephalus [ In males with complicated spastic paraplegia, the prevalence of L1 syndrome is unknown. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The differential diagnosis of males with developmental delay or intellectual disability and early hypotonia evolving into spastic paraplegia during childhood, with or without adducted thumbs, includes many conditions. See Nonsyndromic congenital hydrocephalus may also occur as part of (or secondary to) the following: Neural tube defect Congenital aqueductal stenosis (isolated hydrocephalus) CNS malformation Arnold-Chiari malformation Dandy-Walker malformation Hydranencephaly Vein of Galen malformation Midline hyperplasia with malformation of the fornical system Congenital cyst Other midline abnormalities Congenital communicating hydrocephalus secondary to hemorrhage • Neural tube defect • Congenital aqueductal stenosis (isolated hydrocephalus) • CNS malformation • Arnold-Chiari malformation • Dandy-Walker malformation • Hydranencephaly • Vein of Galen malformation • Midline hyperplasia with malformation of the fornical system • Congenital cyst • Other midline abnormalities • Arnold-Chiari malformation • Dandy-Walker malformation • Hydranencephaly • Vein of Galen malformation • Midline hyperplasia with malformation of the fornical system • Congenital cyst • Other midline abnormalities • Congenital communicating hydrocephalus secondary to hemorrhage • Arnold-Chiari malformation • Dandy-Walker malformation • Hydranencephaly • Vein of Galen malformation • Midline hyperplasia with malformation of the fornical system • Congenital cyst • Other midline abnormalities ## Management To establish the extent of disease and needs in an individual diagnosed with L1 syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with L1 Syndrome Use of community or Need for social work involvement for parental support; Need for home nursing referral. MOI = mode of inheritance Medical geneticist, certified genetic counselor, or certified advanced genetic nurse Optimal management involves a multidisciplinary team with expertise in pediatrics, child neurology, neurosurgery, rehabilitation, and clinical genetics. Treatment of Manifestations in Individuals with L1 Syndrome Shunting of CSF is indicated to ↓ intracranial pressure. Prenatal shunting offers no advantage [ Surgical intervention is not generally indicated. In some milder cases, tendon transfer may improve thumb function. CSF = cerebrospinal fluid; 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. Recommended Surveillance for Individuals with L1 Syndrome DD = developmental delay; ID = intellectual disability See Search • Use of community or • Need for social work involvement for parental support; • Need for home nursing referral. • Shunting of CSF is indicated to ↓ intracranial pressure. • Prenatal shunting offers no advantage [ • Surgical intervention is not generally indicated. • In some milder cases, tendon transfer may improve thumb function. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in 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 ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with L1 syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with L1 Syndrome Use of community or Need for social work involvement for parental support; Need for home nursing referral. MOI = mode of inheritance Medical geneticist, certified genetic counselor, or certified advanced genetic nurse • Use of community or • Need for social work involvement for parental support; • Need for home nursing referral. ## Treatment of Manifestations Optimal management involves a multidisciplinary team with expertise in pediatrics, child neurology, neurosurgery, rehabilitation, and clinical genetics. Treatment of Manifestations in Individuals with L1 Syndrome Shunting of CSF is indicated to ↓ intracranial pressure. Prenatal shunting offers no advantage [ Surgical intervention is not generally indicated. In some milder cases, tendon transfer may improve thumb function. CSF = cerebrospinal fluid; 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. • Shunting of CSF is indicated to ↓ intracranial pressure. • Prenatal shunting offers no advantage [ • Surgical intervention is not generally indicated. • In some milder cases, tendon transfer may improve thumb function. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Motor Dysfunction Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## Social/Behavioral Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ## Surveillance Recommended Surveillance for Individuals with L1 Syndrome DD = developmental delay; ID = intellectual disability ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling L1 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 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 Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. Note: Paternal somatic and germline mosaicism for an If the mother of the proband is heterozygous for an Males who inherit the pathogenic variant will be affected. Note: All phenotypes within the L1 syndrome spectrum can be observed in affected individuals within the same family. Females who inherit the pathogenic variant will be heterozygotes and will usually not be affected. However, they may manifest minor features such as adducted thumbs and/or mild intellectual disability. Females rarely manifest the complete L1 syndrome phenotype. Severe hydrocephalus has been reported in a heterozygous female [ If the proband represents a simplex case (i.e., a single occurrence in a family) and if the Affected males transmit the In one family, a male with a very mild phenotype transmitted an Note: Molecular genetic testing may be able to identify the family member in whom a Identification of female heterozygotes requires either prior identification of the Note: Females who are heterozygotes for this X-linked disorder will usually not be affected but may have a range of clinical manifestations (see Clinical Description, 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 heterozygous or are at risk of being heterozygous. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The father of an affected male will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have • 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 is heterozygous for an • Males who inherit the pathogenic variant will be affected. Note: All phenotypes within the L1 syndrome spectrum can be observed in affected individuals within the same family. • Females who inherit the pathogenic variant will be heterozygotes and will usually not be affected. However, they may manifest minor features such as adducted thumbs and/or mild intellectual disability. Females rarely manifest the complete L1 syndrome phenotype. Severe hydrocephalus has been reported in a heterozygous female [ • Males who inherit the pathogenic variant will be affected. Note: All phenotypes within the L1 syndrome spectrum can be observed in affected individuals within the same family. • Females who inherit the pathogenic variant will be heterozygotes and will usually not be affected. However, they may manifest minor features such as adducted thumbs and/or mild intellectual disability. Females rarely manifest the complete L1 syndrome phenotype. Severe hydrocephalus has been reported in a heterozygous female [ • 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. Note: All phenotypes within the L1 syndrome spectrum can be observed in affected individuals within the same family. • Females who inherit the pathogenic variant will be heterozygotes and will usually not be affected. However, they may manifest minor features such as adducted thumbs and/or mild intellectual disability. Females rarely manifest the complete L1 syndrome phenotype. Severe hydrocephalus has been reported in a heterozygous female [ • Affected males transmit the • In one family, a male with a very mild phenotype transmitted an • 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 heterozygous or are at risk of being heterozygous. ## Mode of Inheritance L1 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 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 Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. Note: Paternal somatic and germline mosaicism for an If the mother of the proband is heterozygous for an Males who inherit the pathogenic variant will be affected. Note: All phenotypes within the L1 syndrome spectrum can be observed in affected individuals within the same family. Females who inherit the pathogenic variant will be heterozygotes and will usually not be affected. However, they may manifest minor features such as adducted thumbs and/or mild intellectual disability. Females rarely manifest the complete L1 syndrome phenotype. Severe hydrocephalus has been reported in a heterozygous female [ If the proband represents a simplex case (i.e., a single occurrence in a family) and if the Affected males transmit the In one family, a male with a very mild phenotype transmitted an Note: Molecular genetic testing may be able to identify the family member in whom a • The father of an affected male will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have • 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 is heterozygous for an • Males who inherit the pathogenic variant will be affected. Note: All phenotypes within the L1 syndrome spectrum can be observed in affected individuals within the same family. • Females who inherit the pathogenic variant will be heterozygotes and will usually not be affected. However, they may manifest minor features such as adducted thumbs and/or mild intellectual disability. Females rarely manifest the complete L1 syndrome phenotype. Severe hydrocephalus has been reported in a heterozygous female [ • Males who inherit the pathogenic variant will be affected. Note: All phenotypes within the L1 syndrome spectrum can be observed in affected individuals within the same family. • Females who inherit the pathogenic variant will be heterozygotes and will usually not be affected. However, they may manifest minor features such as adducted thumbs and/or mild intellectual disability. Females rarely manifest the complete L1 syndrome phenotype. Severe hydrocephalus has been reported in a heterozygous female [ • 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. Note: All phenotypes within the L1 syndrome spectrum can be observed in affected individuals within the same family. • Females who inherit the pathogenic variant will be heterozygotes and will usually not be affected. However, they may manifest minor features such as adducted thumbs and/or mild intellectual disability. Females rarely manifest the complete L1 syndrome phenotype. Severe hydrocephalus has been reported in a heterozygous female [ • Affected males transmit the • In one family, a male with a very mild phenotype transmitted an ## Heterozygote Detection Identification of female heterozygotes requires either prior identification of the Note: Females who are heterozygotes for this X-linked disorder will usually not be affected but may have a range of clinical manifestations (see Clinical Description, ## Related Genetic Counseling Issues 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 heterozygous or are at risk of being heterozygous. • 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 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 testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources 870 Market Street Suite 705 San Francisco CA 94102 • • • • 870 Market Street • Suite 705 • San Francisco CA 94102 • ## Molecular Genetics L1 Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for L1 Syndrome ( L1 is a transmembrane glycoprotein belonging to the immunoglobulin superfamily cell adhesion molecules; it contains thirteen distinct domains: six immunoglobulin- (Ig) and five fibronectin (Fn) III-like domains at the extracellular surface, one single-pass transmembrane domain, and one short cytoplasmic domain. L1 may mediate axon growth during development and axon bundling (fasciculation). It is also involved in interactions between Schwann cells and axons, neuronal cell migration, and neuronal cell survival. The activity is known to be mediated by hemophilic (L1-L1) and heterophilic (L1-non L1 protein) interactions and transduction of a variety of signaling events through associated proteins [ ## Molecular Pathogenesis L1 is a transmembrane glycoprotein belonging to the immunoglobulin superfamily cell adhesion molecules; it contains thirteen distinct domains: six immunoglobulin- (Ig) and five fibronectin (Fn) III-like domains at the extracellular surface, one single-pass transmembrane domain, and one short cytoplasmic domain. L1 may mediate axon growth during development and axon bundling (fasciculation). It is also involved in interactions between Schwann cells and axons, neuronal cell migration, and neuronal cell survival. The activity is known to be mediated by hemophilic (L1-L1) and heterophilic (L1-non L1 protein) interactions and transduction of a variety of signaling events through associated proteins [ ## Chapter Notes Connie Stumpel is a professor of clinical genetics in Maastricht, the Netherlands. She wrote her thesis on the X-linked type of hydrocephalus and is especially interested in X-linked intellectual disability and Kabuki syndrome. Web page: Yvonne J Vos is a clinical laboratory geneticist at the University Medical Center in Groningen, the Netherlands. She wrote her thesis on the genetics of L1 syndrome. 7 January 2021 (ha) Comprehensive update posted live 5 March 2015 (me) Comprehensive update posted live 23 December 2010 (me) Comprehensive update posted live 20 October 2006 (me) Comprehensive update posted live 28 April 2004 (me) Review posted live 14 October 2003 (css) Original submission • 7 January 2021 (ha) Comprehensive update posted live • 5 March 2015 (me) Comprehensive update posted live • 23 December 2010 (me) Comprehensive update posted live • 20 October 2006 (me) Comprehensive update posted live • 28 April 2004 (me) Review posted live • 14 October 2003 (css) Original submission ## Author Notes Connie Stumpel is a professor of clinical genetics in Maastricht, the Netherlands. She wrote her thesis on the X-linked type of hydrocephalus and is especially interested in X-linked intellectual disability and Kabuki syndrome. Web page: Yvonne J Vos is a clinical laboratory geneticist at the University Medical Center in Groningen, the Netherlands. She wrote her thesis on the genetics of L1 syndrome. ## Revision History 7 January 2021 (ha) Comprehensive update posted live 5 March 2015 (me) Comprehensive update posted live 23 December 2010 (me) Comprehensive update posted live 20 October 2006 (me) Comprehensive update posted live 28 April 2004 (me) Review posted live 14 October 2003 (css) Original submission • 7 January 2021 (ha) Comprehensive update posted live • 5 March 2015 (me) Comprehensive update posted live • 23 December 2010 (me) Comprehensive update posted live • 20 October 2006 (me) Comprehensive update posted live • 28 April 2004 (me) Review posted live • 14 October 2003 (css) Original submission ## References ## Literature Cited	[ "H Adle-Biassette, P Saugier-Veber, C Fallet-Bianco, AL Delezoide, F Razavi, N Drouot, A Bazin, AM Beaufrère, B Bessières, S Blesson, M Bucourt, D Carles, L Devisme, F Dijoud, B Fabre, C Fernandez, D Gaillard, M Gonzales, F Jossic, M Joubert, N Laurent, B Leroy, L Loeuillet, P Loget, P Marcorelles, J Martinovic, MJ Perez, D Satge, M Sinico, M Tosi, J Benichou, P Gressens, T Frebourg, A Laquerrière. Neuropathological review of 138 cases genetically tested for X-linked hydrocephalus: evidence for closely related clinical entities of unknown molecular bases.. Acta Neuropathol. 2013;126:427-42", "C Alby, V Malan, L Boutaud, MA Marangoni, B Bessieres, M Bonniere, A Ichkou, N Elkhartoufi, N Bahi-Buisson, P Songo, AE Millischer, S Thomas, Y Ville, M Vekemans, F Encha-Razavi, T Attie-Bitach. Clinical, genetic and neuropathological findings in a series of 138 fetuses with a corpus callosum malformation.. Birth Defects Res A Clin Mol Teratol. 2016;106:36-46", "L Basel-Vanagaite, R Straussberg, MJ Friez, D Inbar, L Korenreich, M Shohat, CE Schwartz. Expanding the phenotypic spectrum of L1CAM-associated disease.. Clin Genet 2006;69:414-9", "A Bateman, M Jouet, J MacFarlane, JS Du, S Kenwrick, C Chothia. Outline structure of the human L1 cell adhesion molecule and the sites where mutations cause neurological disorders.. EMBO J 1996;15:6050-9", "L Bott, O Boute, K Mention, M Vinchon, F Boman, F Gottrand. Congenital idiopathic intestinal pseudo-obstruction and hydrocephalus with stenosis of the aqueduct of sylvius.. Am J Med Genet A. 2004;130A:84-7", "CW Chow, JL Halliday, RM Anderson, DM Danks, DW Fortune. Congenital absence of pyramids and its significance in genetic diseases.. Acta Neuropathol (Berl) 1985;65:313-7", "YZ Du, C Dickerson, AS Aylsworth, CE Schwartz. A silent mutation, C924T (G308G), in the L1CAM gene results in X linked hydrocephalus (HSAS).. J Med Genet 1998;35:456-62", "U Finckh, J Schroder, B Ressler, A Veske, A Gal. Spectrum and detection rate of L1CAM mutations in isolated and familial cases with clinically suspected L1-disease.. Am J Med Genet 2000;92:40-6", "P Griseri, Y Vos, R Giorda, S Gimelli, S Beri, G Santamaria, G Mognato, R Hofstra, G Gimelli, I. Ceccherini. Complex pathogenesis of Hirschsprung's disease in a patient with hydrocephalus, vesico-ureteral reflux and a balanced translocation t(3;17)(p12;q11). Eur J Hum Genet. 2009;17:483-90", "L Kaepernick, E Legius, J Higgins, S Kapur. Clinical aspects of the MASA syndrome in a large family, including expressing females.. Clin Genet. 1994;45:181-5", "S Kenwrick, A Watkins, E De Angelis. Neural cell recognition molecule L1: relating biological complexity to human disease mutations.. Hum Mol Genet 2000;9:879-86", "M Otter, M Wevers, M Pisters, R Pfundt, Y Vos, RJ Nievelstein, C Stumpel. A novel mutation in L1CAM causes a mild form of L1 syndrome: a case report.. Clin Case Rep. 2017;5:1213-7", "MA Parisi, RP Kapur, I Neilson, RM Hofstra, LW Holloway, RC Michaelis, KA Leppig. Hydrocephalus and intestinal aganglionosis: is L1CAM a modifier gene in Hirschsprung disease?. Am J Med Genet 2002;108:51-6", "TL Pinckert, MS Golbus. Fetal surgery.. Clin Perinatol. 1988;15:943-53", "MS Sato, M Kyriakopoulos, A James, S Marwedel, C Borsay, AA Gutierrez, AI Blakemore, AC Need. Hemizygous mutations in L1CAM in two unrelated male probands with childhood onset psychosis.. Psychiatric Genetics 2020;30:73-82", "C Schrander-Stumpel, JP Fryns. Congenital hydrocephalus: nosology and guidelines for clinical approach and genetic counselling.. Eur J Pediatr 1998;157:355-62", "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", "T Takenouchi, M Nakazawa, Y Kanemura, S Shimozato, M Yamasaki, T Takahashi, K Kosaki. Hydrocephalus with Hirschsprung disease: severe end of X-linked hydrocephalus spectrum.. Am J Med Genet A 2012;158A:812-5", "DH Tegay, AH Lane, J Roohi, E Hatchwell. Contiguous gene deletion involving L1CAM and AVPR2 causes X-linked hydrocephalus with nephrogenic diabetes insipidus.. Am J Med Genet A. 2007;143A:594-8", "YJ Vos, HE de Walle, KK Bos, JA Stegeman, AM Ten Berge, M Bruining, MC van Maarle, MW Elting, NS den Hollander, B Hamel, AM Fortuna, LE Sunde, I Stolte-Dijkstra, CT Schrander-Stumpel, RM Hofstra. Genotype-phenotype correlations in L1 syndrome: a guide for genetic counselling and mutation analysis.. J Med Genet. 2010;47:169-75", "YJ Vos, RM Hofstra. An updated and upgraded L1CAM mutation database.. Hum Mutat. 2010;31:E1102-9", "S Weller, J Gärtner. Genetic and clinical aspects of X-linked hydrocephalus (L1 disease): Mutations in the L1CAM gene.. Hum Mutat. 2001;18:1-12", "M Yamasaki, N Arita, S Hiraga, S Izumoto, K Morimoto, S Nakatani, K Fujitani, N Sato, T Hayakawa. A clinical and neuroradiological study of X-linked hydrocephalus in Japan.. J Neurosurg 1995;83:50-5", "W Yang, S-C Chen, J-Y Lai, Y-C Ming, J-C Chen, P-L Chen. Distinctive genetic variation of long-segment Hirschsprung’s disease in Taiwan.. Neurogastroenterol Motil 2019;31" ]	28/4/2004	7/1/2021		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
lad-ad	lad-ad	[ "Adult-Onset Autosomal Dominant Leukodystrophy with Autonomic Symptoms", "Autosomal Dominant Adult-Onset Demyelinating Leukodystrophy", "Autosomal Dominant Leukodystrophy with Autonomic Symptoms", "LMNB1-Related ADLD", "Onset Autosomal Dominant Leukodystrophy with Autonomic Symptoms", "Autosomal Dominant Adult-Onset Demyelinating Leukodystrophy", "Autosomal Dominant Leukodystrophy with Autonomic Symptoms", "LMNB1-Related ADLD", "Lamin-B1", "LMNB1", "LMNB1-Related Autosomal Dominant Leukodystrophy" ]		Raili Raininko, Michael Gosky, Quasar S Padiath	Summary The diagnosis of Neurogenic bladder may require management of urinary retention and/or urgency and recurrent urinary tract infection. Constipation may require good hydration, increased dietary fiber, stool softeners, and/or laxatives. Orthostatic hypotension can be minimized by pharmacologic intervention, compression stockings, physical therapy, and increased dietary salt. Erectile dysfunction is treated medically. Impaired sweating is managed with cool environment and attention to fever during infection. Spasticity may be treated with medications and physical therapy. Ataxia can be managed with strategies to minimize falls and increase strength, and adaptive equipment such as walkers or wheelchairs. Feeding difficulties can be managed with speech therapy and appropriate feeding interventions to assure adequate nutrition while preventing aspiration pneumonia.	## Diagnosis No formal diagnostic criteria exist. Onset in the fourth to fifth decade of signs and symptoms of autonomic dysfunction including bladder dysfunction, constipation, erectile dysfunction, and postural hypotension Subsequent onset of motor and cerebellar impairment resulting in spasticity, ataxia, and tremor Specific brain and spine MRI findings suggestive of Symmetric T Periventricular rims around the lateral ventricles are spared or mildly affected. Early involvement of the upper and middle cerebellar peduncles with marked T Atrophy of the spinal cord is common, often with an increased T Brain atrophy may develop over time. No pathologic enhancement is seen after contrast medium administration. The diagnosis of Note: Identification of a heterozygous Molecular genetic testing approaches can include Note: (1) For an introduction to multigene panels click Molecular Genetic Testing Used in A heterozygous deletion upstream of the See See Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. To include analysis upstream of the • Onset in the fourth to fifth decade of signs and symptoms of autonomic dysfunction including bladder dysfunction, constipation, erectile dysfunction, and postural hypotension • Subsequent onset of motor and cerebellar impairment resulting in spasticity, ataxia, and tremor • Symmetric T • Periventricular rims around the lateral ventricles are spared or mildly affected. • Early involvement of the upper and middle cerebellar peduncles with marked T • Atrophy of the spinal cord is common, often with an increased T • Brain atrophy may develop over time. • No pathologic enhancement is seen after contrast medium administration. • Note: (1) • For an introduction to multigene panels click • A heterozygous deletion upstream of the ## Suggestive Findings Onset in the fourth to fifth decade of signs and symptoms of autonomic dysfunction including bladder dysfunction, constipation, erectile dysfunction, and postural hypotension Subsequent onset of motor and cerebellar impairment resulting in spasticity, ataxia, and tremor Specific brain and spine MRI findings suggestive of Symmetric T Periventricular rims around the lateral ventricles are spared or mildly affected. Early involvement of the upper and middle cerebellar peduncles with marked T Atrophy of the spinal cord is common, often with an increased T Brain atrophy may develop over time. No pathologic enhancement is seen after contrast medium administration. • Onset in the fourth to fifth decade of signs and symptoms of autonomic dysfunction including bladder dysfunction, constipation, erectile dysfunction, and postural hypotension • Subsequent onset of motor and cerebellar impairment resulting in spasticity, ataxia, and tremor • Symmetric T • Periventricular rims around the lateral ventricles are spared or mildly affected. • Early involvement of the upper and middle cerebellar peduncles with marked T • Atrophy of the spinal cord is common, often with an increased T • Brain atrophy may develop over time. • No pathologic enhancement is seen after contrast medium administration. ## Establishing the Diagnosis The diagnosis of Note: Identification of a heterozygous Molecular genetic testing approaches can include Note: (1) For an introduction to multigene panels click Molecular Genetic Testing Used in A heterozygous deletion upstream of the See See Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. To include analysis upstream of the • Note: (1) • For an introduction to multigene panels click • A heterozygous deletion upstream of the ## Clinical Characteristics To date, at least 33 families have been identified with a pathogenic variant in Neurogenic bladder is commonly complicated by urinary urgency and/or incomplete bladder emptying, which is often complicated by urinary tract infection. Orthostatic hypotension can be asymptomatic or symptomatic (frequent fainting results in significant functional disability) [ Temperature dysregulation and heat intolerance can be a common feature in individuals with It has been hypothesized that spinal cord white matter involvement [ Pseudobulbar palsy with dysarthria, dysphagia, and forced crying and laughing [ Many individuals have sensory deficits starting in the lower limbs associated with loss of position and vibration sensation attributed to extensive involvement of the spinal cord. Sensorineural hearing loss is seen in rare cases [ Differences in clinical findings and MRI features have been noted between individuals with The disease presents in the fourth to fifth decade of adulthood, with equal frequency in males and females. Penetrance is not known but is thought to be 100%. The exact prevalence of Families of European, Middle Eastern, Asian, and Mexican ancestry have been reported. • Neurogenic bladder is commonly complicated by urinary urgency and/or incomplete bladder emptying, which is often complicated by urinary tract infection. • Orthostatic hypotension can be asymptomatic or symptomatic (frequent fainting results in significant functional disability) [ • Temperature dysregulation and heat intolerance can be a common feature in individuals with • It has been hypothesized that spinal cord white matter involvement [ • Pseudobulbar palsy with dysarthria, dysphagia, and forced crying and laughing [ • Many individuals have sensory deficits starting in the lower limbs associated with loss of position and vibration sensation attributed to extensive involvement of the spinal cord. • Sensorineural hearing loss is seen in rare cases [ ## Clinical Description To date, at least 33 families have been identified with a pathogenic variant in Neurogenic bladder is commonly complicated by urinary urgency and/or incomplete bladder emptying, which is often complicated by urinary tract infection. Orthostatic hypotension can be asymptomatic or symptomatic (frequent fainting results in significant functional disability) [ Temperature dysregulation and heat intolerance can be a common feature in individuals with It has been hypothesized that spinal cord white matter involvement [ Pseudobulbar palsy with dysarthria, dysphagia, and forced crying and laughing [ Many individuals have sensory deficits starting in the lower limbs associated with loss of position and vibration sensation attributed to extensive involvement of the spinal cord. Sensorineural hearing loss is seen in rare cases [ • Neurogenic bladder is commonly complicated by urinary urgency and/or incomplete bladder emptying, which is often complicated by urinary tract infection. • Orthostatic hypotension can be asymptomatic or symptomatic (frequent fainting results in significant functional disability) [ • Temperature dysregulation and heat intolerance can be a common feature in individuals with • It has been hypothesized that spinal cord white matter involvement [ • Pseudobulbar palsy with dysarthria, dysphagia, and forced crying and laughing [ • Many individuals have sensory deficits starting in the lower limbs associated with loss of position and vibration sensation attributed to extensive involvement of the spinal cord. • Sensorineural hearing loss is seen in rare cases [ ## Genotype-Phenotype Correlations Differences in clinical findings and MRI features have been noted between individuals with ## Penetrance The disease presents in the fourth to fifth decade of adulthood, with equal frequency in males and females. Penetrance is not known but is thought to be 100%. ## Nomenclature ## Prevalence The exact prevalence of Families of European, Middle Eastern, Asian, and Mexican ancestry have been reported. ## Genetically Related (Allelic) Disorders Heterozygous ## Differential Diagnosis The differential diagnosis of Because untreated vitamin B Genes and Disorders of Interest in the Differential Diagnosis of AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; MOI = mode of inheritance; SCA = spinocerebellar ataxia; WM = while matter; XL = X-linked See also ## Acquired Demyelinating Disorders Because untreated vitamin B ## Hereditary Disorders Genes and Disorders of Interest in the Differential Diagnosis of AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; MOI = mode of inheritance; SCA = spinocerebellar ataxia; WM = while matter; XL = X-linked See also ## 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 Social work involvement for family support; Home nursing referral. MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse Treatment of Manifestations in Individuals with Address recurrent urinary tract infections w/attn to bladder regimens for managing neurogenic bladders, which may (rarely) require antibiotic prophylaxis. Spasmolytics (e.g., solifenacine succinate) for urinary urgency Pharmacologic treatment (mineralocorticoids such as fludrocortisone or vasopressors such as hydrochloride) Compression stockings PT (to help w/rising from supine positions) ↑ salt in the diet Can use cooling vests, fans, air conditioning Intensive mgmt of infections should incl adequate antipyretic treatment. Medications to help ↓ muscle tone such as oral baclofen or diazepam (GABA agonists) or injectable botulinum toxin for focal muscle spasticity Individualized PT regimen to improve joint mobility & function Strategies to minimize falls & ↑ strength Adaptive equipment such as walkers or wheelchairs Work w/social worker & financial planner to help anticipate issues of guardianship that may accompany progressive decline. Family & patient support/advocacy groups to help address progressive psychosocial consequences of ADLD PT = physical therapy Recommended surveillance: Routine assessment of weight, nutrition, and feeding; pulmonary status (re possible recurrent pneumonia); bladder and erectile function; psychosocial well-being; and medications and dosage to avoid iatrogenic polypharmacy At least annual assessment by multidisciplinary specialists including a neurologist for disease manifestations and progression; and by a physiatrist, orthopedist, physical therapist, and occupational therapist to address orthopedic, equipment, and functional needs Because disease manifestations may be exacerbated with fever and infection, care should be taken to avoid whenever possible exposure to those with infections. See Search • Social work involvement for family support; • Home nursing referral. • Address recurrent urinary tract infections w/attn to bladder regimens for managing neurogenic bladders, which may (rarely) require antibiotic prophylaxis. • Spasmolytics (e.g., solifenacine succinate) for urinary urgency • Pharmacologic treatment (mineralocorticoids such as fludrocortisone or vasopressors such as hydrochloride) • Compression stockings • PT (to help w/rising from supine positions) • ↑ salt in the diet • Can use cooling vests, fans, air conditioning • Intensive mgmt of infections should incl adequate antipyretic treatment. • Medications to help ↓ muscle tone such as oral baclofen or diazepam (GABA agonists) or injectable botulinum toxin for focal muscle spasticity • Individualized PT regimen to improve joint mobility & function • Strategies to minimize falls & ↑ strength • Adaptive equipment such as walkers or wheelchairs • Work w/social worker & financial planner to help anticipate issues of guardianship that may accompany progressive decline. • Family & patient support/advocacy groups to help address progressive psychosocial consequences of ADLD • Routine assessment of weight, nutrition, and feeding; pulmonary status (re possible recurrent pneumonia); bladder and erectile function; psychosocial well-being; and medications and dosage to avoid iatrogenic polypharmacy • At least annual assessment by multidisciplinary specialists including a neurologist for disease manifestations and progression; and by a physiatrist, orthopedist, physical therapist, and occupational therapist to address orthopedic, equipment, and functional needs ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with Social work involvement for family support; Home nursing referral. MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Social work involvement for family support; • Home nursing referral. ## Treatment of Manifestations Treatment of Manifestations in Individuals with Address recurrent urinary tract infections w/attn to bladder regimens for managing neurogenic bladders, which may (rarely) require antibiotic prophylaxis. Spasmolytics (e.g., solifenacine succinate) for urinary urgency Pharmacologic treatment (mineralocorticoids such as fludrocortisone or vasopressors such as hydrochloride) Compression stockings PT (to help w/rising from supine positions) ↑ salt in the diet Can use cooling vests, fans, air conditioning Intensive mgmt of infections should incl adequate antipyretic treatment. Medications to help ↓ muscle tone such as oral baclofen or diazepam (GABA agonists) or injectable botulinum toxin for focal muscle spasticity Individualized PT regimen to improve joint mobility & function Strategies to minimize falls & ↑ strength Adaptive equipment such as walkers or wheelchairs Work w/social worker & financial planner to help anticipate issues of guardianship that may accompany progressive decline. Family & patient support/advocacy groups to help address progressive psychosocial consequences of ADLD PT = physical therapy • Address recurrent urinary tract infections w/attn to bladder regimens for managing neurogenic bladders, which may (rarely) require antibiotic prophylaxis. • Spasmolytics (e.g., solifenacine succinate) for urinary urgency • Pharmacologic treatment (mineralocorticoids such as fludrocortisone or vasopressors such as hydrochloride) • Compression stockings • PT (to help w/rising from supine positions) • ↑ salt in the diet • Can use cooling vests, fans, air conditioning • Intensive mgmt of infections should incl adequate antipyretic treatment. • Medications to help ↓ muscle tone such as oral baclofen or diazepam (GABA agonists) or injectable botulinum toxin for focal muscle spasticity • Individualized PT regimen to improve joint mobility & function • Strategies to minimize falls & ↑ strength • Adaptive equipment such as walkers or wheelchairs • Work w/social worker & financial planner to help anticipate issues of guardianship that may accompany progressive decline. • Family & patient support/advocacy groups to help address progressive psychosocial consequences of ADLD ## Surveillance Recommended surveillance: Routine assessment of weight, nutrition, and feeding; pulmonary status (re possible recurrent pneumonia); bladder and erectile function; psychosocial well-being; and medications and dosage to avoid iatrogenic polypharmacy At least annual assessment by multidisciplinary specialists including a neurologist for disease manifestations and progression; and by a physiatrist, orthopedist, physical therapist, and occupational therapist to address orthopedic, equipment, and functional needs • Routine assessment of weight, nutrition, and feeding; pulmonary status (re possible recurrent pneumonia); bladder and erectile function; psychosocial well-being; and medications and dosage to avoid iatrogenic polypharmacy • At least annual assessment by multidisciplinary specialists including a neurologist for disease manifestations and progression; and by a physiatrist, orthopedist, physical therapist, and occupational therapist to address orthopedic, equipment, and functional needs ## Agents/Circumstances to Avoid Because disease manifestations may be exacerbated with fever and infection, care should be taken to avoid whenever possible exposure to those with infections. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling To date, all individuals diagnosed with To date, a If the proband appears to be the only affected family member (i.e., a simplex case) and the proband’s parents are available for testing, molecular genetic testing is recommended for the parents to confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. The family history of some individuals diagnosed with If a parent of the proband is affected and/or has an If the If the parents are clinically unaffected but have not been tested for the pathogenic variant identified in the proband, sibs of the proband are still presumed to be at increased risk for Predictive testing for at-risk relatives is possible once the Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. 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 causative pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for Differences in perspective may exist among medical professionals and within families regarding the use 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 individuals diagnosed with • To date, a • If the proband appears to be the only affected family member (i.e., a simplex case) and the proband’s parents are available for testing, molecular genetic testing is recommended for the parents to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The family history of some individuals diagnosed with • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If a parent of the proband is affected and/or has an • If the • If the parents are clinically unaffected but have not been tested for the pathogenic variant identified in the proband, sibs of the proband are still presumed to be at increased risk for • Predictive testing for at-risk relatives is possible once the • Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. • 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 To date, all individuals diagnosed with To date, a If the proband appears to be the only affected family member (i.e., a simplex case) and the proband’s parents are available for testing, molecular genetic testing is recommended for the parents to confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. The family history of some individuals diagnosed with If a parent of the proband is affected and/or has an If the If the parents are clinically unaffected but have not been tested for the pathogenic variant identified in the proband, sibs of the proband are still presumed to be at increased risk for • To date, all individuals diagnosed with • To date, a • If the proband appears to be the only affected family member (i.e., a simplex case) and the proband’s parents are available for testing, molecular genetic testing is recommended for the parents to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The family history of some individuals diagnosed with • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If a parent of the proband is affected and/or has an • If the • If the parents are clinically unaffected but have not been tested for the pathogenic variant identified in the proband, sibs of the proband are still presumed to be at increased risk for ## Related Genetic Counseling Issues Predictive testing for at-risk relatives is possible once 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 causative pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for Differences in perspective may exist among medical professionals and within families regarding the use 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 2609 Crooks Road Suite 116 Troy 48084 Australia • • 2609 Crooks Road • Suite 116 • Troy 48084 • • • • • Australia • • • • • ## Molecular Genetics LMNB1-Related Autosomal Dominant Leukodystrophy: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for LMNB1-Related Autosomal Dominant Leukodystrophy ( Both duplications of Fibroblasts have exhibited nuclear abnormalities, increased nuclear stiffness, and alterations in RNA splicing [ Overexpression in muscle cells had an effect on actin and sarcomere function [ Overexpression of lamin-B1 reduces the ability of astrocytes to support oligodendrocytes during the myelination process [ Overexpression of lamin-B1 was found to have deleterious effects in model organisms. • Fibroblasts have exhibited nuclear abnormalities, increased nuclear stiffness, and alterations in RNA splicing [ • Overexpression in muscle cells had an effect on actin and sarcomere function [ • Overexpression of lamin-B1 reduces the ability of astrocytes to support oligodendrocytes during the myelination process [ ## Molecular Pathogenesis Both duplications of Fibroblasts have exhibited nuclear abnormalities, increased nuclear stiffness, and alterations in RNA splicing [ Overexpression in muscle cells had an effect on actin and sarcomere function [ Overexpression of lamin-B1 reduces the ability of astrocytes to support oligodendrocytes during the myelination process [ Overexpression of lamin-B1 was found to have deleterious effects in model organisms. • Fibroblasts have exhibited nuclear abnormalities, increased nuclear stiffness, and alterations in RNA splicing [ • Overexpression in muscle cells had an effect on actin and sarcomere function [ • Overexpression of lamin-B1 reduces the ability of astrocytes to support oligodendrocytes during the myelination process [ ## Chapter Notes Raili RaininkoProfessor of Neuroradiology (emerita), Uppsala University, Uppsala, SwedenEmail: [email protected] Dr Raininko has ceased participation in clinical neuroradiologic work but continues in research projects. One of the main research areas is inherited neurologic diseases in children and adults. Disease development and mechanism have been investigated in collaboration with clinicians, geneticists, and pathologists. Michael GoskyGenetic Counselor, University of KentuckyEmail: [email protected]. Mr Gosky recently completed his Masters degree in genetic counseling at the University of Pittsburgh and is currently a genetic counselor at the University of Kentucky. His research interests include neuroscience and genetics. The major focus of the Padiath lab is to understand the molecular mechanisms underlying various neurologic diseases with an emphasis on the disorders of myelin known as leukodystrophies. This work involves the use of clinical-based family studies to identify disease-related genes and the development of animal and cell culture models to elucidate disease mechanisms. Dr Padiath identified lamin B1 duplications as the cause of ADLD; understanding the molecular mechanisms of this disease remains an important area of research in his lab at the University of Pittsburgh. This work was supported by NIH grants R33NS106087, R01NS095884 and R21NS104384 to QSP. The authors would also like to acknowledge the support and participation of ADLD patients and family members, without which none of this work would be possible. Michael Gosky, BS, MS (2021-present)Norah Nahhas, MD; Children's National Health System (2016-2021)Quasar S Padiath, MBBS, PhD (2016-present)Raili Raininko, MD, PhD (2021-present)Parisa Sadet Rasekh, MD, Children's National Health System (2016-2021)Adeline Vanderver, MD; Children's Hospital of Philadelphia (2016-2021) 15 July 2021 (ha) Comprehensive update posted live 7 January 2016 (me) Review posted live 27 August 2015 (nn) Original submission • 15 July 2021 (ha) Comprehensive update posted live • 7 January 2016 (me) Review posted live • 27 August 2015 (nn) Original submission ## Author Notes Raili RaininkoProfessor of Neuroradiology (emerita), Uppsala University, Uppsala, SwedenEmail: [email protected] Dr Raininko has ceased participation in clinical neuroradiologic work but continues in research projects. One of the main research areas is inherited neurologic diseases in children and adults. Disease development and mechanism have been investigated in collaboration with clinicians, geneticists, and pathologists. Michael GoskyGenetic Counselor, University of KentuckyEmail: [email protected]. Mr Gosky recently completed his Masters degree in genetic counseling at the University of Pittsburgh and is currently a genetic counselor at the University of Kentucky. His research interests include neuroscience and genetics. The major focus of the Padiath lab is to understand the molecular mechanisms underlying various neurologic diseases with an emphasis on the disorders of myelin known as leukodystrophies. This work involves the use of clinical-based family studies to identify disease-related genes and the development of animal and cell culture models to elucidate disease mechanisms. Dr Padiath identified lamin B1 duplications as the cause of ADLD; understanding the molecular mechanisms of this disease remains an important area of research in his lab at the University of Pittsburgh. ## Acknowledgments This work was supported by NIH grants R33NS106087, R01NS095884 and R21NS104384 to QSP. The authors would also like to acknowledge the support and participation of ADLD patients and family members, without which none of this work would be possible. ## Author History Michael Gosky, BS, MS (2021-present)Norah Nahhas, MD; Children's National Health System (2016-2021)Quasar S Padiath, MBBS, PhD (2016-present)Raili Raininko, MD, PhD (2021-present)Parisa Sadet Rasekh, MD, Children's National Health System (2016-2021)Adeline Vanderver, MD; Children's Hospital of Philadelphia (2016-2021) ## Revision History 15 July 2021 (ha) Comprehensive update posted live 7 January 2016 (me) Review posted live 27 August 2015 (nn) Original submission • 15 July 2021 (ha) Comprehensive update posted live • 7 January 2016 (me) Review posted live • 27 August 2015 (nn) Original submission ## References ## Literature Cited T * lateral ventricle Transverse T	[ "A Bartoletti-Stella, L Gasparini, C Giacomini, P Corrado, R Terlizzi, E Giorgio, P Magini, M Seri, A Baruzzi, P Parchi, A Brusco, P Cortelli, S. Capellari. Messenger RNA processing is altered in autosomal dominant leukodystrophy.. Hum Mol Genet. 2015;24:2746-56", "M Bergui, GB Bradac, S Leombruni, G Vaula, G Quattrocolo. MRI and CT in an autosomal-dominant, adult-onset leukodystrophy.. Neuroradiology. 1997;39:423-6", "A Brussino, G Vaula, C Cagnoli, A Mauro, L Pradotto, D Daniele, E Di Gregorio, M Barberis, C Arduino, S Squadrone, MC Abete, N Migone, O Calabrese, A Brusco. A novel family with Lamin B1 duplication associated with adult-onset leucoencephalopathy.. J Neurol Neurosurg Psychiatry. 2009;80:237-40", "V Butin-Israeli, SA Adam, AE Goldman, RD Goldman. Nuclear lamin functions and disease.. Trends Genet. 2012;28:464-71", "CM Coffeen. Genetic localization of an autosomal dominant leukodystrophy mimicking chronic progressive multiple sclerosis to chromosome 5q31.. Hum Mol Genet 2000;9:787-93", "M Columbaro, E Mattioli, NM Maraldi, M Ortolani, L Gasparini, MR D'Apice, D Postorivo, AM Nardone, S Avnet, P Cortelli, R Liguori, G Lattanzi. Oct-1 recruitment to the nuclear envelope in adult-onset autosomal dominant leukodystrophy.. Biochim Biophys Acta. 2013;1832:411-20", "L Cousyn, B Law-Ye, N Pyatigorskaya, R Debs, R Froissart, M Piraud, A Federico, S Salvatore, A Cerase, MC Macário, J Durães, SH Kim, H Adachi, B Audoin, X Ayrignac, Y Da, R Henderson, R La Piana, C Laule, K Nakamagoe, R Raininko, L Schols, SM Sirrs, F Viader, K Jastrzębski, D Leclercq, Y Nadjar. Brain MRI features and scoring of leukodystrophy in adult-onset Krabbe disease.. Neurology 2019;93:e647-652", "F Cristofoli, T Moss, HW Moore, K Devriendt, H Flanagan-Steet, M May, J Jones, F Roelens, C Fons, A Fernandez, L Martorell, A Selicorni, S Maitz, G Vitiello, G Van der Hoeven, SA Skinner, M Bollen, JR Vermeesch, R Steet, H Van Esch. De novo variants in LMNB1 cause pronounced syndromic microcephaly and disruption of nuclear envelope integrity.. Am J Hum Genet 2020;107:753-62", "Y Dai, Y Ma, S Li, S Banerjee, S Liang, Q Liu, Y Yang, B Peng, L Cui, L. Jin. An LMNB1 duplication caused adult-onset autosomal dominant leukodystrophy in Chinese family: clinical manifestations, neuroradiology and genetic diagnosis.. Front Mol Neurosci. 2017;10:215", "R Debs, R Froissart, P Aubourg, C Papeix, C Douillard, B Degos, B Fontaine, B Audoin, A Lacour, G Said, MT Vanier, F Sedel. Krabbe disease in adults: phenotypic and genotypic update from a series of 11 cases and a review.. J Inherit Metab Dis. 2013;36:859-68", "V Devalia, MS Hamilton, AM Molloy. Guidelines for the diagnosis and treatment of cobalamin and folate disorders.. Br J Haematol. 2014;166:496-513", "MM Dos Santos, C Grond-Ginsbach, SS Aksay, B Chen, S Tchatchou, NI Wolf, MS van der Knaap, AJ Grau. Adult-onset autosomal dominant leukodystrophy due to LMNB1 gene duplication.. J Neurol. 2012;259:579-81", "R Eldridge, CP Anayiotos, S Schlesinger, D Cowen, C Bever, N Patronas, H McFarland. Hereditary adult-onset leukodystrophy simulating chronic progressive multiple sclerosis.. N Engl J Med. 1984;311:948-53", "D Ferrera, C Canale, R Marotta, N Mazzaro, M Gritti, M Mazzanti, S Capellari, P Cortelli, L. Gasparini. Lamin B1 overexpression increases nuclear rigidity in autosomal dominant leukodystrophy fibroblasts.. FASEB J. 2014;28:3906-18", "J Finnsson, J Sundblom, N Dahl, A Melberg, R. Raininko. LMNB1-related autosomal-dominant leukodystrophy: Clinical and radiological course.. Ann Neurol. 2015;78:412-25", "E Giorgio, D Robyr, M Spielmann, E Ferrero, E Di Gregorio, D Imperiale, G Vaula, G Stamoulis, F Santoni, C Atzori, L Gasparini, D Ferrera, C Canale, M Guipponi, LA Pennacchio, SE Antonarakis, A Brussino, A Brusco. A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD).. Hum Mol Genet. 2015;24:3143-54", "E Giorgio, H Rolyan, L Kropp, AB Chakka, S Yatsenko, E Di Gregorio, D Lacerenza, G Vaula, F Talarico, P Mandich, C Toro, EE Pierre, P Labauge, S Capellari, P Cortelli, FP Vairo, D Miguel, D Stubbolo, LC Marques, W Gahl, O Boespflug-Tanguy, A Melberg, S Hassin-Baer, OS Cohen, R Pjontek, A Grau, T Klopstock, B Fogel, I Meijer, G Rouleau, JP Bouchard, M Ganapathiraju, A Vanderver, N Dahl, G Hobson, A Brusco, A Brussino, QS Padiath. Analysis of LMNB1 duplications in autosomal dominant leukodystrophy provides insights into duplication mechanisms and allele-specific expression.. Hum Mutat. 2013;34:1160-71", "P Guaraldi, V Donadio, S Capellari, M Contin, MC Casadio, P Montagna, R Liguori, P Cortelli. Isolated noradrenergic failure in adult-onset autosomal dominant leukodystrophy.. Auton Neurosci. 2011;159:123-6", "MY Heng, ST Lin, L Verret, Y Huang, S Kamiya, QS Padiath, Y Tong, JJ Palop, EJ Huang, LJ Ptáček, YH Fu. Lamin B1 mediates cell-autonomous neuropathology in a leukodystrophy mouse model.. J Clin Invest. 2013;123:2719-29", "TG Issac, S Soundarya, R Christopher, SR Chandra. Vitamin B12 deficiency: an important reversible co-morbidity in neuropsychiatric manifestations.. Indian J Psychol Med. 2015;37:26-9", "HJ Jung, JM Lee, SH Yang, SG Young, LG Fong. Nuclear lamins in the brain - new insights into function and regulation.. Mol Neurobiol. 2013;47:290-301", "V Lo Martire, S Alvente, S Bastianini, C Berteotti, C Bombardi, G Calandra-Buonaura, S Capellari, G Cohen, P Cortelli, L Gasparini, Q Padiath, A Valli, G Zoccoli, A. Silvani. Mice overexpressing lamin B1 in oligodendrocytes recapitulate the age-dependent motor signs, but not the early autonomic cardiovascular dysfunction of autosomal dominant leukodystrophy (ADLD).. Exp Neurol. 2018;301:1-12", "L Marklund, M Melin, A Melberg, V Giedraitis, N Dahl. Adult-onset autosomal dominant leukodystrophy with autonomic symptoms restricted to 1.5 Mbp on chromosome 5q23.. Am J Med Genet B Neuropsychiatr Genet. 2006;141B:608-14", "IA Meijer, AA Simoes-Lopes, S Laurent, T Katz, J St-Onge, DJ Verlaan, N Dupré, M Thibault, J Mathurin, JP Bouchard, GA Rouleau. A novel duplication confirms the involvement of 5q23.2 in autosomal dominant leukodystrophy.. Arch Neurol. 2008;65:1496-501", "A Melberg, L Hallberg, H Kalimo, R. Raininko. MR characteristics and neuropathology in adult-onset autosomal dominant leukodystrophy with autonomic symptoms.. AJNR Am J Neuroradiol. 2006;27:904-11", "N Mezaki, T Miura, K Ogaki, M Eriguchi, Y Mizuno, K Komatsu, H Yamazaki, N Suetsugi, S Kawajiri, R Yamasaki, T Ishiguro, T Konno, H Nozaki, K Kasuga, Y Okuma, JI Kira, H Hara, O Onodera, T Ikeuchi. Duplication and deletion upstream of LMNB1 in autosomal dominant adult-onset leukodystrophy.. Neurol Genet. 2018;4", "A Molloy, O Cotter, R van Spaendonk, E Sistermans, B. Sweeney. A patient with a rare leukodystrophy related to lamin B1 duplication.. Ir Med J. 2012;105:186-7", "B Nmezi, E Giorgio, R Raininko, A Lehman, M Spielmann, MK Koenig, R Adejumo, M Knight, R Gavrilova, M Alturkustani, M Sharma, R Hammond, WA Gahl, C Toro, A Brusco, QS Padiath. Genomic deletions upstream of lamin B1 lead to atypical autosomal dominant leukodystrophy.. Neurol Genet. 2019;5", "JH Noseworthy, C Lucchinetti, M Rodriguez, BG Weinshenker. Multiple sclerosis.. N Engl J Med. 2000;343:938-52", "QS Padiath, YH Fu. Autosomal dominant leukodystrophy caused by lamin B1 duplications a clinical and molecular case study of altered nuclear function and disease.. Methods Cell Biol. 2010;98:337-57", "QS Padiath, K Saigoh, R Schiffmann, H Asahara, T Yamada, A Koeppen, K Hogan, LJ Ptácek, YH Fu. Lamin B1 duplications cause autosomal dominant leukodystrophy.. Nat Genet. 2006;38:1114-23", "CM Poser, DW Paty, L Scheinberg, WI McDonald, FA Davis, GC Ebers, KP Johnson, WA Sibley, DH Silberberg, WW Tourtellotte. New diagnostic criteria for multiple sclerosis: guidelines for research protocols.. Ann Neurol. 1983;13:227-31", "A Potic, AM Pavlovic, G Uziel, D Kozic, J Ostojic, A Rovelli, N Sternic, M Bjelan, E Sarto, D Di Bella, F Taroni. Adult-onset autosomal dominant leukodystrophy without early autonomic dysfunctions linked to lamin B1 duplication: a phenotypic variant.. J Neurol. 2013;260:2124-9", "G Quattrocolo, S Leombruni, G Vaula, M Bergui, A Riva, GB Bradac, L Bergamini. Autosomal dominant late-onset leukoencephalopathy. Clinical report of a new Italian family.. Eur Neurol. 1997;37:53-61", "S Rabhi, M Maaroufi, H Khibri, F Belahsen, S Tizniti, R Berrady, W Bono. Magnetic resonance imaging findings within the posterior and lateral columns of the spinal cord extended from the medulla oblongata to the thoracic spine in a woman with subacute combined degeneration without hematologic disorders: a case report and review of the literature.. J Med Case Rep. 2011;5:166", "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 Ratti, I Rusciano, S Mongiorgi, E Owusu Obeng, A Cappellini, G Teti, M Falconi, L Talozzi, S Capellari, A Bartoletti-Stella, P Guaraldi, P Cortelli, PG Suh, L Cocco, L Manzoli, G Ramazzotti. Cell signaling pathways in autosomal-dominant leukodystrophy (ADLD): the intriguing role of the astrocytes.. Cell Mol Life Sci 2021;78:2781-95", "H Rolyan, YY Tyurina, M Hernandez, AA Amoscato, LJ Sparvero, BC Nmezi, Y Lu, MR Estécio, K Lin, J Chen, RR He, P Gong, LH Rigatti, J Dupree, H Bayır, VE Kagan, P Casaccia, QS Padiath. Defects of lipid synthesis are linked to the age-dependent demyelination caused by lamin B1 overexpression.. J Neurosci. 2015;35:12002-17", "V Sandoval-Rodríguez, MA Cansino-Torres, M Sáenz-Farret, G Castañeda-Cisneros, G Moreno, C Zúñiga-Ramírez. Autosomal dominant leukodystrophy presenting as Alzheimer’s-type dementia.. Mult Scler Relat Disord 2017;17:230-3", "J Schuster, J Sundblom, AC Thuresson, S Hassin-Baer, T Klopstock, M Dichgans, OS Cohen, R Raininko, A Melberg, N Dahl. Genomic duplications mediate overexpression of lamin B1 in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms.. Neurogenetics. 2011;12:65-72", "JD Schwankhaus, DA Katz, R Eldridge, S Schlesinger, H McFarland. Clinical and pathological features of an autosomal dominant, adult-onset leukodystrophy simulating chronic progressive multiple sclerosis.. Arch Neurol. 1994;51:757-66", "JD Schwankhaus, N Patronas, R Dorwart, R Eldridge, S Schlesinger, H McFarland. Computed tomography and magnetic resonance imaging in adult-onset leukodystrophy.. Arch Neurol. 1988;45:1004-8", "I Stancheva, EC Schirmer. Nuclear envelope: connecting structural genome organization to regulation of gene expression.. Adv Exp Med Biol. 2014;773:209-44", "J Sundblom, A Melberg, H Kalimo, A Smits, R. Raininko. MR imaging characteristics and neuropathology of the spinal cord in adult-onset autosomal dominant leukodystrophy with autonomic symptoms.. AJNR Am J Neuroradiol. 2009;30:328-35", "Y Zhang, J Li, R Bai, J Wang, T Peng, L Chen, J Wang, Y Liu, T Tian, H. Lu. LMNB1-related adult-onset autosomal dominant leukodystrophy presenting as movement disorder: a case report and review of the literature.. Front Neurosci. 2019;13:1030" ]	7/1/2016	15/7/2021		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
lafora	lafora	[ "Lafora Body Disease", "Lafora Disease", "Progressive Myoclonic Epilepsy Type 2 (EPM2)", "Lafora Body Disease", "Lafora Disease", "Progressive Myoclonic Epilepsy Type 2 (EPM2)", "E3 ubiquitin-protein ligase NHLRC1", "Laforin", "EPM2A", "NHLRC1", "Progressive Myoclonus Epilepsy, Lafora Type" ]	Progressive Myoclonus Epilepsy, Lafora Type	Berge Minassian	Summary Progressive myoclonus epilepsy, Lafora type (also known as Lafora disease) is characterized by focal occipital seizures presenting as transient blindness or visual hallucinations and fragmentary, symmetric, or generalized myoclonus occurring in previously healthy individuals. Typical age of onset is eight to 19 years (peak: age14-16 years). Generalized tonic-clonic seizures, atypical absence seizures, atonic seizures, and focal seizures with impaired awareness may also occur. The course of the disease is characterized by increasing frequency and intractability of seizures. Status epilepticus with any of the seizure types is common. Cognitive decline becomes apparent at or soon after the onset of seizures. Dysarthria and ataxia appear early, while spasticity appears late. Emotional disturbances and confusion are common in the early stages of the disease and are followed by dementia. Most affected individuals die within ten years of onset, usually from status epilepticus or from complications related to neurologic degeneration. The diagnosis of Lafora disease is established in a proband with characteristic neurologic findings and/or biallelic pathogenic variants in one of the two known causative genes, Lafora disease is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an	## Diagnosis No consensus clinical diagnostic criteria for progressive myoclonus epilepsy, Lafora type, also known as Lafora disease, have been published. Lafora disease Focal occipital seizures presenting as transient blindness or visual hallucinations Fragmentary, symmetric, or generalized myoclonus Generalized seizures including tonic-clonic seizures, absence seizures, or drop attacks Progressive neurologic degeneration including cognitive and/or behavioral deterioration, dysarthria, ataxia, and, at later stages, spasticity and dementia Slowing of EEG background activity, loss of alpha rhythm and sleep features, posteriorly dominant irregular spike-wave discharges, and photosensitivity on early EEGs Periodic acid Schiff-positive intracellular inclusion bodies (Lafora bodies) on skin biopsy (See Normal brain MRI at disease onset; progressive cortical atrophy possible later in the course of the disease The diagnosis of Lafora disease 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 findings suggest the diagnosis of Lafora disease, the molecular genetic testing approach is use of a For an introduction to multigene panels click When the diagnosis of Lafora disease has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Progressive Myoclonus Epilepsy, Lafora Type LD = Lafora disease Genes are listed alphabetically. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small 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. Heterozygous deletions of the entire Note: (1) Normal PAS-positive apical granules in secretory apocrine cells found in the axilla can be mistaken for Lafora bodies; thus, biopsy of skin outside the axilla and genital regions is favored, as eccrine duct cell Lafora bodies are unmistakable [ • Focal occipital seizures presenting as transient blindness or visual hallucinations • Fragmentary, symmetric, or generalized myoclonus • Generalized seizures including tonic-clonic seizures, absence seizures, or drop attacks • Progressive neurologic degeneration including cognitive and/or behavioral deterioration, dysarthria, ataxia, and, at later stages, spasticity and dementia • Slowing of EEG background activity, loss of alpha rhythm and sleep features, posteriorly dominant irregular spike-wave discharges, and photosensitivity on early EEGs • Periodic acid Schiff-positive intracellular inclusion bodies (Lafora bodies) on skin biopsy (See • Normal brain MRI at disease onset; progressive cortical atrophy possible later in the course of the disease ## Suggestive Findings Lafora disease Focal occipital seizures presenting as transient blindness or visual hallucinations Fragmentary, symmetric, or generalized myoclonus Generalized seizures including tonic-clonic seizures, absence seizures, or drop attacks Progressive neurologic degeneration including cognitive and/or behavioral deterioration, dysarthria, ataxia, and, at later stages, spasticity and dementia Slowing of EEG background activity, loss of alpha rhythm and sleep features, posteriorly dominant irregular spike-wave discharges, and photosensitivity on early EEGs Periodic acid Schiff-positive intracellular inclusion bodies (Lafora bodies) on skin biopsy (See Normal brain MRI at disease onset; progressive cortical atrophy possible later in the course of the disease • Focal occipital seizures presenting as transient blindness or visual hallucinations • Fragmentary, symmetric, or generalized myoclonus • Generalized seizures including tonic-clonic seizures, absence seizures, or drop attacks • Progressive neurologic degeneration including cognitive and/or behavioral deterioration, dysarthria, ataxia, and, at later stages, spasticity and dementia • Slowing of EEG background activity, loss of alpha rhythm and sleep features, posteriorly dominant irregular spike-wave discharges, and photosensitivity on early EEGs • Periodic acid Schiff-positive intracellular inclusion bodies (Lafora bodies) on skin biopsy (See • Normal brain MRI at disease onset; progressive cortical atrophy possible later in the course of the disease ## Establishing the Diagnosis The diagnosis of Lafora disease 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 findings suggest the diagnosis of Lafora disease, the molecular genetic testing approach is use of a For an introduction to multigene panels click When the diagnosis of Lafora disease has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Progressive Myoclonus Epilepsy, Lafora Type LD = Lafora disease Genes are listed alphabetically. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small 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. Heterozygous deletions of the entire Note: (1) Normal PAS-positive apical granules in secretory apocrine cells found in the axilla can be mistaken for Lafora bodies; thus, biopsy of skin outside the axilla and genital regions is favored, as eccrine duct cell Lafora bodies are unmistakable [ ## Option 1 When the phenotypic findings suggest the diagnosis of Lafora disease, the molecular genetic testing approach is use of a For an introduction to multigene panels click ## Option 2 When the diagnosis of Lafora disease has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Progressive Myoclonus Epilepsy, Lafora Type LD = Lafora disease Genes are listed alphabetically. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small 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. Heterozygous deletions of the entire Note: (1) Normal PAS-positive apical granules in secretory apocrine cells found in the axilla can be mistaken for Lafora bodies; thus, biopsy of skin outside the axilla and genital regions is favored, as eccrine duct cell Lafora bodies are unmistakable [ ## Clinical Characteristics Progressive myoclonus epilepsy, Lafora type, also known as Lafora disease, is a rare teenage-onset progressive myoclonus epilepsy. The term "myoclonus" is emphasized because this is a relatively infrequent neurologic symptom in teenagers. When seen in an otherwise healthy adolescent, it strongly suggests a common benign form of epilepsy, juvenile myoclonic epilepsy (JME). For this reason, most individuals with Lafora disease are briefly misdiagnosed with JME. However, while the EEG background in JME is normal, it is already abnormal (slow) when myoclonus appears in individuals with Lafora disease. Lafora disease is associated with inexorable worsening of the epilepsy. Myoclonus gradually becomes near constant. Generalized tonic-clonic seizures gradually become intractable; atypical absences with or without myoclonus eventually take over. The affected individual's interactions become such that every thought, speech, feeding, etc., are interrupted, and each of these and other functions become slow and protracted. Walking ability is lost usually in most affected individuals before age 21 years. Within ten years of disease onset, most individuals are in a vegetative state and usually die in status epilepticus or complications of poor airway control. To date, at least 300 individuals have been identified with Lafora disease [ Clinical Findings of Progressive Myoclonus Epilepsy, Lafora Type Based on G6P = glucose-6-phosphate; GABA = gamma-aminobutyric acid; ISI = interstimulus intervals; NAA = N-acetylaspartate; UDPG = uridine diphosphate glucose At least two years after onset of symptoms By their mid-twenties, most affected individuals are in a vegetative state with continuous myoclonus and require tube feeding. Some maintain minimal interactions with the family such as a reflex-like smiling upon cajoling. Affected individuals who are not tube fed aspirate frequently because of seizures; death from aspiration pneumonia is common. Most affected individuals die within ten years of onset, usually from status epilepticus or from complications related to neurologic deterioration [ Most pathogenic variants in There are reports of mild Lafora disease with slow disease progression in association with missense variants. For example, the Progressive myoclonus epilepsy, Lafora type, also known as Lafora disease, is also referred to as myoclonic epilepsy of Lafora. The term "progressive myoclonus epilepsy" (PME) covers a large and varied group of diseases characterized by myoclonus, generalized tonic-clonic seizures, and progressive neurologic deterioration [ Exact prevalence figures for Lafora disease are lacking. Based on all published reports of Lafora disease-causing pathogenic variants to date, the overall global frequency is estimated at 4:1,000,000 [ Lafora disease occurs worldwide. While relatively rare in the nonconsanguineous populations of the United States, Canada, China, and Japan, Lafora disease is relatively common in the Mediterranean basin of Spain, France, and Italy, in restricted regions of central Asia, India, Pakistan, northern Africa, and the Middle East, in ethnic isolates from the southern United States and Quebec, and in other parts of the world with a high rate of consanguinity [ Within the Italian and Japanese populations, pathogenic variants in Note: Lafora disease has not been reported in Finland, where founder effects for a number of genetic disorders are common, and where progressive myoclonic epilepsy type 1 (EPM1; ## Clinical Description Progressive myoclonus epilepsy, Lafora type, also known as Lafora disease, is a rare teenage-onset progressive myoclonus epilepsy. The term "myoclonus" is emphasized because this is a relatively infrequent neurologic symptom in teenagers. When seen in an otherwise healthy adolescent, it strongly suggests a common benign form of epilepsy, juvenile myoclonic epilepsy (JME). For this reason, most individuals with Lafora disease are briefly misdiagnosed with JME. However, while the EEG background in JME is normal, it is already abnormal (slow) when myoclonus appears in individuals with Lafora disease. Lafora disease is associated with inexorable worsening of the epilepsy. Myoclonus gradually becomes near constant. Generalized tonic-clonic seizures gradually become intractable; atypical absences with or without myoclonus eventually take over. The affected individual's interactions become such that every thought, speech, feeding, etc., are interrupted, and each of these and other functions become slow and protracted. Walking ability is lost usually in most affected individuals before age 21 years. Within ten years of disease onset, most individuals are in a vegetative state and usually die in status epilepticus or complications of poor airway control. To date, at least 300 individuals have been identified with Lafora disease [ Clinical Findings of Progressive Myoclonus Epilepsy, Lafora Type Based on G6P = glucose-6-phosphate; GABA = gamma-aminobutyric acid; ISI = interstimulus intervals; NAA = N-acetylaspartate; UDPG = uridine diphosphate glucose At least two years after onset of symptoms By their mid-twenties, most affected individuals are in a vegetative state with continuous myoclonus and require tube feeding. Some maintain minimal interactions with the family such as a reflex-like smiling upon cajoling. Affected individuals who are not tube fed aspirate frequently because of seizures; death from aspiration pneumonia is common. Most affected individuals die within ten years of onset, usually from status epilepticus or from complications related to neurologic deterioration [ ## Genotype-Phenotype Correlations Most pathogenic variants in There are reports of mild Lafora disease with slow disease progression in association with missense variants. For example, the ## Nomenclature Progressive myoclonus epilepsy, Lafora type, also known as Lafora disease, is also referred to as myoclonic epilepsy of Lafora. The term "progressive myoclonus epilepsy" (PME) covers a large and varied group of diseases characterized by myoclonus, generalized tonic-clonic seizures, and progressive neurologic deterioration [ ## Prevalence Exact prevalence figures for Lafora disease are lacking. Based on all published reports of Lafora disease-causing pathogenic variants to date, the overall global frequency is estimated at 4:1,000,000 [ Lafora disease occurs worldwide. While relatively rare in the nonconsanguineous populations of the United States, Canada, China, and Japan, Lafora disease is relatively common in the Mediterranean basin of Spain, France, and Italy, in restricted regions of central Asia, India, Pakistan, northern Africa, and the Middle East, in ethnic isolates from the southern United States and Quebec, and in other parts of the world with a high rate of consanguinity [ Within the Italian and Japanese populations, pathogenic variants in Note: Lafora disease has not been reported in Finland, where founder effects for a number of genetic disorders are common, and where progressive myoclonic epilepsy type 1 (EPM1; ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Genes of interest in the differential diagnosis of progressive myoclonus epilepsy, Lafora type (also known as Lafora disease), are listed in Genes of Interest in the Differential Diagnosis of Progressive Myoclonus Epilepsy, Lafora Type Brain MRI often shows brain atrophy & basal ganglia lesions. Muscle biopsy typically shows ragged red fibers. Presents at age ~5 years; disease course is much more protracted than either typical LD or the phenotypically similar infantile neuronal ceroid lipofuscinosis. Note: Early-onset LD has been reported in 2 families to date. AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; LD = Lafora disease; Mat = maternal; PME = progressive myoclonic epilepsy Visual hallucinations, withdrawal, and cognitive decline raise concerns of schizophrenia, which becomes less likely with the onset of convulsions and the appearance of an epileptiform EEG. Brain MRI excludes structural abnormalities. • Brain MRI often shows brain atrophy & basal ganglia lesions. • Muscle biopsy typically shows ragged red fibers. • Presents at age ~5 years; disease course is much more protracted than either typical LD or the phenotypically similar infantile neuronal ceroid lipofuscinosis. • Note: Early-onset LD has been reported in 2 families to date. ## Management No clinical practice guidelines for progressive myoclonus epilepsy, Lafora type, also known as Lafora disease, 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 Lafora disease, the evaluations summarized in Lafora Disease: Recommended Evaluations Following Initial Diagnosis To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Community or Social work involvement for parental support Home nursing referral ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; LD = Lafora disease; MOI = mode of inheritance Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Lafora Disease: Treatment of Manifestations Many ASMs may be effective (see As the disease progresses, generalized seizures become more frequent & myoclonus more disabling, requiring more intensive support in the home environment or through institutionalization, depending on availability of care & family preferences. Serial seizures &/or status epilepticus may require admission to critical care. 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 In general, treatment recommendations for Lafora disease follow those of other progressive myoclonic epilepsies (PMEs) [ Valproic acid is the traditional treatment for seizures in Lafora disease. Because it is a broad-spectrum ASM, it suppresses the generalized tonic-clonic seizures and myoclonic jerks for some time. Benzodiazepines (clonazepam, clobazam, diazepam) can be used as an adjunctive medication for control of myoclonus, as in other forms of PME, although the literature does not provide clear evidence for its effect on myoclonus in Lafora disease. Some individuals may develop tolerance, requiring dose adjustment or switching to another benzodiazepine. Because the myoclonus associated with Lafora disease may be drug resistant, overmedication may be a risk in individuals with Lafora disease. Common polytherapy combinations consist of valproic acid with perampanel, topiramate, zonisamide, or levetiracetam, and a benzodiazepine. An open-label trial with add-on perampanel in ten individuals with Lafora disease showed significant reduction in seizures (see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Lafora Disease: Recommended Surveillance Monitor seizures as clinically indicated. Assess for new manifestations such as seizures, changes in tone & ataxia. 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 As in other forms of progressive myoclonic epilepsies, the use of phenytoin as maintenance therapy should be avoided. Anecdotal reports describe possible exacerbation of myoclonus with the following: Lamotrigine [ Carbamazepine [ Oxcarbazepine [ See Due to the severity of the disorder, individuals with Lafora disease typically do not have children. However, in cases of mild Lafora disease with slow disease progression (as reported with the See An open-label trial with add-on perampanel in ten individuals with Lafora disease showed significant reduction in seizures greater than 74% from baseline in four individuals. Seven had major improvement in myoclonus. Three withdrew due to inefficacy or side effects. There was no improvement in disability or cognition [ Search • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Community or • Social work involvement for parental support • Home nursing referral • Many ASMs may be effective (see • As the disease progresses, generalized seizures become more frequent & myoclonus more disabling, requiring more intensive support in the home environment or through institutionalization, depending on availability of care & family preferences. • Serial seizures &/or status epilepticus may require admission to critical care. • 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 • Valproic acid is the traditional treatment for seizures in Lafora disease. Because it is a broad-spectrum ASM, it suppresses the generalized tonic-clonic seizures and myoclonic jerks for some time. • Benzodiazepines (clonazepam, clobazam, diazepam) can be used as an adjunctive medication for control of myoclonus, as in other forms of PME, although the literature does not provide clear evidence for its effect on myoclonus in Lafora disease. Some individuals may develop tolerance, requiring dose adjustment or switching to another benzodiazepine. • Because the myoclonus associated with Lafora disease may be drug resistant, overmedication may be a risk in individuals with Lafora disease. • Valproic acid is the traditional treatment for seizures in Lafora disease. Because it is a broad-spectrum ASM, it suppresses the generalized tonic-clonic seizures and myoclonic jerks for some time. • Benzodiazepines (clonazepam, clobazam, diazepam) can be used as an adjunctive medication for control of myoclonus, as in other forms of PME, although the literature does not provide clear evidence for its effect on myoclonus in Lafora disease. Some individuals may develop tolerance, requiring dose adjustment or switching to another benzodiazepine. • Because the myoclonus associated with Lafora disease may be drug resistant, overmedication may be a risk in individuals with Lafora disease. • Common polytherapy combinations consist of valproic acid with perampanel, topiramate, zonisamide, or levetiracetam, and a benzodiazepine. • An open-label trial with add-on perampanel in ten individuals with Lafora disease showed significant reduction in seizures (see • Common polytherapy combinations consist of valproic acid with perampanel, topiramate, zonisamide, or levetiracetam, and a benzodiazepine. • An open-label trial with add-on perampanel in ten individuals with Lafora disease showed significant reduction in seizures (see • Valproic acid is the traditional treatment for seizures in Lafora disease. Because it is a broad-spectrum ASM, it suppresses the generalized tonic-clonic seizures and myoclonic jerks for some time. • Benzodiazepines (clonazepam, clobazam, diazepam) can be used as an adjunctive medication for control of myoclonus, as in other forms of PME, although the literature does not provide clear evidence for its effect on myoclonus in Lafora disease. Some individuals may develop tolerance, requiring dose adjustment or switching to another benzodiazepine. • Because the myoclonus associated with Lafora disease may be drug resistant, overmedication may be a risk in individuals with Lafora disease. • Common polytherapy combinations consist of valproic acid with perampanel, topiramate, zonisamide, or levetiracetam, and a benzodiazepine. • An open-label trial with add-on perampanel in ten individuals with Lafora disease showed significant reduction in seizures (see • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox • Monitor seizures as clinically indicated. • Assess for new manifestations such as seizures, changes in tone & ataxia. • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Lamotrigine [ • Carbamazepine [ • Oxcarbazepine [ ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Lafora disease, the evaluations summarized in Lafora Disease: Recommended Evaluations Following Initial Diagnosis To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Community or Social work involvement for parental support Home nursing referral ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; LD = Lafora disease; MOI = mode of inheritance Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Lafora Disease: Treatment of Manifestations Many ASMs may be effective (see As the disease progresses, generalized seizures become more frequent & myoclonus more disabling, requiring more intensive support in the home environment or through institutionalization, depending on availability of care & family preferences. Serial seizures &/or status epilepticus may require admission to critical care. 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 In general, treatment recommendations for Lafora disease follow those of other progressive myoclonic epilepsies (PMEs) [ Valproic acid is the traditional treatment for seizures in Lafora disease. Because it is a broad-spectrum ASM, it suppresses the generalized tonic-clonic seizures and myoclonic jerks for some time. Benzodiazepines (clonazepam, clobazam, diazepam) can be used as an adjunctive medication for control of myoclonus, as in other forms of PME, although the literature does not provide clear evidence for its effect on myoclonus in Lafora disease. Some individuals may develop tolerance, requiring dose adjustment or switching to another benzodiazepine. Because the myoclonus associated with Lafora disease may be drug resistant, overmedication may be a risk in individuals with Lafora disease. Common polytherapy combinations consist of valproic acid with perampanel, topiramate, zonisamide, or levetiracetam, and a benzodiazepine. An open-label trial with add-on perampanel in ten individuals with Lafora disease showed significant reduction in seizures (see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. • Many ASMs may be effective (see • As the disease progresses, generalized seizures become more frequent & myoclonus more disabling, requiring more intensive support in the home environment or through institutionalization, depending on availability of care & family preferences. • Serial seizures &/or status epilepticus may require admission to critical care. • 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 • Valproic acid is the traditional treatment for seizures in Lafora disease. Because it is a broad-spectrum ASM, it suppresses the generalized tonic-clonic seizures and myoclonic jerks for some time. • Benzodiazepines (clonazepam, clobazam, diazepam) can be used as an adjunctive medication for control of myoclonus, as in other forms of PME, although the literature does not provide clear evidence for its effect on myoclonus in Lafora disease. Some individuals may develop tolerance, requiring dose adjustment or switching to another benzodiazepine. • Because the myoclonus associated with Lafora disease may be drug resistant, overmedication may be a risk in individuals with Lafora disease. • Valproic acid is the traditional treatment for seizures in Lafora disease. Because it is a broad-spectrum ASM, it suppresses the generalized tonic-clonic seizures and myoclonic jerks for some time. • Benzodiazepines (clonazepam, clobazam, diazepam) can be used as an adjunctive medication for control of myoclonus, as in other forms of PME, although the literature does not provide clear evidence for its effect on myoclonus in Lafora disease. Some individuals may develop tolerance, requiring dose adjustment or switching to another benzodiazepine. • Because the myoclonus associated with Lafora disease may be drug resistant, overmedication may be a risk in individuals with Lafora disease. • Common polytherapy combinations consist of valproic acid with perampanel, topiramate, zonisamide, or levetiracetam, and a benzodiazepine. • An open-label trial with add-on perampanel in ten individuals with Lafora disease showed significant reduction in seizures (see • Common polytherapy combinations consist of valproic acid with perampanel, topiramate, zonisamide, or levetiracetam, and a benzodiazepine. • An open-label trial with add-on perampanel in ten individuals with Lafora disease showed significant reduction in seizures (see • Valproic acid is the traditional treatment for seizures in Lafora disease. Because it is a broad-spectrum ASM, it suppresses the generalized tonic-clonic seizures and myoclonic jerks for some time. • Benzodiazepines (clonazepam, clobazam, diazepam) can be used as an adjunctive medication for control of myoclonus, as in other forms of PME, although the literature does not provide clear evidence for its effect on myoclonus in Lafora disease. Some individuals may develop tolerance, requiring dose adjustment or switching to another benzodiazepine. • Because the myoclonus associated with Lafora disease may be drug resistant, overmedication may be a risk in individuals with Lafora disease. • Common polytherapy combinations consist of valproic acid with perampanel, topiramate, zonisamide, or levetiracetam, and a benzodiazepine. • An open-label trial with add-on perampanel in ten individuals with Lafora disease showed significant reduction in seizures (see • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in 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 ## Epilepsy Treatment In general, treatment recommendations for Lafora disease follow those of other progressive myoclonic epilepsies (PMEs) [ Valproic acid is the traditional treatment for seizures in Lafora disease. Because it is a broad-spectrum ASM, it suppresses the generalized tonic-clonic seizures and myoclonic jerks for some time. Benzodiazepines (clonazepam, clobazam, diazepam) can be used as an adjunctive medication for control of myoclonus, as in other forms of PME, although the literature does not provide clear evidence for its effect on myoclonus in Lafora disease. Some individuals may develop tolerance, requiring dose adjustment or switching to another benzodiazepine. Because the myoclonus associated with Lafora disease may be drug resistant, overmedication may be a risk in individuals with Lafora disease. Common polytherapy combinations consist of valproic acid with perampanel, topiramate, zonisamide, or levetiracetam, and a benzodiazepine. An open-label trial with add-on perampanel in ten individuals with Lafora disease showed significant reduction in seizures (see • Valproic acid is the traditional treatment for seizures in Lafora disease. Because it is a broad-spectrum ASM, it suppresses the generalized tonic-clonic seizures and myoclonic jerks for some time. • Benzodiazepines (clonazepam, clobazam, diazepam) can be used as an adjunctive medication for control of myoclonus, as in other forms of PME, although the literature does not provide clear evidence for its effect on myoclonus in Lafora disease. Some individuals may develop tolerance, requiring dose adjustment or switching to another benzodiazepine. • Because the myoclonus associated with Lafora disease may be drug resistant, overmedication may be a risk in individuals with Lafora disease. • Valproic acid is the traditional treatment for seizures in Lafora disease. Because it is a broad-spectrum ASM, it suppresses the generalized tonic-clonic seizures and myoclonic jerks for some time. • Benzodiazepines (clonazepam, clobazam, diazepam) can be used as an adjunctive medication for control of myoclonus, as in other forms of PME, although the literature does not provide clear evidence for its effect on myoclonus in Lafora disease. Some individuals may develop tolerance, requiring dose adjustment or switching to another benzodiazepine. • Because the myoclonus associated with Lafora disease may be drug resistant, overmedication may be a risk in individuals with Lafora disease. • Common polytherapy combinations consist of valproic acid with perampanel, topiramate, zonisamide, or levetiracetam, and a benzodiazepine. • An open-label trial with add-on perampanel in ten individuals with Lafora disease showed significant reduction in seizures (see • Common polytherapy combinations consist of valproic acid with perampanel, topiramate, zonisamide, or levetiracetam, and a benzodiazepine. • An open-label trial with add-on perampanel in ten individuals with Lafora disease showed significant reduction in seizures (see • Valproic acid is the traditional treatment for seizures in Lafora disease. Because it is a broad-spectrum ASM, it suppresses the generalized tonic-clonic seizures and myoclonic jerks for some time. • Benzodiazepines (clonazepam, clobazam, diazepam) can be used as an adjunctive medication for control of myoclonus, as in other forms of PME, although the literature does not provide clear evidence for its effect on myoclonus in Lafora disease. Some individuals may develop tolerance, requiring dose adjustment or switching to another benzodiazepine. • Because the myoclonus associated with Lafora disease may be drug resistant, overmedication may be a risk in individuals with Lafora disease. • Common polytherapy combinations consist of valproic acid with perampanel, topiramate, zonisamide, or levetiracetam, and a benzodiazepine. • An open-label trial with add-on perampanel in ten individuals with Lafora disease showed significant reduction in seizures (see ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Motor Dysfunction Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## Neurobehavioral/Psychiatric Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Lafora Disease: Recommended Surveillance Monitor seizures as clinically indicated. Assess for new manifestations such as seizures, changes in tone & ataxia. 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 seizures as clinically indicated. • Assess for new manifestations such as seizures, changes in tone & ataxia. • Measurement of growth parameters • Eval of nutritional status & safety of oral intake ## Agents/Circumstances to Avoid As in other forms of progressive myoclonic epilepsies, the use of phenytoin as maintenance therapy should be avoided. Anecdotal reports describe possible exacerbation of myoclonus with the following: Lamotrigine [ Carbamazepine [ Oxcarbazepine [ • Lamotrigine [ • Carbamazepine [ • Oxcarbazepine [ ## Evaluation of Relatives at Risk See ## Pregnancy Management Due to the severity of the disorder, individuals with Lafora disease typically do not have children. However, in cases of mild Lafora disease with slow disease progression (as reported with the See ## Therapies Under Investigation An open-label trial with add-on perampanel in ten individuals with Lafora disease showed significant reduction in seizures greater than 74% from baseline in four individuals. Seven had major improvement in myoclonus. Three withdrew due to inefficacy or side effects. There was no improvement in disability or cognition [ Search ## Genetic Counseling Progressive myoclonus epilepsy, Lafora type (also known as Lafora disease), 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) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an Variability in age at onset among affected family members is considerable (see Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. The offspring of an individual with Lafora disease would be obligate heterozygotes (carriers) for a pathogenic variant in Because of the early onset and rapid deterioration, individuals with Lafora disease typically do not reproduce. Carrier testing for at-risk relatives requires prior identification of the The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. It is appropriate to offer Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected child are presumed to be heterozygous for an • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for 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 • Variability in age at onset among affected family members is considerable (see • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The offspring of an individual with Lafora disease would be obligate heterozygotes (carriers) for a pathogenic variant in • Because of the early onset and rapid deterioration, individuals with Lafora disease typically do not reproduce. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • It is appropriate to offer ## Mode of Inheritance Progressive myoclonus epilepsy, Lafora type (also known as Lafora disease), 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) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an Variability in age at onset among affected family members is considerable (see Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. The offspring of an individual with Lafora disease would be obligate heterozygotes (carriers) for a pathogenic variant in Because of the early onset and rapid deterioration, individuals with Lafora disease typically do not reproduce. • 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) 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 • Variability in age at onset among affected family members is considerable (see • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The offspring of an individual with Lafora disease would be obligate heterozygotes (carriers) for a pathogenic variant in • Because of the early onset and rapid deterioration, individuals with Lafora disease typically do not reproduce. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. It is appropriate to offer • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • It is appropriate to offer ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal 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 Progressive Myoclonus Epilepsy, Lafora Type: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Progressive Myoclonus Epilepsy, Lafora Type ( LD = Lafora disease Variants listed in the table have been provided by the author. ## Molecular Pathogenesis LD = Lafora disease Variants listed in the table have been provided by the author. ## Chapter Notes Eva Andermann, MD, PhD, FCCMG; McGill University (2007-2025)Anna C Jansen, MD, PhD; Vrije Universiteit Brussel (2007-2025)Berge Minassian, MD (2025-present) 23 January 2025 (gm) Comprehensive update posted live 21 February 2019 (ha) Comprehensive update posted live 22 January 2015 (me) Comprehensive update posted live 3 November 2011 (me) Comprehensive update posted live 28 December 2007 (me) Review posted live 2 January 2007 (ea) Original submission • 23 January 2025 (gm) Comprehensive update posted live • 21 February 2019 (ha) Comprehensive update posted live • 22 January 2015 (me) Comprehensive update posted live • 3 November 2011 (me) Comprehensive update posted live • 28 December 2007 (me) Review posted live • 2 January 2007 (ea) Original submission ## Author Notes ## Author History Eva Andermann, MD, PhD, FCCMG; McGill University (2007-2025)Anna C Jansen, MD, PhD; Vrije Universiteit Brussel (2007-2025)Berge Minassian, MD (2025-present) ## Revision History 23 January 2025 (gm) Comprehensive update posted live 21 February 2019 (ha) Comprehensive update posted live 22 January 2015 (me) Comprehensive update posted live 3 November 2011 (me) Comprehensive update posted live 28 December 2007 (me) Review posted live 2 January 2007 (ea) Original submission • 23 January 2025 (gm) Comprehensive update posted live • 21 February 2019 (ha) Comprehensive update posted live • 22 January 2015 (me) Comprehensive update posted live • 3 November 2011 (me) Comprehensive update posted live • 28 December 2007 (me) Review posted live • 2 January 2007 (ea) Original submission ## References ## Literature Cited	[]	28/12/2007	23/1/2025		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
lal-def	lal-def	[ "Acid Lipase Deficiency", "LAL Deficiency", "LAL Deficiency", "Acid Lipase Deficiency", "Wolman Disease", "Cholesterol Ester Storage Disease", "Lysosomal acid lipase/cholesteryl ester hydrolase", "LIPA", "Lysosomal Acid Lipase Deficiency" ]	Lysosomal Acid Lipase Deficiency	Erin P Hoffman, Marci L Barr, Monica A Giovanni, Michael F Murray	Summary The phenotypic spectrum of lysosomal acid lipase (LAL) deficiency ranges from the infantile-onset form (Wolman disease) to later-onset forms collectively known as cholesterol ester storage disease (CESD). Diagnosis of LAL deficiency is suspected in individuals with characteristic clinical findings such as hepatomegaly, elevated transaminases, and a typical serum lipid profile: high total serum concentrations of cholesterol, low-density lipoprotein, and triglycerides; and low serum concentration of high-density lipoprotein. The diagnosis is confirmed by identification of either biallelic pathogenic variants in Both Wolman disease and CESD: Enzyme replacement therapy (ERT) with sebelipase alfa was recently approved by the FDA and is administered at a dose of 1 mg/kg body weight every other week; this treatment can be life saving for those with severe Wolman syndrome and life improving with prolonged survival in those who have CESD. Consider referral to a liver specialist. Liver transplantation may be indicated when liver disease progresses to cirrhosis and liver failure. Wolman disease: Consultation with a nutrition team to limit malnutrition if possible, including use of parenteral nutrition; corticosteroid and mineralocorticoid replacement in the presence of adrenal insufficiency. CESD: Reduce cholesterol through the use of statins, cholestyramine, and a diet low in cholesterol and triglycerides. Aggressive reduction of additional cardiovascular risk factors and lipophilic vitamins may also be beneficial. Consult with a nutrition team for children with failure to thrive or adults with weight loss. For children: Monitor growth and nutritional status; evaluate fasting lipid levels, platelet count, and liver enzymes every six months. For adults: reevaluate every 6-12 months depending on disease severity. Monitor nutritional status. Evaluate fasting lipid levels, platelet count, and liver enzymes routinely. Evaluate those with severe liver disease for esophageal varices by upper endoscopy every three years. Monitor and treat those with hepatosplenomegaly thrombocytopenia to prevent bleeding complications. For children and adults: monitor hepatosplenic volume and screen for hepatocellular carcinoma with serial liver and spleen imaging. LAL deficiency is inherited in an autosomal recessive manner. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing of a pregnancy at increased risk are possible if the	Cholesterol ester storage disease Wolman disease For synonyms and outdated names see For other genetic causes of these phenotypes see • Cholesterol ester storage disease • Wolman disease ## Diagnosis The phenotypic spectrum of lysosomal acid lipase (LAL) deficiency ranges from infantile-onset form (Wolman disease) to later-onset forms, collectively known as cholesterol ester storage disease (CESD). LAL deficiency cannot be diagnosed on clinical findings alone. Serum concentrations of lipids and lipoproteins are almost always abnormal ( Total serum concentration of cholesterol is often high, as are serum concentrations of low-density lipoprotein (LDL) and triglycerides. Serum concentration of high-density lipoprotein (HDL) is typically low. Note: Normal serum lipid levels do not exclude the diagnosis of LAL deficiency [ Lipid Values Found in 33 Individuals with LAL Deficiency Values in mg/dL 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 testing approaches can include For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Lysosomal Acid Lipase 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. Large deletions appear to be rare, but have been reported [ Examples of homozygosity for exon or whole-gene deletions have not been reported. Note: (1) Assay of LAL enzyme activity in peripheral blood leukocytes is the confirmatory diagnostic test for LAL deficiency; however, enzyme activity can also be diagnostically measured in hepatocytes, skin fibroblasts, or dried blood spots that have been promptly transported and properly stored [ • Total serum concentration of cholesterol is often high, as are serum concentrations of low-density lipoprotein (LDL) and triglycerides. • Serum concentration of high-density lipoprotein (HDL) is typically low. • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings Serum concentrations of lipids and lipoproteins are almost always abnormal ( Total serum concentration of cholesterol is often high, as are serum concentrations of low-density lipoprotein (LDL) and triglycerides. Serum concentration of high-density lipoprotein (HDL) is typically low. Note: Normal serum lipid levels do not exclude the diagnosis of LAL deficiency [ Lipid Values Found in 33 Individuals with LAL Deficiency Values in mg/dL • Total serum concentration of cholesterol is often high, as are serum concentrations of low-density lipoprotein (LDL) and triglycerides. • Serum concentration of high-density lipoprotein (HDL) is typically low. ## Preliminary Testing Serum concentrations of lipids and lipoproteins are almost always abnormal ( Total serum concentration of cholesterol is often high, as are serum concentrations of low-density lipoprotein (LDL) and triglycerides. Serum concentration of high-density lipoprotein (HDL) is typically low. Note: Normal serum lipid levels do not exclude the diagnosis of LAL deficiency [ Lipid Values Found in 33 Individuals with LAL Deficiency Values in mg/dL • Total serum concentration of cholesterol is often high, as are serum concentrations of low-density lipoprotein (LDL) and triglycerides. • Serum concentration of high-density lipoprotein (HDL) is typically low. ## Establishing the Diagnosis 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 testing approaches can include For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Lysosomal Acid Lipase 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. Large deletions appear to be rare, but have been reported [ Examples of homozygosity for exon or whole-gene deletions have not been reported. Note: (1) Assay of LAL enzyme activity in peripheral blood leukocytes is the confirmatory diagnostic test for LAL deficiency; however, enzyme activity can also be diagnostically measured in hepatocytes, skin fibroblasts, or dried blood spots that have been promptly transported and properly stored [ • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics Lysosomal acid lipase (LAL) deficiency, like other diseases caused by enzyme deficiencies, has a wide phenotypic spectrum. Infantile-onset LAL deficiency is known as Wolman disease. All later-onset LAL deficiency, which may present from early childhood to late adulthood (often with subclinical disease), is known as cholesterol ester storage disease (CESD). Infants with Wolman disease may present as early as the first day of life with vomiting, steatorrhea, and abdominal distention [ Hepatomegaly, the result of build-up of cholesterol esters and triglycerides in macrophages of the liver, is common and can be dramatic. Splenomegaly, the result of the same mechanism, may also be present. Increased lipid deposition along the gastrointestinal tract leads to thickened bowel walls with resultant malnutrition and wasting [ Steatosis may progress to liver failure. Enlarged adrenal glands with calcification, a classic finding in Wolman disease, can lead to adrenal cortical insufficiency. Infants with Wolman disease do not usually survive beyond the first year of life. Treatment with hematopoietic stem cell transplantation (HSCT) has had mixed results, and requires further study [ Although CESD may present in childhood in a manner similar to Wolman disease with failure to thrive and delayed milestones [ Atherosclerosis due to hyperlipidemia accounts for much of the morbidity associated with late-onset CESD, such as coronary artery disease and catastrophic vascular events including stroke [ Hepatomegaly with or without splenomegaly is frequently present as a result of cholesterol ester and triglyceride build-up in macrophages. Organomegaly, often among the first findings noted, may be present for years before a diagnosis is reached [ Liver disease is common. It may present as altered liver function with or without jaundice, steatosis, fibrosis, or cirrhosis. Liver disease can lead to esophageal varices, which are associated with risk for hemorrhage and can be life-threatening [ Hepatocellular carcinoma has occurred in the setting of advanced cirrhosis [ Lipid deposition in the wall of the intestinal tract can contribute to diarrhea and weight loss [ On occasion, signs of hyperlipidemia (e.g., xanthelasma, particularly of the palpebral area) may be visible [ Enlarged adrenal glands with punctate calcifications can be present, more often in those with more severe disease [ Individuals with CESD may have a normal life span depending on the severity of disease manifestations. Liver biopsy demonstrates microvesicular steatosis or "fatty liver." To help distinguish LAL deficiency (both Wolman and CESD) from common diagnoses with overlapping findings (see Presence of additional supportive findings including "sea-blue" histiocytes, large Kupffer cells with increased vacuoles, lipid droplets, and/or cholesterol crystals [ Immunohistochemistry including use of the lysosomal markers cathepsin D, lysosomal-associated membrane protein 1 (LAMP1), LAMP2, and lysosomal integral membrane protein 2 [ Identification of Maltese cross-type birefringence in frozen sections [ In general, null allelic variants with no residual enzyme function result in Wolman disease and pathogenic variants that allow for residual LAL enzyme activity result in CESD. The Among individuals with the same genotype, varying levels of residual enzyme activity have been reported; therefore, the predictive value of genotype is only in distinguishing Wolman disease from CESD. The level of residual LAL enzyme activity identified on enzyme assay is not useful for predicting disease course, as manifestations of disease vary greatly among individuals with similar levels of enzyme activity. Other names used for lysosomal acid lipase (LAL) deficiency in the past that are no longer in use include: Acid cholesterol ester hydrolase deficiency Cholesterol ester hydrolase deficiency storage disease Cholesterol ester storage disease is also known as cholesteryl ester storage disease. Due to the rarity and under-recognition of LAL deficiency, precise prevalence rates are not known at this time. Estimates in a German cohort suggested 1:50,000 for CESD and 1:350,000 for Wolman disease; however, LAL deficiency may be found to be more common as milder phenotypes continue to be recognized [ LAL deficiency may be more common in individuals of Iranian-Jewish ancestry: one study suggested rates as high as 1:4200 in the Iranian-Jewish population of the Los Angeles area due to a • Presence of additional supportive findings including "sea-blue" histiocytes, large Kupffer cells with increased vacuoles, lipid droplets, and/or cholesterol crystals [ • Immunohistochemistry including use of the lysosomal markers cathepsin D, lysosomal-associated membrane protein 1 (LAMP1), LAMP2, and lysosomal integral membrane protein 2 [ • Identification of Maltese cross-type birefringence in frozen sections [ • Acid cholesterol ester hydrolase deficiency • Cholesterol ester hydrolase deficiency storage disease ## Clinical Description Lysosomal acid lipase (LAL) deficiency, like other diseases caused by enzyme deficiencies, has a wide phenotypic spectrum. Infantile-onset LAL deficiency is known as Wolman disease. All later-onset LAL deficiency, which may present from early childhood to late adulthood (often with subclinical disease), is known as cholesterol ester storage disease (CESD). Infants with Wolman disease may present as early as the first day of life with vomiting, steatorrhea, and abdominal distention [ Hepatomegaly, the result of build-up of cholesterol esters and triglycerides in macrophages of the liver, is common and can be dramatic. Splenomegaly, the result of the same mechanism, may also be present. Increased lipid deposition along the gastrointestinal tract leads to thickened bowel walls with resultant malnutrition and wasting [ Steatosis may progress to liver failure. Enlarged adrenal glands with calcification, a classic finding in Wolman disease, can lead to adrenal cortical insufficiency. Infants with Wolman disease do not usually survive beyond the first year of life. Treatment with hematopoietic stem cell transplantation (HSCT) has had mixed results, and requires further study [ Although CESD may present in childhood in a manner similar to Wolman disease with failure to thrive and delayed milestones [ Atherosclerosis due to hyperlipidemia accounts for much of the morbidity associated with late-onset CESD, such as coronary artery disease and catastrophic vascular events including stroke [ Hepatomegaly with or without splenomegaly is frequently present as a result of cholesterol ester and triglyceride build-up in macrophages. Organomegaly, often among the first findings noted, may be present for years before a diagnosis is reached [ Liver disease is common. It may present as altered liver function with or without jaundice, steatosis, fibrosis, or cirrhosis. Liver disease can lead to esophageal varices, which are associated with risk for hemorrhage and can be life-threatening [ Hepatocellular carcinoma has occurred in the setting of advanced cirrhosis [ Lipid deposition in the wall of the intestinal tract can contribute to diarrhea and weight loss [ On occasion, signs of hyperlipidemia (e.g., xanthelasma, particularly of the palpebral area) may be visible [ Enlarged adrenal glands with punctate calcifications can be present, more often in those with more severe disease [ Individuals with CESD may have a normal life span depending on the severity of disease manifestations. Liver biopsy demonstrates microvesicular steatosis or "fatty liver." To help distinguish LAL deficiency (both Wolman and CESD) from common diagnoses with overlapping findings (see Presence of additional supportive findings including "sea-blue" histiocytes, large Kupffer cells with increased vacuoles, lipid droplets, and/or cholesterol crystals [ Immunohistochemistry including use of the lysosomal markers cathepsin D, lysosomal-associated membrane protein 1 (LAMP1), LAMP2, and lysosomal integral membrane protein 2 [ Identification of Maltese cross-type birefringence in frozen sections [ • Presence of additional supportive findings including "sea-blue" histiocytes, large Kupffer cells with increased vacuoles, lipid droplets, and/or cholesterol crystals [ • Immunohistochemistry including use of the lysosomal markers cathepsin D, lysosomal-associated membrane protein 1 (LAMP1), LAMP2, and lysosomal integral membrane protein 2 [ • Identification of Maltese cross-type birefringence in frozen sections [ ## Wolman Disease Infants with Wolman disease may present as early as the first day of life with vomiting, steatorrhea, and abdominal distention [ Hepatomegaly, the result of build-up of cholesterol esters and triglycerides in macrophages of the liver, is common and can be dramatic. Splenomegaly, the result of the same mechanism, may also be present. Increased lipid deposition along the gastrointestinal tract leads to thickened bowel walls with resultant malnutrition and wasting [ Steatosis may progress to liver failure. Enlarged adrenal glands with calcification, a classic finding in Wolman disease, can lead to adrenal cortical insufficiency. Infants with Wolman disease do not usually survive beyond the first year of life. Treatment with hematopoietic stem cell transplantation (HSCT) has had mixed results, and requires further study [ ## Cholesterol Ester Storage Disease (CESD) Although CESD may present in childhood in a manner similar to Wolman disease with failure to thrive and delayed milestones [ Atherosclerosis due to hyperlipidemia accounts for much of the morbidity associated with late-onset CESD, such as coronary artery disease and catastrophic vascular events including stroke [ Hepatomegaly with or without splenomegaly is frequently present as a result of cholesterol ester and triglyceride build-up in macrophages. Organomegaly, often among the first findings noted, may be present for years before a diagnosis is reached [ Liver disease is common. It may present as altered liver function with or without jaundice, steatosis, fibrosis, or cirrhosis. Liver disease can lead to esophageal varices, which are associated with risk for hemorrhage and can be life-threatening [ Hepatocellular carcinoma has occurred in the setting of advanced cirrhosis [ Lipid deposition in the wall of the intestinal tract can contribute to diarrhea and weight loss [ On occasion, signs of hyperlipidemia (e.g., xanthelasma, particularly of the palpebral area) may be visible [ Enlarged adrenal glands with punctate calcifications can be present, more often in those with more severe disease [ Individuals with CESD may have a normal life span depending on the severity of disease manifestations. ## Liver Biopsy Liver biopsy demonstrates microvesicular steatosis or "fatty liver." To help distinguish LAL deficiency (both Wolman and CESD) from common diagnoses with overlapping findings (see Presence of additional supportive findings including "sea-blue" histiocytes, large Kupffer cells with increased vacuoles, lipid droplets, and/or cholesterol crystals [ Immunohistochemistry including use of the lysosomal markers cathepsin D, lysosomal-associated membrane protein 1 (LAMP1), LAMP2, and lysosomal integral membrane protein 2 [ Identification of Maltese cross-type birefringence in frozen sections [ • Presence of additional supportive findings including "sea-blue" histiocytes, large Kupffer cells with increased vacuoles, lipid droplets, and/or cholesterol crystals [ • Immunohistochemistry including use of the lysosomal markers cathepsin D, lysosomal-associated membrane protein 1 (LAMP1), LAMP2, and lysosomal integral membrane protein 2 [ • Identification of Maltese cross-type birefringence in frozen sections [ ## Genotype-Phenotype Correlations In general, null allelic variants with no residual enzyme function result in Wolman disease and pathogenic variants that allow for residual LAL enzyme activity result in CESD. The Among individuals with the same genotype, varying levels of residual enzyme activity have been reported; therefore, the predictive value of genotype is only in distinguishing Wolman disease from CESD. The level of residual LAL enzyme activity identified on enzyme assay is not useful for predicting disease course, as manifestations of disease vary greatly among individuals with similar levels of enzyme activity. ## Nomenclature Other names used for lysosomal acid lipase (LAL) deficiency in the past that are no longer in use include: Acid cholesterol ester hydrolase deficiency Cholesterol ester hydrolase deficiency storage disease Cholesterol ester storage disease is also known as cholesteryl ester storage disease. • Acid cholesterol ester hydrolase deficiency • Cholesterol ester hydrolase deficiency storage disease ## Prevalence Due to the rarity and under-recognition of LAL deficiency, precise prevalence rates are not known at this time. Estimates in a German cohort suggested 1:50,000 for CESD and 1:350,000 for Wolman disease; however, LAL deficiency may be found to be more common as milder phenotypes continue to be recognized [ LAL deficiency may be more common in individuals of Iranian-Jewish ancestry: one study suggested rates as high as 1:4200 in the Iranian-Jewish population of the Los Angeles area due to a ## Genetically Related (Allelic) Disorders No phenotypes other than those described in this ## Differential Diagnosis In contrast, the interstitial lung disease and ophthalmologic findings common to Niemann-Pick disease are not observed in LAL deficiency. Biochemical analysis distinguishes between the two disorders [ In contrast, the adrenal calcifications typical of Wolman disease (and occasionally CESD) and the abnormal lipid profile typical of LAL deficiency are not seen in GD. The bone manifestations common to GD type 1 are not observed in CESD. Biochemical analysis can distinguish between the two diseases [ Contractures, skeletal dysplasia, and coarse features which can be found in Hypoglycemia, kidney disease, and cardiomyopathy, which can be seen in the glycogen storage diseases ( Biochemical analysis can distinguish between storage disorders. • Contractures, skeletal dysplasia, and coarse features which can be found in • Hypoglycemia, kidney disease, and cardiomyopathy, which can be seen in the glycogen storage diseases ( ## Management To establish the extent of disease and needs in an individual diagnosed with lysosomal acid lipase (LAL) deficiency, the following evaluations are recommended: Complete blood count Complete fasting lipid profile, if not done at the time of diagnosis Liver function tests Upper endoscopy to evaluate individuals with severe liver disease for the presence of esophageal varices Consultation with a clinical geneticist and/or genetic counselor Enzyme replacement therapy (ERT) with sebelipase alfa was approved by the FDA in late 2015. Results from a Phase III clinical trial of 66 affected individuals demonstrated that ERT can be life saving for those with severe Wolman syndrome and life improving with prolonged survival in those who have cholesterol ester storage disease [ ERT is administered intravenously at a dose of 1 mg/kg body weight every other week. Symptoms should generally be treated in a routine manner, while keeping in mind the limited life expectancy of infants with untreated Wolman disease. Consider discussion of comfort care options. Lipophilic vitamin supplementation may also be beneficial. Aggressive reduction of additional cardiovascular disease risk factors should be encouraged. Individuals found to have esophageal varices should be placed on nonspecific beta-blockers to reduce the risk of bleeding; beta-blockers have not been shown to prevent the formation of esophageal varices. No standard guidelines for the surveillance of individuals with LAL deficiency have been developed. The following screening practices can be considered to monitor for the most common symptoms associated with CESD. Special attention should be paid to growth and nutritional status. Chronic diarrhea or failure to thrive could indicate malabsorption. Consider monitoring fasting lipid levels, platelet count, and liver enzymes every six months. Special attention should be paid to nutritional status. Chronic diarrhea or weight loss could indicate malabsorption. Monitor routinely fasting lipid levels, platelet count, and liver enzymes. Individuals with severe liver disease should be evaluated for esophageal varices by upper endoscopy every three years. Individuals with hepatosplenomegaly should be monitored and treated for thrombocytopenia to prevent bleeding complications. Those with thrombocytopenia should avoid use of nonsteroidal anti-inflammatory drugs. It is appropriate to evaluate the sibs of a proband in order to identify those who would benefit from early institution of treatment. If the If the See Clinical trials are under way for enzyme replacement therapy [ Search • Complete blood count • Complete fasting lipid profile, if not done at the time of diagnosis • Liver function tests • Upper endoscopy to evaluate individuals with severe liver disease for the presence of esophageal varices • Consultation with a clinical geneticist and/or genetic counselor • Results from a Phase III clinical trial of 66 affected individuals demonstrated that ERT can be life saving for those with severe Wolman syndrome and life improving with prolonged survival in those who have cholesterol ester storage disease [ • ERT is administered intravenously at a dose of 1 mg/kg body weight every other week. • Special attention should be paid to growth and nutritional status. Chronic diarrhea or failure to thrive could indicate malabsorption. • Consider monitoring fasting lipid levels, platelet count, and liver enzymes every six months. • Special attention should be paid to nutritional status. Chronic diarrhea or weight loss could indicate malabsorption. • Monitor routinely fasting lipid levels, platelet count, and liver enzymes. • Individuals with severe liver disease should be evaluated for esophageal varices by upper endoscopy every three years. • Individuals with hepatosplenomegaly should be monitored and treated for thrombocytopenia to prevent bleeding complications. • If the • If the ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with lysosomal acid lipase (LAL) deficiency, the following evaluations are recommended: Complete blood count Complete fasting lipid profile, if not done at the time of diagnosis Liver function tests Upper endoscopy to evaluate individuals with severe liver disease for the presence of esophageal varices Consultation with a clinical geneticist and/or genetic counselor • Complete blood count • Complete fasting lipid profile, if not done at the time of diagnosis • Liver function tests • Upper endoscopy to evaluate individuals with severe liver disease for the presence of esophageal varices • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations Enzyme replacement therapy (ERT) with sebelipase alfa was approved by the FDA in late 2015. Results from a Phase III clinical trial of 66 affected individuals demonstrated that ERT can be life saving for those with severe Wolman syndrome and life improving with prolonged survival in those who have cholesterol ester storage disease [ ERT is administered intravenously at a dose of 1 mg/kg body weight every other week. Symptoms should generally be treated in a routine manner, while keeping in mind the limited life expectancy of infants with untreated Wolman disease. Consider discussion of comfort care options. Lipophilic vitamin supplementation may also be beneficial. Aggressive reduction of additional cardiovascular disease risk factors should be encouraged. • Results from a Phase III clinical trial of 66 affected individuals demonstrated that ERT can be life saving for those with severe Wolman syndrome and life improving with prolonged survival in those who have cholesterol ester storage disease [ • ERT is administered intravenously at a dose of 1 mg/kg body weight every other week. ## Wolman Disease Symptoms should generally be treated in a routine manner, while keeping in mind the limited life expectancy of infants with untreated Wolman disease. Consider discussion of comfort care options. ## CESD Lipophilic vitamin supplementation may also be beneficial. Aggressive reduction of additional cardiovascular disease risk factors should be encouraged. ## Prevention of Secondary Complications Individuals found to have esophageal varices should be placed on nonspecific beta-blockers to reduce the risk of bleeding; beta-blockers have not been shown to prevent the formation of esophageal varices. ## Surveillance No standard guidelines for the surveillance of individuals with LAL deficiency have been developed. The following screening practices can be considered to monitor for the most common symptoms associated with CESD. Special attention should be paid to growth and nutritional status. Chronic diarrhea or failure to thrive could indicate malabsorption. Consider monitoring fasting lipid levels, platelet count, and liver enzymes every six months. Special attention should be paid to nutritional status. Chronic diarrhea or weight loss could indicate malabsorption. Monitor routinely fasting lipid levels, platelet count, and liver enzymes. Individuals with severe liver disease should be evaluated for esophageal varices by upper endoscopy every three years. Individuals with hepatosplenomegaly should be monitored and treated for thrombocytopenia to prevent bleeding complications. • Special attention should be paid to growth and nutritional status. Chronic diarrhea or failure to thrive could indicate malabsorption. • Consider monitoring fasting lipid levels, platelet count, and liver enzymes every six months. • Special attention should be paid to nutritional status. Chronic diarrhea or weight loss could indicate malabsorption. • Monitor routinely fasting lipid levels, platelet count, and liver enzymes. • Individuals with severe liver disease should be evaluated for esophageal varices by upper endoscopy every three years. • Individuals with hepatosplenomegaly should be monitored and treated for thrombocytopenia to prevent bleeding complications. ## Agents/Circumstances to Avoid Those with thrombocytopenia should avoid use of nonsteroidal anti-inflammatory drugs. ## Evaluation of Relatives at Risk It is appropriate to evaluate the sibs of a proband in order to identify those who would benefit from early institution of treatment. If the If the See • If the • If the ## Therapies Under Investigation Clinical trials are under way for enzyme replacement therapy [ Search ## Genetic Counseling Lysosomal acid lipase (LAL) deficiency 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. 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. The offspring of an individual with lysosomal acid lipase deficiency are obligate heterozygotes (carriers of a The risk that offspring will inherit a second Carrier testing for at-risk relatives requires prior identification of the Note: Because of the overlap of lysosomal acid lipase (LAL) enzymatic activity between carriers and non-carriers, assay of LAL enzyme activity is not an appropriate method to determine carrier status. 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 • The parents of an affected child are obligate heterozygotes (i.e., carriers of one • Heterozygotes(carriers) are asymptomatic. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic. • The offspring of an individual with lysosomal acid lipase deficiency are obligate heterozygotes (carriers of a • The risk that offspring will inherit a second • 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 Lysosomal acid lipase (LAL) deficiency is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected child are obligate heterozygotes (i.e., carriers of one Heterozygotes(carriers) are asymptomatic. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic. The offspring of an individual with lysosomal acid lipase deficiency are obligate heterozygotes (carriers of a The risk that offspring will inherit a second • The parents of an affected child are obligate heterozygotes (i.e., carriers of one • Heterozygotes(carriers) are asymptomatic. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic. • The offspring of an individual with lysosomal acid lipase deficiency are obligate heterozygotes (carriers of a • The risk that offspring will inherit a second ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the Note: Because of the overlap of lysosomal acid lipase (LAL) enzymatic activity between carriers and non-carriers, assay of LAL enzyme activity is not an appropriate method to determine carrier status. ## 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 ## Resources United Kingdom United Kingdom • • • • • • • • United Kingdom • • • United Kingdom • • • ## Molecular Genetics Lysosomal Acid Lipase Deficiency: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Lysosomal Acid Lipase Deficiency ( In the normal state, the enzyme lysosomal acid lipase (LAL) degrades LDL cholesterol esters and triglycerides in lysosomes. The intracellular free cholesterol that results from the degradation of these molecules is transferred to the endoplasmic reticulum, where it interacts with transcription factors that suppress: HMG-CoA reductase activity, which reduces the cellular synthesis of cholesterol; LDL receptor gene transcription, which results in reduced intracellular uptake of LDL. In the disease state, deficient LAL enzyme activity leads to accumulation of cholesterol esters and triglycerides within lysosomes. Less free intracellular cholesterol results in heightened synthesis of endogenous cholesterol and endocytosis via LDL receptors. The relationship between the disease state and LDL receptor gene expression and activity is not entirely understood [ The most common pathogenic variant resulting in CESD, c.894G>A, involves a G-to-A transition at the last base of exon 8 disrupting the normal donor splice consensus sequence ( Selected Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions Founder variant; see At splice donor site of exon 8, resulting in alternative splicing and subsequent skipping of exon 8 The catalytic active site of LAL is composed of amino acid residues Ser153, Asp324, and His353. The active-site serine is part of a lipase consensus sequence connecting a β-strand to an α-helix, known as the nucleophilic elbow, which facilitates interaction between the nucleophile and the histidine and ester carbon in the appropriately oriented complex [ • HMG-CoA reductase activity, which reduces the cellular synthesis of cholesterol; • LDL receptor gene transcription, which results in reduced intracellular uptake of LDL. ## Molecular Pathogenesis In the normal state, the enzyme lysosomal acid lipase (LAL) degrades LDL cholesterol esters and triglycerides in lysosomes. The intracellular free cholesterol that results from the degradation of these molecules is transferred to the endoplasmic reticulum, where it interacts with transcription factors that suppress: HMG-CoA reductase activity, which reduces the cellular synthesis of cholesterol; LDL receptor gene transcription, which results in reduced intracellular uptake of LDL. In the disease state, deficient LAL enzyme activity leads to accumulation of cholesterol esters and triglycerides within lysosomes. Less free intracellular cholesterol results in heightened synthesis of endogenous cholesterol and endocytosis via LDL receptors. The relationship between the disease state and LDL receptor gene expression and activity is not entirely understood [ The most common pathogenic variant resulting in CESD, c.894G>A, involves a G-to-A transition at the last base of exon 8 disrupting the normal donor splice consensus sequence ( Selected Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions Founder variant; see At splice donor site of exon 8, resulting in alternative splicing and subsequent skipping of exon 8 The catalytic active site of LAL is composed of amino acid residues Ser153, Asp324, and His353. The active-site serine is part of a lipase consensus sequence connecting a β-strand to an α-helix, known as the nucleophilic elbow, which facilitates interaction between the nucleophile and the histidine and ester carbon in the appropriately oriented complex [ • HMG-CoA reductase activity, which reduces the cellular synthesis of cholesterol; • LDL receptor gene transcription, which results in reduced intracellular uptake of LDL. ## Chapter Notes 1 September 2016 (ma) Revision: enzyme replacement therapy ( 30 July 2015 (me) Review posted live 4 October 2012 (mfm) Original submission • 1 September 2016 (ma) Revision: enzyme replacement therapy ( • 30 July 2015 (me) Review posted live • 4 October 2012 (mfm) Original submission ## Revision History 1 September 2016 (ma) Revision: enzyme replacement therapy ( 30 July 2015 (me) Review posted live 4 October 2012 (mfm) Original submission • 1 September 2016 (ma) Revision: enzyme replacement therapy ( • 30 July 2015 (me) Review posted live • 4 October 2012 (mfm) Original submission ## References ## Literature Cited	[]	30/7/2015		1/9/2016	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
lathosterolosis	lathosterolosis	[ "Sterol C-5 Desaturase Deficiency", "Sterol-C5-Desaturase Deficiency", "SC5D Deficiency", "SC5D Deficiency", "Sterol C5-Desaturase Deficiency", "Sterol-C5-Desaturase Deficiency", "Lathosterol oxidase", "SC5D", "Lathosterolosis" ]	Lathosterolosis	Pankaj Prasun, Jaya Ganesh	Summary Lathosterolosis is characterized by global developmental delays, intellectual disability, microcephaly, characteristic facial features (bitemporal narrowing, sloping forehead, epicanthal folds, ptosis, downslanting palpebral fissures, anteverted nares, broad nasal tip, long philtrum, high-arched palate, and micrognathia), cataracts, digit anomalies (postaxial polydactyly, toe syndactyly), and liver disease. The severity of liver disease can range from asymptomatic elevation of liver enzymes to cirrhosis and liver failure. The diagnosis of lathosterolosis is established in a proband by identification of elevated lathosterol on plasma sterol analysis and/or biallelic pathogenic variants in Lathosterolosis is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an	## Diagnosis Lathosterolosis Global developmental delays Intellectual disability Microcephaly Characteristic facial features, including bitemporal narrowing, sloping forehead, epicanthal folds, ptosis, downslanting palpebral fissures, anteverted nares, broad nasal tip, long philtrum, high-arched palate, and micrognathia (similar to individuals with Cataracts Digit anomalies (postaxial polydactyly, toe syndactyly) Liver disease Elevated liver enzymes (alanine aminotransferase, alkaline phosphatase, and gamma-glutamyl transferase) Elevated lathosterol level on plasma sterol analysis The diagnosis of lathosterolosis 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 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 congenital malformations, developmental delay, and liver disease, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Lathosterolosis See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small 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. • Global developmental delays • Intellectual disability • Microcephaly • Characteristic facial features, including bitemporal narrowing, sloping forehead, epicanthal folds, ptosis, downslanting palpebral fissures, anteverted nares, broad nasal tip, long philtrum, high-arched palate, and micrognathia (similar to individuals with • Cataracts • Digit anomalies (postaxial polydactyly, toe syndactyly) • Liver disease • Elevated liver enzymes (alanine aminotransferase, alkaline phosphatase, and gamma-glutamyl transferase) • Elevated lathosterol level on plasma sterol analysis ## Suggestive Findings Lathosterolosis Global developmental delays Intellectual disability Microcephaly Characteristic facial features, including bitemporal narrowing, sloping forehead, epicanthal folds, ptosis, downslanting palpebral fissures, anteverted nares, broad nasal tip, long philtrum, high-arched palate, and micrognathia (similar to individuals with Cataracts Digit anomalies (postaxial polydactyly, toe syndactyly) Liver disease Elevated liver enzymes (alanine aminotransferase, alkaline phosphatase, and gamma-glutamyl transferase) Elevated lathosterol level on plasma sterol analysis • Global developmental delays • Intellectual disability • Microcephaly • Characteristic facial features, including bitemporal narrowing, sloping forehead, epicanthal folds, ptosis, downslanting palpebral fissures, anteverted nares, broad nasal tip, long philtrum, high-arched palate, and micrognathia (similar to individuals with • Cataracts • Digit anomalies (postaxial polydactyly, toe syndactyly) • Liver disease • Elevated liver enzymes (alanine aminotransferase, alkaline phosphatase, and gamma-glutamyl transferase) • Elevated lathosterol level on plasma sterol analysis ## Establishing the Diagnosis The diagnosis of lathosterolosis 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 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 congenital malformations, developmental delay, and liver disease, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Lathosterolosis See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. ## Option 1 For an introduction to multigene panels click ## Option 2 When the phenotype is indistinguishable from many other inherited disorders characterized by congenital malformations, developmental delay, and liver disease, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Lathosterolosis See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small 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 Lathosterolosis is an ultra-rare disorder of cholesterol biosynthesis. To date, seven affected individuals have been reported [ Lathosterolosis: Frequency of Select Features Seven individuals with lathosterolosis have been described in the literature thus far. However, diagnosis was established based on histopathologic and molecular studies of a fetus aborted at 21 weeks' gestation [ Intrahepatic cholestasis caused by abnormal bile acids lead to hepatocellular and biliary damage and subsequent progression to fibrosis, cirrhosis, portal hypertension, and liver failure. There are no characteristic biopsy findings; intrahepatic cholestasis, portal and lobular hepatitis, and portal, focal, and bridging fibrosis have been described [ Rarely, features of a storage disorder may be present. One individual with lathosterolosis was described with poor weight gain, global developmental delay, progressive hepatosplenomegaly, corneal clouding, gingival hypertrophy, and death at 18 weeks of life. Autopsy showed widespread storage of mucopolysaccharides [ Chiari malformation Hydrocephalus ex vacuo Cerebral calcifications Lumbosacral meningocele Butterfly vertebra Bilobed gallbladder Severe food aversion leading to growth failure Single umbilical artery No genotype-phenotype correlations have been identified. Lathosterolosis is extremely rare; only seven individuals have been reported thus far. However, it is possible that individuals with milder manifestations have not been identified. • Chiari malformation • Hydrocephalus ex vacuo • Cerebral calcifications • Lumbosacral meningocele • Butterfly vertebra • Bilobed gallbladder • Severe food aversion leading to growth failure • Single umbilical artery ## Clinical Description Lathosterolosis is an ultra-rare disorder of cholesterol biosynthesis. To date, seven affected individuals have been reported [ Lathosterolosis: Frequency of Select Features Seven individuals with lathosterolosis have been described in the literature thus far. However, diagnosis was established based on histopathologic and molecular studies of a fetus aborted at 21 weeks' gestation [ Intrahepatic cholestasis caused by abnormal bile acids lead to hepatocellular and biliary damage and subsequent progression to fibrosis, cirrhosis, portal hypertension, and liver failure. There are no characteristic biopsy findings; intrahepatic cholestasis, portal and lobular hepatitis, and portal, focal, and bridging fibrosis have been described [ Rarely, features of a storage disorder may be present. One individual with lathosterolosis was described with poor weight gain, global developmental delay, progressive hepatosplenomegaly, corneal clouding, gingival hypertrophy, and death at 18 weeks of life. Autopsy showed widespread storage of mucopolysaccharides [ Chiari malformation Hydrocephalus ex vacuo Cerebral calcifications Lumbosacral meningocele Butterfly vertebra Bilobed gallbladder Severe food aversion leading to growth failure Single umbilical artery • Chiari malformation • Hydrocephalus ex vacuo • Cerebral calcifications • Lumbosacral meningocele • Butterfly vertebra • Bilobed gallbladder • Severe food aversion leading to growth failure • Single umbilical artery ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been identified. ## Prevalence Lathosterolosis is extremely rare; only seven individuals have been reported thus far. However, it is possible that individuals with milder manifestations have not been identified. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Another autosomal recessive disorder of cholesterol biosynthesis, Genes of Interest in the Differential Diagnosis of Lathosterolosis ## Management No clinical practice guidelines for lathosterolosis have been published. To establish the extent of disease and needs in an individual diagnosed with lathosterolosis, the evaluations summarized in Lathosterolosis: Recommended Evaluations Following Initial Diagnosis To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Liver enzymes: ALT, ALP, & GGT Liver ultrasound Liver FibroScan Clinical exam for genitourinary anomalies Renal ultrasound Community or Social work involvement for parental support Home nursing referral ALP = alkaline phosphatase; ALT = alanine aminotransferase; GGT = gamma-glutamyl transferase; MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse There is no proven effective treatment or cure for lathosterolosis. Lathosterolosis: Treatment of Manifestations 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 US; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., 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 Lathosterolosis: Recommended Surveillance Neuropsychological testing using age-appropriate standardized assessment batteries Standardized quality of life assessment tools for affected persons & parents/caregivers Liver ultrasound FibroScan Before initiating simvastatin treatment Repeat every 1-2 mos while on simvastatin to optimize simvastatin dose ALP = alkaline phosphatase; ALT = alanine aminotransferase; GGT = gamma-glutamyl transferase Avoid medications and chemicals that are hepatotoxic. It is appropriate to clarify the status of at-risk relatives of an affected individual to identify as early as possible those who would benefit from initiation of potential treatment, surveillance, and awareness of agents and circumstances to avoid. Evaluations can include: Molecular genetic testing if the pathogenic variants in the family are known; Plasma comprehensive sterol profile if the pathogenic variants in the family are not known. See Search • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Liver enzymes: ALT, ALP, & GGT • Liver ultrasound • Liver FibroScan • Clinical exam for genitourinary anomalies • Renal ultrasound • Community or • Social work involvement for parental support • Home nursing referral • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an 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 • Neuropsychological testing using age-appropriate standardized assessment batteries • Standardized quality of life assessment tools for affected persons & parents/caregivers • Liver ultrasound • FibroScan • Before initiating simvastatin treatment • Repeat every 1-2 mos while on simvastatin to optimize simvastatin dose • Molecular genetic testing if the pathogenic variants in the family are known; • Plasma comprehensive sterol profile 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 lathosterolosis, the evaluations summarized in Lathosterolosis: Recommended Evaluations Following Initial Diagnosis To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Liver enzymes: ALT, ALP, & GGT Liver ultrasound Liver FibroScan Clinical exam for genitourinary anomalies Renal ultrasound Community or Social work involvement for parental support Home nursing referral ALP = alkaline phosphatase; ALT = alanine aminotransferase; GGT = gamma-glutamyl transferase; 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 • Liver enzymes: ALT, ALP, & GGT • Liver ultrasound • Liver FibroScan • Clinical exam for genitourinary anomalies • Renal ultrasound • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations There is no proven effective treatment or cure for lathosterolosis. Lathosterolosis: Treatment of Manifestations 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 US; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., 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. • 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 baclofen, tizanidine, Botox ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the US; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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 Lathosterolosis: Recommended Surveillance Neuropsychological testing using age-appropriate standardized assessment batteries Standardized quality of life assessment tools for affected persons & parents/caregivers Liver ultrasound FibroScan Before initiating simvastatin treatment Repeat every 1-2 mos while on simvastatin to optimize simvastatin dose ALP = alkaline phosphatase; ALT = alanine aminotransferase; GGT = gamma-glutamyl transferase • Neuropsychological testing using age-appropriate standardized assessment batteries • Standardized quality of life assessment tools for affected persons & parents/caregivers • Liver ultrasound • FibroScan • Before initiating simvastatin treatment • Repeat every 1-2 mos while on simvastatin to optimize simvastatin dose ## Agents/Circumstances to Avoid Avoid medications and chemicals that are hepatotoxic. ## Evaluation of Relatives at Risk It is appropriate to clarify the status of at-risk relatives of an affected individual to identify as early as possible those who would benefit from initiation of potential treatment, surveillance, and awareness of agents and circumstances to avoid. Evaluations can include: Molecular genetic testing if the pathogenic variants in the family are known; Plasma comprehensive sterol profile if the pathogenic variants in the family are not known. See • Molecular genetic testing if the pathogenic variants in the family are known; • Plasma comprehensive sterol profile if the pathogenic variants in the family are not known. ## Therapies Under Investigation Search ## Genetic Counseling Lathosterolosis 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) 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. Molecular genetic carrier testing for at-risk relatives requires prior identification of the Note: The utility of plasma lathosterol level for carrier detection is unknown but is unlikely to be a sensitive or specific test. See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. Note: The utility of amniotic fluid sterol profile in prenatal diagnosis is unknown. Lathosterol may be normally abundant in the amniotic fluid [ Differences in perspective may exist among medical professionals and within families regarding the use 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) 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 Lathosterolosis 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) 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 • 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) 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 Molecular genetic carrier testing for at-risk relatives requires prior identification of the Note: The utility of plasma lathosterol level for carrier detection is unknown but is unlikely to be a sensitive or specific test. ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Note: The utility of amniotic fluid sterol profile in prenatal diagnosis is unknown. Lathosterol may be normally abundant in the amniotic fluid [ Differences in perspective may exist among medical professionals and within families regarding the use 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 Lathosterolosis: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Lathosterolosis ( Lathosterolosis is a disorder of cholesterol biosynthesis. It is due to deficiency of the enzyme lathosterol oxidase (sterol-C5-desaturase), encoded by ## Molecular Pathogenesis Lathosterolosis is a disorder of cholesterol biosynthesis. It is due to deficiency of the enzyme lathosterol oxidase (sterol-C5-desaturase), encoded by ## Chapter Notes Dr Pankaj Prasun is actively involved in clinical research regarding individuals with lathosterolosis and would be happy to communicate with persons who have any questions regarding diagnosis of lathosterolosis or other considerations. 7 December 2023 (sw) Review posted live 12 January 2023 (pp) Original submission • 7 December 2023 (sw) Review posted live • 12 January 2023 (pp) Original submission ## Author Notes Dr Pankaj Prasun is actively involved in clinical research regarding individuals with lathosterolosis and would be happy to communicate with persons who have any questions regarding diagnosis of lathosterolosis or other considerations. ## Revision History 7 December 2023 (sw) Review posted live 12 January 2023 (pp) Original submission • 7 December 2023 (sw) Review posted live • 12 January 2023 (pp) Original submission ## References ## Literature Cited	[]	7/12/2023			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
lbsl	lbsl	[ "LBSL", "Mitochondrial Aspartyl-tRNA Synthetase Deficiency", "LBSL", "Mitochondrial Aspartyl-tRNA Synthetase Deficiency", "Aspartate--tRNA ligase, mitochondrial", "DARS2", "Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation" ]	Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation	Marc Engelen, Truus EM Abbink, Gajja S Salomons, Marjo S van der Knaap	Summary Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) is characterized by slowly progressive cerebellar ataxia and spasticity with dorsal column dysfunction (decreased position and vibration sense) in most individuals. The neurologic dysfunction involves the legs more than the arms. The tendon reflexes are retained. Deterioration of motor skills usually starts in childhood or adolescence, but occasionally not until adulthood. Dysarthria develops over time. Occasional findings include epilepsy; learning problems; cognitive decline; and reduced consciousness, neurologic deterioration, and fever following minor head trauma. Individuals with neonatal or early-infantile onset have a severe disease course often associated with early death. Those with childhood onset have slow progression with wheelchair dependence in the teens or twenties. Adult onset is associated with slow progression and mild impairment. The clinical diagnosis of LBSL can be established in a proband with characteristic abnormalities observed on brain and spinal cord MRI using MRI-based criteria. The molecular diagnosis can be established in a proband with suggestive findings and biallelic pathogenic variants in LBSL is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a	## Diagnosis Diagnosis of leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) should be suspected in individuals with characteristic abnormalities observed on brain and spinal cord MRI [ See Signal abnormalities (abnormally low signal on T Cerebral white matter, which is either nonhomogeneous and spotty or homogeneous and confluent, with relative sparing of the directly subcortical white matter Dorsal columns and lateral corticospinal tracts of the spinal cord (Visualization of such abnormalities in the cervical spinal cord is sufficient.) Pyramids and/or decussation of the medial lemniscus in the medulla oblongata OR Profound atrophy of the cerebral hemispheres in infancy (often with numerous tortuous blood vessels at the brain surface in early stages) Splenium of the corpus callosum Posterior limb of the internal capsule Superior cerebellar peduncles Inferior cerebellar peduncles Intraparenchymal part of the trigeminal nerve Mesencephalic trigeminal tracts Anterior spinocerebellar tracts in the medulla Cerebellar white matter * NOTE: (1) Individuals with antenatal and early-infantile onset have either a cerebral cortical degeneration followed by profound cerebral atrophy or a leukoencephalopathy. The brain stem abnormalities typical of LBSL may or may not be present [ The clinical diagnosis of LBSL The molecular diagnosis of LBSL can be established in proband with suggestive findings and biallelic pathogenic variants in If molecular results are inconclusive, a functional assay to identify reduced MtAspRS enzyme activity in lymphoblasts can confirm the diagnosis [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in For an introduction to multigene panels click If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation See See Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Affected individuals are almost invariably compound heterozygous for two pathogenic variants in In a few individuals it has not been possible to determine both pathogenic variants: in four of 43 families the second pathogenic variant could not be found in gDNA; in two of three the second pathogenic variant was detected using cDNA; cells of the fourth individual were not available for isolation of mRNA for cDNA synthesis. 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. Intragenic deletion of exon 12 has been reported [ In one person fulfilling the • Signal abnormalities (abnormally low signal on T • Cerebral white matter, which is either nonhomogeneous and spotty or homogeneous and confluent, with relative sparing of the directly subcortical white matter • Dorsal columns and lateral corticospinal tracts of the spinal cord (Visualization of such abnormalities in the cervical spinal cord is sufficient.) • Pyramids and/or decussation of the medial lemniscus in the medulla oblongata • OR • Cerebral white matter, which is either nonhomogeneous and spotty or homogeneous and confluent, with relative sparing of the directly subcortical white matter • Dorsal columns and lateral corticospinal tracts of the spinal cord (Visualization of such abnormalities in the cervical spinal cord is sufficient.) • Pyramids and/or decussation of the medial lemniscus in the medulla oblongata • Profound atrophy of the cerebral hemispheres in infancy (often with numerous tortuous blood vessels at the brain surface in early stages) • Cerebral white matter, which is either nonhomogeneous and spotty or homogeneous and confluent, with relative sparing of the directly subcortical white matter • Dorsal columns and lateral corticospinal tracts of the spinal cord (Visualization of such abnormalities in the cervical spinal cord is sufficient.) • Pyramids and/or decussation of the medial lemniscus in the medulla oblongata • Splenium of the corpus callosum • Posterior limb of the internal capsule • Superior cerebellar peduncles • Inferior cerebellar peduncles • Intraparenchymal part of the trigeminal nerve • Mesencephalic trigeminal tracts • Anterior spinocerebellar tracts in the medulla • Cerebellar white matter • For an introduction to multigene panels click ## Suggestive Findings Diagnosis of leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) should be suspected in individuals with characteristic abnormalities observed on brain and spinal cord MRI [ See Signal abnormalities (abnormally low signal on T Cerebral white matter, which is either nonhomogeneous and spotty or homogeneous and confluent, with relative sparing of the directly subcortical white matter Dorsal columns and lateral corticospinal tracts of the spinal cord (Visualization of such abnormalities in the cervical spinal cord is sufficient.) Pyramids and/or decussation of the medial lemniscus in the medulla oblongata OR Profound atrophy of the cerebral hemispheres in infancy (often with numerous tortuous blood vessels at the brain surface in early stages) Splenium of the corpus callosum Posterior limb of the internal capsule Superior cerebellar peduncles Inferior cerebellar peduncles Intraparenchymal part of the trigeminal nerve Mesencephalic trigeminal tracts Anterior spinocerebellar tracts in the medulla Cerebellar white matter * NOTE: (1) Individuals with antenatal and early-infantile onset have either a cerebral cortical degeneration followed by profound cerebral atrophy or a leukoencephalopathy. The brain stem abnormalities typical of LBSL may or may not be present [ • Signal abnormalities (abnormally low signal on T • Cerebral white matter, which is either nonhomogeneous and spotty or homogeneous and confluent, with relative sparing of the directly subcortical white matter • Dorsal columns and lateral corticospinal tracts of the spinal cord (Visualization of such abnormalities in the cervical spinal cord is sufficient.) • Pyramids and/or decussation of the medial lemniscus in the medulla oblongata • OR • Cerebral white matter, which is either nonhomogeneous and spotty or homogeneous and confluent, with relative sparing of the directly subcortical white matter • Dorsal columns and lateral corticospinal tracts of the spinal cord (Visualization of such abnormalities in the cervical spinal cord is sufficient.) • Pyramids and/or decussation of the medial lemniscus in the medulla oblongata • Profound atrophy of the cerebral hemispheres in infancy (often with numerous tortuous blood vessels at the brain surface in early stages) • Cerebral white matter, which is either nonhomogeneous and spotty or homogeneous and confluent, with relative sparing of the directly subcortical white matter • Dorsal columns and lateral corticospinal tracts of the spinal cord (Visualization of such abnormalities in the cervical spinal cord is sufficient.) • Pyramids and/or decussation of the medial lemniscus in the medulla oblongata • Splenium of the corpus callosum • Posterior limb of the internal capsule • Superior cerebellar peduncles • Inferior cerebellar peduncles • Intraparenchymal part of the trigeminal nerve • Mesencephalic trigeminal tracts • Anterior spinocerebellar tracts in the medulla • Cerebellar white matter ## MRI Criteria for LBSL See Signal abnormalities (abnormally low signal on T Cerebral white matter, which is either nonhomogeneous and spotty or homogeneous and confluent, with relative sparing of the directly subcortical white matter Dorsal columns and lateral corticospinal tracts of the spinal cord (Visualization of such abnormalities in the cervical spinal cord is sufficient.) Pyramids and/or decussation of the medial lemniscus in the medulla oblongata OR Profound atrophy of the cerebral hemispheres in infancy (often with numerous tortuous blood vessels at the brain surface in early stages) Splenium of the corpus callosum Posterior limb of the internal capsule Superior cerebellar peduncles Inferior cerebellar peduncles Intraparenchymal part of the trigeminal nerve Mesencephalic trigeminal tracts Anterior spinocerebellar tracts in the medulla Cerebellar white matter * NOTE: (1) Individuals with antenatal and early-infantile onset have either a cerebral cortical degeneration followed by profound cerebral atrophy or a leukoencephalopathy. The brain stem abnormalities typical of LBSL may or may not be present [ • Signal abnormalities (abnormally low signal on T • Cerebral white matter, which is either nonhomogeneous and spotty or homogeneous and confluent, with relative sparing of the directly subcortical white matter • Dorsal columns and lateral corticospinal tracts of the spinal cord (Visualization of such abnormalities in the cervical spinal cord is sufficient.) • Pyramids and/or decussation of the medial lemniscus in the medulla oblongata • OR • Cerebral white matter, which is either nonhomogeneous and spotty or homogeneous and confluent, with relative sparing of the directly subcortical white matter • Dorsal columns and lateral corticospinal tracts of the spinal cord (Visualization of such abnormalities in the cervical spinal cord is sufficient.) • Pyramids and/or decussation of the medial lemniscus in the medulla oblongata • Profound atrophy of the cerebral hemispheres in infancy (often with numerous tortuous blood vessels at the brain surface in early stages) • Cerebral white matter, which is either nonhomogeneous and spotty or homogeneous and confluent, with relative sparing of the directly subcortical white matter • Dorsal columns and lateral corticospinal tracts of the spinal cord (Visualization of such abnormalities in the cervical spinal cord is sufficient.) • Pyramids and/or decussation of the medial lemniscus in the medulla oblongata • Splenium of the corpus callosum • Posterior limb of the internal capsule • Superior cerebellar peduncles • Inferior cerebellar peduncles • Intraparenchymal part of the trigeminal nerve • Mesencephalic trigeminal tracts • Anterior spinocerebellar tracts in the medulla • Cerebellar white matter ## Establishing the Diagnosis The clinical diagnosis of LBSL The molecular diagnosis of LBSL can be established in proband with suggestive findings and biallelic pathogenic variants in If molecular results are inconclusive, a functional assay to identify reduced MtAspRS enzyme activity in lymphoblasts can confirm the diagnosis [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in For an introduction to multigene panels click If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation See See Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Affected individuals are almost invariably compound heterozygous for two pathogenic variants in In a few individuals it has not been possible to determine both pathogenic variants: in four of 43 families the second pathogenic variant could not be found in gDNA; in two of three the second pathogenic variant was detected using cDNA; cells of the fourth individual were not available for isolation of mRNA for cDNA synthesis. 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. Intragenic deletion of exon 12 has been reported [ In one person fulfilling the • For an introduction to multigene panels click ## Clinical Diagnosis The clinical diagnosis of LBSL ## Molecular Diagnosis The molecular diagnosis of LBSL can be established in proband with suggestive findings and biallelic pathogenic variants in If molecular results are inconclusive, a functional assay to identify reduced MtAspRS enzyme activity in lymphoblasts can confirm the diagnosis [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in For an introduction to multigene panels click If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation See See Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Affected individuals are almost invariably compound heterozygous for two pathogenic variants in In a few individuals it has not been possible to determine both pathogenic variants: in four of 43 families the second pathogenic variant could not be found in gDNA; in two of three the second pathogenic variant was detected using cDNA; cells of the fourth individual were not available for isolation of mRNA for cDNA synthesis. 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. Intragenic deletion of exon 12 has been reported [ In one person fulfilling the • For an introduction to multigene panels click ## Clinical Characteristics The clinical picture of LBSL consists of slowly progressive cerebellar ataxia, spasticity, and dorsal column dysfunction, involving the legs more than the arms. Most affected individuals have decreased position and vibration sense of the legs more than the arms, leading to increased difficulty walking in the dark. Manual dexterity becomes impaired to a variable degree. To date, more than 100 individuals have been identified with biallelic pathogenic variants in Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation: Frequency of Select Features ASM = anti-seizure medication In the individuals with antenatal or early-infantile onset, motor involvement is severe and typically no or very few motor milestones are achieved [ An overview study of 66 affected individuals revealed preliminary evidence in support of a genotype-phenotype correlation [ LBSL is rare. Carrier rate in the general population is low, with the exception of Finland, where a carrier rate of 1:95 has been reported [ ## Clinical Description The clinical picture of LBSL consists of slowly progressive cerebellar ataxia, spasticity, and dorsal column dysfunction, involving the legs more than the arms. Most affected individuals have decreased position and vibration sense of the legs more than the arms, leading to increased difficulty walking in the dark. Manual dexterity becomes impaired to a variable degree. To date, more than 100 individuals have been identified with biallelic pathogenic variants in Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation: Frequency of Select Features ASM = anti-seizure medication In the individuals with antenatal or early-infantile onset, motor involvement is severe and typically no or very few motor milestones are achieved [ ## Genotype-Phenotype Correlations An overview study of 66 affected individuals revealed preliminary evidence in support of a genotype-phenotype correlation [ ## Prevalence LBSL is rare. Carrier rate in the general population is low, with the exception of Finland, where a carrier rate of 1:95 has been reported [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The classic clinical picture of leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) consists of slowly progressive cerebellar ataxia, spasticity, and dorsal column dysfunction, involving the legs more than the arms. The tendon reflexes are retained. Based on these findings alone, many disorders can be considered [ The clinical findings of ataxia and spasticity in combination with MRI abnormalities of the dorsal columns, lateral corticospinal tracts, and cerebral white matter are compatible with vitamin B Hypomyelination with brain stem and spinal cord involvement and leg spasticity (HBSL; OMIM A variant form of LBSL is characterized by antenatal or early infantile presentation and profoundly delayed or absent development and epilepsy [ Additionally, • The clinical findings of ataxia and spasticity in combination with MRI abnormalities of the dorsal columns, lateral corticospinal tracts, and cerebral white matter are compatible with vitamin B • Hypomyelination with brain stem and spinal cord involvement and leg spasticity (HBSL; OMIM ## Classic Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation The classic clinical picture of leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) consists of slowly progressive cerebellar ataxia, spasticity, and dorsal column dysfunction, involving the legs more than the arms. The tendon reflexes are retained. Based on these findings alone, many disorders can be considered [ The clinical findings of ataxia and spasticity in combination with MRI abnormalities of the dorsal columns, lateral corticospinal tracts, and cerebral white matter are compatible with vitamin B Hypomyelination with brain stem and spinal cord involvement and leg spasticity (HBSL; OMIM • The clinical findings of ataxia and spasticity in combination with MRI abnormalities of the dorsal columns, lateral corticospinal tracts, and cerebral white matter are compatible with vitamin B • Hypomyelination with brain stem and spinal cord involvement and leg spasticity (HBSL; OMIM ## Variant LBSL: Antenatal and Early-Infantile Onset A variant form of LBSL is characterized by antenatal or early infantile presentation and profoundly delayed or absent development and epilepsy [ Additionally, ## Management To establish the extent of disease and needs in an individual diagnosed with leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation Brain & spinal cord MRI & proton MRS of abnormal cerebral white matter; EEG if seizures are suspected. Use of community or Need for social work involvement for parental support; Need for home nursing referral. LBSL = leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Medical geneticist, certified genetic counselor, or certified advanced genetic nurse Treatment of Manifestations in Individuals with Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Care coordination to manage multiple subspecialty appointments, equipment, medications, & supplies ASM = anti-seizure medication; IEP = individualized education plan; PT = physical therapy Recommended Surveillance for Individuals with Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation Case reports have described neurologic deterioration following head trauma (as has been reported for several other leukodystrophies including vanishing white matter and adrenoleukodystrophy). The exact risk is not clear. No specific guidelines exist for contact sports or other activities. Affected individuals should be counseled on the above-mentioned observations and can then make an individual decision based on personal preference [ See Search Studies of muscle biopsies, fibroblasts, and lymphoblasts show no evidence of mitochondrial dysfunction; therefore, there is no rationale for the "mitochondrial cocktail" of vitamins and cofactors, often given to persons with mitochondrial dysfunction. • Brain & spinal cord MRI & proton MRS of abnormal cerebral white matter; • EEG if seizures are suspected. • Use of community or • Need for social work involvement for parental support; • Need for home nursing referral. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Care coordination to manage multiple subspecialty appointments, equipment, medications, & supplies ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation Brain & spinal cord MRI & proton MRS of abnormal cerebral white matter; EEG if seizures are suspected. Use of community or Need for social work involvement for parental support; Need for home nursing referral. LBSL = leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Medical geneticist, certified genetic counselor, or certified advanced genetic nurse • Brain & spinal cord MRI & proton MRS of abnormal cerebral white matter; • EEG if seizures are suspected. • 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 Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Care coordination to manage multiple subspecialty appointments, equipment, medications, & supplies ASM = anti-seizure medication; IEP = individualized education plan; PT = physical therapy • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Care coordination to manage multiple subspecialty appointments, equipment, medications, & supplies ## Surveillance Recommended Surveillance for Individuals with Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation ## Agents/Circumstances to Avoid Case reports have described neurologic deterioration following head trauma (as has been reported for several other leukodystrophies including vanishing white matter and adrenoleukodystrophy). The exact risk is not clear. No specific guidelines exist for contact sports or other activities. Affected individuals should be counseled on the above-mentioned observations and can then make an individual decision based on personal preference [ ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Other Studies of muscle biopsies, fibroblasts, and lymphoblasts show no evidence of mitochondrial dysfunction; therefore, there is no rationale for the "mitochondrial cocktail" of vitamins and cofactors, often given to persons with mitochondrial dysfunction. ## Genetic Counseling Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) is inherited in an autosomal recessive manner. The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a The clinical manifestations in sibs with biallelic Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Carrier testing for at-risk family members requires prior identification of the The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • The clinical manifestations in sibs with biallelic • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a The clinical manifestations in sibs with biallelic Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • 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 • The clinical manifestations in sibs with biallelic • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Carrier Detection Carrier testing for at-risk family members requires prior identification of the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom • • • • • • • • • • United Kingdom • • • • • ## Molecular Genetics Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation ( Almost all affected individuals have a pathogenic variant that affects splicing of exon 3. Incorrect splicing of this exon results in a frameshift in the reading frame and nonsense-mediated decay of the wrongly spliced mRNA. It should be noted that these pathogenic variants upstream of exon 3 diminish but do not completely abolish correct splicing. As a result, a low amount of wild type protein is produced in the cells of an affected individual. A total lack of mtAspRS activity is thought to be incompatible with life. Another common pathogenic variant, Notable Variants listed in the table have been provided by the authors. Several individuals share haplotypes involving five or six microsatellite markers on chromosome 1p25. The pathogenic variants c.492+2T>C and c.455G>T are correlated with two of these haplotypes and are often seen in affected individuals of northeastern European origin [ Variant designation that does not conform to current naming conventions; no breakpoints were delineated in the original report. ## Molecular Pathogenesis Almost all affected individuals have a pathogenic variant that affects splicing of exon 3. Incorrect splicing of this exon results in a frameshift in the reading frame and nonsense-mediated decay of the wrongly spliced mRNA. It should be noted that these pathogenic variants upstream of exon 3 diminish but do not completely abolish correct splicing. As a result, a low amount of wild type protein is produced in the cells of an affected individual. A total lack of mtAspRS activity is thought to be incompatible with life. Another common pathogenic variant, Notable Variants listed in the table have been provided by the authors. Several individuals share haplotypes involving five or six microsatellite markers on chromosome 1p25. The pathogenic variants c.492+2T>C and c.455G>T are correlated with two of these haplotypes and are often seen in affected individuals of northeastern European origin [ Variant designation that does not conform to current naming conventions; no breakpoints were delineated in the original report. ## Chapter Notes We would like to thank Drs Ali Fatemi and Amena Smith for ongoing collaboration in LBSL research. Truus EM Abbink, PhD (2021-present)Marc Engelen, MD, PhD (2021-present)Gajja S Salomons, PhD (2015-present)Gert C Scheper, PhD; Vrije Universiteit Medical Center, Amsterdam (2010-2015)Marjo S van der Knaap, MD, PhD (2010-present) 18 February 2021 (sw) Comprehensive update posted live 12 February 2015 (me) Comprehensive update posted live 25 May 2010 (me) Review posted live 22 February 2010 (mvdk) Original submission • 18 February 2021 (sw) Comprehensive update posted live • 12 February 2015 (me) Comprehensive update posted live • 25 May 2010 (me) Review posted live • 22 February 2010 (mvdk) Original submission ## Author Notes ## Acknowledgments We would like to thank Drs Ali Fatemi and Amena Smith for ongoing collaboration in LBSL research. ## Author History Truus EM Abbink, PhD (2021-present)Marc Engelen, MD, PhD (2021-present)Gajja S Salomons, PhD (2015-present)Gert C Scheper, PhD; Vrije Universiteit Medical Center, Amsterdam (2010-2015)Marjo S van der Knaap, MD, PhD (2010-present) ## Revision History 18 February 2021 (sw) Comprehensive update posted live 12 February 2015 (me) Comprehensive update posted live 25 May 2010 (me) Review posted live 22 February 2010 (mvdk) Original submission • 18 February 2021 (sw) Comprehensive update posted live • 12 February 2015 (me) Comprehensive update posted live • 25 May 2010 (me) Review posted live • 22 February 2010 (mvdk) Original submission ## References ## Literature Cited T Axial FLAIR images of the brain (A-C) in a young individual (toddler) with early presentation of LBSL show abnormal signal intensity (with some areas of rarefaction) of almost all cerebral white matter, only sparing the directly subcortical areas. The internal capsule (B), brain stem (C), cerebellum (C), and spinal cord (D) are spared. Images for this figure courtesy of Dr Menno Stellingwerff The MRI in a severe, early-onset form of LBSL at age two days (A, B, C) and age five months (D, E, F) shows striking progression of abnormalities. At two days, sagittal T Images for this figure courtesy of Dr Menno Stellingwerff	[ "L Bonnefond, A Fender, J Rudinger-Thirion, R Giegé, C Florentz, M Sissler. Toward the full set of human mitochondrial aminoacyl-tRNA synthetases: characterization of AspRS and TyrRS.. Biochemistry 2005;44:4805-16", "A Budhram, SK Pandey. Activation of cerebral X-linked adrenoleukodystrophy after head trauma.. Can J Neurol Sci 2017;44:597-8", "M Delarue, A Poterszman, S Nikonov, M Garber, D Moras, JC Thierry. Crystal structure of a prokaryotic aspartyl tRNA-synthetase.. EMBO J 1994;13:3219-29", "P Isohanni, T Linnankivi, J Buzkova, T Lonnqvist, H Pihko, L Valanne, PJ Tienari, I Elovaara, T Pirttila, M Reunanen, K Koivisto, S Marjavaara, A Suomalainen. DARS2 mutations in mitochondrial leukoencephalopathy and multiple sclerosis.. J Med Genet 2010;47:66-70", "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", "C Köhler, C Heyer, S Hoffjan, S Stemmler, T Lücke, C Thielsa, A Kohlschütter, U Lobele, R Horvath, S Kleinle, A Benet-Pages, A Abicht. Early-onset leukoencephalopathy due to a homozygous missense mutation in the DARS2 gene.. Mol Cell Probes 2015;29:319-22", "MY Lan, YY Chang, TH Yeh, TK Lin, CS Lu. Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) with a novel. J Neurol Sci 2017;372:229-31", "ER Locatelli, R Laureno, P Ballard, AS Mark. MRI in vitamin B12 deficiency myelopathy.. Can J Neurol Sci. 1999;26:60-3", "MI Mendes, LMC Green, E Bertini, D Tonduti, C Aiello, D Smith, E Salsano, S Beerepoot, J Hertecant, S von Spiczak, JH Livingston, L Emrick, J Fraser, L Russell, G Bernard, S Magri, D Di Bella, F Taroni, MK Koenig, I Moroni, G Cappuccio, N Brunetti-Pierri, J Rhee, BA Mendelsohn, I Helbig, K Helbig, H Muhle, O Ismayl, AL Vanderver, GS Salomons, MS van der Knaap, NI Wolf. RARS1-related hypomyelinating leukodystrophy: expanding the spectrum.. Ann Clin Transl Neurol 2020;7:83-93", "N Miyake, S Yamashita, K Kurosawa, S Miyatake, Y Tsurusaki, H Doi, H Saitsu, N. Matsumoto. A novel homozygous mutation of DARS2 may cause a severe LBSL variant.. Clin Genet. 2011;80:293-6", "F Mochel, C Delorme, V Czernecki, J Froger, F Cormier, E Ellie, N Fegueux, S Lehéricy, S Lumbroso, R Schiffmann, P Aubourg, E Roze, P Labauge, S Nguyen. Haematopoietic stem cell transplantation in CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia.. J Neurol Neurosurg Psychiatry 2019;90:1375-6", "R N'Gbo N'Gbo Ikazabo, C Mostosi, P Jissendi, M Labaisse, I Vandernoot. A new DARS2 mutation discovered in an adult patient.. Case Rep Neurol 2020;12:107-13", "L Parodi, G Coarelli, G Stevanin, A Brice, A Durr. Hereditary ataxias and paraparesias: clinical and genetic update.. Curr Opin Neurol. 2018;31:462-71", "GC Scheper, T van der Klok, RJ van Andel, CG van Berkel, M Sissler, J Smet, TI Muravina, SV Serkov, G Uziel, M Bugiani, R Schiffmann, I Krageloh-Mann, JA Smeitink, C Florentz, CR Van, JC Pronk, MS van der Knaap. Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation.. Nat Genet 2007;39:534-9", "SV Serkov, IN Pronin, OV Bykova, OI Maslova, NV Arutyunov, TI Muravina, VN Kornienko, LM Fadeeva, H Marks, C Bonnemann, R Schiffmann, MS van der Knaap. Five patients with a recently described novel leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate.. Neuropediatrics 2004;35:1-5", "K Shimojima, T Higashiguchi, T Kishimoto, S Miyatake, N Miyake, J Takanashi, N Matsumoto, T. Yamamoto. A novel DARS2 mutation in a Japanese patient with leukoencephalopathy with brainstem and spinal cord involvement but no lactate elevation.. Hum Genome Var. 2017;4:17051", "C Simons, LB Griffin, G Helman, G Golas, A Pizzino, M Bloom, JL Murphy, J Crawford, SH Evans, S Topper, MT Whitehead, JM Schreiber, KA Chapman, C Tifft, KB Lu, H Gamper, M Shigematsu, RJ Taft, A Antonellis, YM Hou, A Vanderver. Loss-of-function alanyl-tRNA synthetase mutations cause an autosomal-recessive early-onset epileptic encephalopathy with persistent myelination defect.. Am J Hum Genet. 2015;96:675-81", "ME Steenweg, PJ Pouwels, NI Wolf, WN van Wieringen, F Barkhof, MS van der Knaap. Leucoencephalopathy with brainstem and spinal cord involvement and high lactate: quantitative magnetic resonance imaging.. Brain. 2011;134:3333-41", "ME Steenweg, L van Berge, CG van Berkel, IF de Coo, IK Temple, K Brockmann, CI Mendonça, S Vojta, A Kolk, D Peck, L Carr, G Uziel, A Feigenbaum, S Blaser, GC Scheper, MS van der Knaap. Early-onset LBSL: how severe does it get?. Neuropediatrics 2012;43:332-8", "MD Stellingwerff, S Figuccia, E Bellacchio, EK Alvarez, C Castiglioni, P Topaloglu, CA Stutterd, CE Erasmus, A Sanchez-Valle, S Lebon, S Hughes, T Schmitt-Mechelke, G Vasco, G Chow, E Rahikkala, C Dallabona, C Okuma, C Aiello, P Goffrini, TEM Abbink, ES Bertini, MS Van der Knaap. LBSL: case series and DARS2 variant analysis in early severe forms with unexpected presentations.. Neurol Genet. 2021;7", "M Synofzik, J Schicks, T Lindig, S Biskup, T Schmidt, J Hansel, F Lehmann-Horn, L Schöls. Acetazolamide-responsive exercise-induced episodic ataxia associated with a novel homozygous DARS2 mutation.. J Med Genet. 2011;48:713-5", "RJ Taft, A Vanderver, RJ Leventer, SA Damiani, C Simons, SM Grimmond, D Miller, J Schmidt, PJ Lockhart, K Pope, K Ru, J Crawford, T Rosser, IF de Coo, M Juneja, IC Verma, P Prabhakar, S Blaser, J Raiman, PJ Pouwels, MR Bevova, TE Abbink, MS van der Knaap, NI Wolf. Mutations in DARS cause hypomyelination with brain stem and spinal cord involvement and leg spasticity.. Am J Hum Genet. 2013;92:774-80", "DG Távora, M Nakayama, RL Gama, TC Alvim, D Portugal, EA Comerlato. Leukoencephalopathy with brainstem and spinal cord involvement and high brain lactate: report of three Brazilian patients.. Arq Neuropsiquiatr 2007;65:506-11", "K Uluc, O Baskan, KA Yildirim, S Ozsahin, M Koseoglu, B Isak, GC Scheper, DI Gunal, MS van der Knaap. Leukoencephalopathy with brain stem and spinal cord involvement and high lactate: a genetically proven case with distinct MRI findings.. J Neurol Sci 2008;273:118-22", "L van Berge, EM Hamilton, T Linnankivi, G Uziel, ME Steenweg, P Isohanni, NI Wolf, I Krägeloh-Mann, NJ Brautaset, PI Andrews, BA de Jong, M al Ghamdi, WN van Wieringen, BA Tannous, E Hulleman, T Würdinger, CG van Berkel, E Polder, TE Abbink, EA Struys, GC Scheper, MS van der Knaap. Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation: clinical and genetic characterization and target for therapy.. Brain. 2014;137:1019-29", "MS van der Knaap, P van der Voorn, F Barkhof, R van Coster, I Krageloh-Mann, A Feigenbaum, S Blaser, JS Vles, P Rieckmann, PJ Pouwels. A new leukoencephalopathy with brainstem and spinal cord involvement and high lactate.. Ann Neurol 2003;53:252-8", "MS van der Knaap, JC Pronk, GC Scheper. Vanishing white matter disease.. Lancet Neurol 2006;5:413-23", "MS van der Knaap, R Schiffman, F Mochel, NI Wolf. Diagnosis, prognosis and treatment of leukodystrophies.. Lancet Neurol. 2019;18:962-72", "HJ Vernon, LA Bindoff. Mitochondrial ataxias.. Handb Clin Neurol 2018;155:129-41", "A Yahia, L Elsayed, A Babai, MA Salih, S Misbah El-Sadig, M Amin, M Koko, R Abubakr, R Idris, SOMA Taha, SA Elmalik, A Brice, A Eltahir Ahmed, G Stevanin. Intra-familial phenotypic heterogeneity in a Sudanese family with DARS2-related leukoencephalopathy, brainstem and spinal cord involvement and lactate elevation: a case report.. BMC Neurology 2018;18:175", "S Yamashita, N Miyake, N Matsumoto, H Osaka, M Iai, N Aida, Y Tanaka. Neuropathology of leukoencephalopathy with brainstem and spinal cord involvement and high lactate caused by a homozygous mutation of DARS2.. Brain Dev 2013;35:312-6", "I Yazici Gencdal, A Dincer, O Obuz, Z. Yapici. Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL): a case with long-term follow-up.. Neurologist. 2020;25:144-7", "A Yelam, E Nagarajan, M Chuquilin, R Govindarajan. Leucoencephalopathy with brain stem and spinal cord involvement and lactate elevation: a novel mutation in the DARS2 gene. BMJ Case Rep. 2019;12", "J Zhang, M Liu, Z Zhang, L Zhou, W Kong, Y Jiang, J Wang, J Xiao, Y Wu. Genotypic spectrum and natural history of cavitating leukoencephalopathies in childhood.. Pediatr Neurol 2019;94:38-47" ]	25/5/2010	18/2/2021		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
lca-ov	lca-ov	[ "EOSRD", "LCA", "LCA", "EOSRD", "Aryl-hydrocarbon-interacting protein-like 1", "Calcium-binding protein 4", "Centrosomal protein of 290 kDa", "Centrosome-associated protein ALMS1", "Clusterin-associated protein 1", "Cone-rod homeobox protein", "Death domain-containing protein 1", "Growth/differentiation factor 6", "Homeobox protein OTX2", "Inosine-5'-monophosphate dehydrogenase 1", "Intraflagellar transport protein 140 homolog", "Inward rectifier potassium channel 13", "IQ calmodulin-binding motif-containing protein 1", "Lebercilin", "Lecithin retinol acyltransferase", "Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1", "Peripherin-2", "Protein crumbs homolog 1", "Protein RD3", "Retinal guanylyl cyclase 1", "Retinoid isomerohydrolase", "Retinol dehydrogenase 12", "Spermatogenesis-associated protein 7", "Tubby-related protein 1", "X-linked retinitis pigmentosa GTPase regulator-interacting protein 1", "AIPL1", "ALMS1", "CABP4", "CEP290", "CLUAP1", "CRB1", "CRX", "DTHD1", "GDF6", "GUCY2D", "IFT140", "IMPDH1", "IQCB1", "KCNJ13", "LCA5", "LRAT", "NMNAT1", "OTX2", "PRPH2", "RD3", "RDH12", "RPE65", "RPGRIP1", "SPATA7", "TULP1", "Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy", "Overview" ]	Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy Overview	Neruban Kumaran, Mark E Pennesi, Paul Yang, Karmen M Trzupek, Catherine Schlechter, Anthony T Moore, Richard G Weleber, Michel Michaelides	Summary The purpose of this overview is to: Describe the Review the Provide an Inform (when possible) Inform	## Clinical Characteristics of Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy Leber congenital amaurosis (LCA) / early-onset severe retinal dystrophy (EOSRD) comprises a spectrum of inherited retinal disorders that ranges from LCA at the severe end to EOSRD at the milder end. The fundus in LCA/EOSRD can appear normal at presentation or show a variety of retinal abnormalities including pigmentary retinopathy, white deposits at the level of the retinal pigment epithelium, vascular attenuation, or pseudopapilledema and macular atrophy. Those with a normal fundus appearance at birth usually develop pigmentary retinopathy, optic disc pallor, and vascular attenuation with time. Other late changes include optic disc drusen, keratoconus, and lens opacities. Some genetic subtypes have a characteristic retinal phenotype. The rate of visual loss varies, and some genes have been associated with faster progression (see Persons with LCA/EOSRD usually present with isolated ocular signs and symptoms and have manifestations that remain confined to the eye. Some infants who present with visual impairment may later develop other systemic issues, particularly kidney disease. Nephronophthisis with subsequent end-stage kidney disease can be seen with certain genetic subtypes of LCA/EOSRD (e.g., Retinal Disorders to be Considered in the Differential Diagnosis of LCA/EOSRD Absent / markedly reduced cone responses w/normal rod ERG responses Stationary natural history Non-recordable / markedly reduced full-field ERGs Progressive disease Clinical exam (hypopigmentation of skin, hair, eyebrows/eyelashes, iris, retina) Retinal imaging (OCT & FAF); OCT can highlight foveal hypoplasia Normal ERG & chiasmal misrouting on VEP Infantile NCL presents w/congenital or early-onset (age <6 mos) blindness. Late-infantile & juvenile-onset NCL present at ages 2-4 & ≥6 yrs, respectively. ERG can show a negative waveform. NCL is assoc w/neurocognitive decline & epilepsy. Presents w/severe visual impairment, ocular motor abnormalities Characteristic MRI appearance incl "molar tooth sign" Nephronophthisis in later childhood Sensorineural deafness Dysmorphic features Developmental delay Hepatomegaly Early death Infantile-onset nystagmus Photophobia Cone-rod dystrophy Childhood obesity Hyperinsulinemia Type 2 diabetes mellitus Hepatic dysfunction Heart failure Sensorineural hearing loss Kidney failure Infantile nystagmus Bull's-eye maculopathy ↓ responses on ERG Adapted from AD = autosomal dominant; AR = autosomal recessive; EOSRD = early-onset severe retinal dystrophy; ERG = electroretinography; FAF = fundus autofluorescence; LCA = Leber congenital amaurosis; MOI = mode of inheritance; OA = ocular albinism; OCA = oculocutaneous albinism; OCT = optical coherence tomography; VEP = visual evoked potentials; XL = X-linked See OMIM Phenotypic Series: X-linked ocular albinism is caused by pathogenic variants in Pathogenic variants in The NCLs are inherited in an autosomal recessive manner; adult-onset NCL can also be inherited in an autosomal dominant manner. Pathogenic variants in Joubert syndrome is predominantly inherited in an autosomal recessive manner. Joubert syndrome caused by pathogenic variants in Pathogenic variants in • Absent / markedly reduced cone responses w/normal rod ERG responses • Stationary natural history • Non-recordable / markedly reduced full-field ERGs • Progressive disease • Clinical exam (hypopigmentation of skin, hair, eyebrows/eyelashes, iris, retina) • Retinal imaging (OCT & FAF); OCT can highlight foveal hypoplasia • Normal ERG & chiasmal misrouting on VEP • Infantile NCL presents w/congenital or early-onset (age <6 mos) blindness. • Late-infantile & juvenile-onset NCL present at ages 2-4 & ≥6 yrs, respectively. • ERG can show a negative waveform. • NCL is assoc w/neurocognitive decline & epilepsy. • Presents w/severe visual impairment, ocular motor abnormalities • Characteristic MRI appearance incl "molar tooth sign" • Nephronophthisis in later childhood • Sensorineural deafness • Dysmorphic features • Developmental delay • Hepatomegaly • Early death • Infantile-onset nystagmus • Photophobia • Cone-rod dystrophy • Childhood obesity • Hyperinsulinemia • Type 2 diabetes mellitus • Hepatic dysfunction • Heart failure • Sensorineural hearing loss • Kidney failure • Infantile nystagmus • Bull's-eye maculopathy • ↓ responses on ERG ## Differential Diagnosis Retinal Disorders to be Considered in the Differential Diagnosis of LCA/EOSRD Absent / markedly reduced cone responses w/normal rod ERG responses Stationary natural history Non-recordable / markedly reduced full-field ERGs Progressive disease Clinical exam (hypopigmentation of skin, hair, eyebrows/eyelashes, iris, retina) Retinal imaging (OCT & FAF); OCT can highlight foveal hypoplasia Normal ERG & chiasmal misrouting on VEP Infantile NCL presents w/congenital or early-onset (age <6 mos) blindness. Late-infantile & juvenile-onset NCL present at ages 2-4 & ≥6 yrs, respectively. ERG can show a negative waveform. NCL is assoc w/neurocognitive decline & epilepsy. Presents w/severe visual impairment, ocular motor abnormalities Characteristic MRI appearance incl "molar tooth sign" Nephronophthisis in later childhood Sensorineural deafness Dysmorphic features Developmental delay Hepatomegaly Early death Infantile-onset nystagmus Photophobia Cone-rod dystrophy Childhood obesity Hyperinsulinemia Type 2 diabetes mellitus Hepatic dysfunction Heart failure Sensorineural hearing loss Kidney failure Infantile nystagmus Bull's-eye maculopathy ↓ responses on ERG Adapted from AD = autosomal dominant; AR = autosomal recessive; EOSRD = early-onset severe retinal dystrophy; ERG = electroretinography; FAF = fundus autofluorescence; LCA = Leber congenital amaurosis; MOI = mode of inheritance; OA = ocular albinism; OCA = oculocutaneous albinism; OCT = optical coherence tomography; VEP = visual evoked potentials; XL = X-linked See OMIM Phenotypic Series: X-linked ocular albinism is caused by pathogenic variants in Pathogenic variants in The NCLs are inherited in an autosomal recessive manner; adult-onset NCL can also be inherited in an autosomal dominant manner. Pathogenic variants in Joubert syndrome is predominantly inherited in an autosomal recessive manner. Joubert syndrome caused by pathogenic variants in Pathogenic variants in • Absent / markedly reduced cone responses w/normal rod ERG responses • Stationary natural history • Non-recordable / markedly reduced full-field ERGs • Progressive disease • Clinical exam (hypopigmentation of skin, hair, eyebrows/eyelashes, iris, retina) • Retinal imaging (OCT & FAF); OCT can highlight foveal hypoplasia • Normal ERG & chiasmal misrouting on VEP • Infantile NCL presents w/congenital or early-onset (age <6 mos) blindness. • Late-infantile & juvenile-onset NCL present at ages 2-4 & ≥6 yrs, respectively. • ERG can show a negative waveform. • NCL is assoc w/neurocognitive decline & epilepsy. • Presents w/severe visual impairment, ocular motor abnormalities • Characteristic MRI appearance incl "molar tooth sign" • Nephronophthisis in later childhood • Sensorineural deafness • Dysmorphic features • Developmental delay • Hepatomegaly • Early death • Infantile-onset nystagmus • Photophobia • Cone-rod dystrophy • Childhood obesity • Hyperinsulinemia • Type 2 diabetes mellitus • Hepatic dysfunction • Heart failure • Sensorineural hearing loss • Kidney failure • Infantile nystagmus • Bull's-eye maculopathy • ↓ responses on ERG ## Causes of Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy To date, mutation of 24 genes accounts for 70%-80% of individuals with Leber congenital amaurosis (LCA) / early-onset severe retinal dystrophy (EOSRD) ( Leber Congenital Amaurosis (LCA) / Early-Onset Severe Retinal Dystrophy (EOSRD): Genes and Distinguishing Clinical Features Relative preservation of outer retinal structure before age 4 yrs Progressive loss from birth to total macular atrophy Significant variability; severe VA loss in most No clear progression in 1st decade On OCT: residual outer retinal structure often present until 4th decade Assoc w/nephronophthisis, Joubert syndrome Phenotypes: LCA/ EOSRD, RP, & others Severity & rate of progression vary significantly. Nummular pigmentation Maculopathy Relative preservation of para-arteriolar RPE Early profound visual loss Lack of color perception Significant photophobia Substantial residual rod-driven visual function Majority have early-onset profound vision loss & extensive maculopathy. Minority have milder phenotype. Early, widespread RPE & retinal atrophy Minimal intraretinal pigmentation in early childhood Dense intraretinal bone-spicule pigmentation developing over time Early progressive macular atrophy On OCT: macular excavation On FAF: loss of autofluorescence Profound night blindness from birth Minimal nystagmus Poor color discrimination Residual cone-mediated vision in 1st 3 decades w/progressive visual field loss Adapted from ? = unknown; FAF = fundus autofluorescence; OCT = optical coherence tomography; RP = retinitis pigmentosa; RPE = retinal pigment epithelium; VA = visual acuity Genes are listed alphabetically. Retinitis pigmentosa may or may not be accompanied by Coats-like vasculopathy, later-onset macular dystrophy, and isolated autosomal recessive foveal retinoschisis. • Relative preservation of outer retinal structure before age 4 yrs • Progressive loss from birth to total macular atrophy • Significant variability; severe VA loss in most • No clear progression in 1st decade • On OCT: residual outer retinal structure often present until 4th decade • Assoc w/nephronophthisis, Joubert syndrome • Phenotypes: LCA/ EOSRD, RP, & others • Severity & rate of progression vary significantly. • Nummular pigmentation • Maculopathy • Relative preservation of para-arteriolar RPE • Early profound visual loss • Lack of color perception • Significant photophobia • Substantial residual rod-driven visual function • Majority have early-onset profound vision loss & extensive maculopathy. • Minority have milder phenotype. • Early, widespread RPE & retinal atrophy • Minimal intraretinal pigmentation in early childhood • Dense intraretinal bone-spicule pigmentation developing over time • Early progressive macular atrophy • On OCT: macular excavation • On FAF: loss of autofluorescence • Profound night blindness from birth • Minimal nystagmus • Poor color discrimination • Residual cone-mediated vision in 1st 3 decades w/progressive visual field loss ## Evaluation Strategies to Identify the Genetic Cause of Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy in a Proband Establishing a specific genetic cause of Leber congenital amaurosis (LCA) / early-onset severe retinal dystrophy (EOSRD): Can aid in discussions of prognosis (which are beyond the scope of this Usually involves a medical history, physical examination, laboratory testing, family history, and genomic/genetic testing. Note: (1) Single-gene testing (sequence analysis of a given gene, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended. (2) Single-gene sequence analysis and/or targeted deletion/duplication analysis MAY be considered if previous testing has identified a heterozygous pathogenic variant in a recessive LCA-associated gene. Of note, large deletions, insertions, and duplications very rarely account for the presumed second variant. For an introduction to multigene panels click Note: Unlike exome sequencing, genome sequencing can identify noncoding variants. Although most confirmed pathogenic variants identified by genome sequencing are within exons [ For an introduction to comprehensive genomic testing click • Can aid in discussions of prognosis (which are beyond the scope of this • Usually involves a medical history, physical examination, laboratory testing, family history, and genomic/genetic testing. • For an introduction to multigene panels click • Note: Unlike exome sequencing, genome sequencing can identify noncoding variants. Although most confirmed pathogenic variants identified by genome sequencing are within exons [ • For an introduction to comprehensive genomic testing click ## Medical Management of Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy Based on Genetic Cause Management of most forms of Leber congenital amaurosis (LCA) / early-onset severe retinal dystrophy (EOSRD) is symptomatic. The only form of LCA/EOSRD for which specific therapy (gene replacement therapy) is available is Children and their parents should be referred to programs for visually impaired children within their state or locality. Subretinal gene therapy administration for LCA has been investigated most extensively in The Phase I/II clinical trials identified varied improvements in aspects of sight [ The Phase III trial of subretinal administration of an AAV2/2 vector has reported benefit at one year, reaching its primary end point for efficacy with improved performance on a novel test of multiluminance mobility [ Following successful gene supplementation therapy in experimental models of Children with LCA/EOSRD who have developmental delay should be referred to a developmental pediatrician and enrolled in a continuing program of care and support. Advice on developmental delay / intellectual disability management issues will vary from country to country, or even region to region within a country, depending on support services available. Overarching principles should include the following: Involving child development and educational specialists at the earliest available opportunity, often with specialist teachers / schools for the visually impaired Early referral to low vision services to access low visual aids, especially with improving technologies, such as the refreshable braille display As affected individuals grow older, identifying further assistance (including financial or employment assistance), which in some countries is available through certification/registration processes Some countries have registration services to record population data on the causes and effects of visual impairment. Note: The following information represents typical management recommendations for individuals with developmental delay / intellectual disability management issues in the United States. Physical therapy is recommended to maximize mobility. Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications (e.g., to treat attention-deficit/hyperactivity disorder) when necessary. • The Phase I/II clinical trials identified varied improvements in aspects of sight [ • The Phase III trial of subretinal administration of an AAV2/2 vector has reported benefit at one year, reaching its primary end point for efficacy with improved performance on a novel test of multiluminance mobility [ • Involving child development and educational specialists at the earliest available opportunity, often with specialist teachers / schools for the visually impaired • Early referral to low vision services to access low visual aids, especially with improving technologies, such as the refreshable braille display • As affected individuals grow older, identifying further assistance (including financial or employment assistance), which in some countries is available through certification/registration processes • Physical therapy is recommended to maximize mobility. • Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## Visual Impairment Children and their parents should be referred to programs for visually impaired children within their state or locality. Subretinal gene therapy administration for LCA has been investigated most extensively in The Phase I/II clinical trials identified varied improvements in aspects of sight [ The Phase III trial of subretinal administration of an AAV2/2 vector has reported benefit at one year, reaching its primary end point for efficacy with improved performance on a novel test of multiluminance mobility [ Following successful gene supplementation therapy in experimental models of • The Phase I/II clinical trials identified varied improvements in aspects of sight [ • The Phase III trial of subretinal administration of an AAV2/2 vector has reported benefit at one year, reaching its primary end point for efficacy with improved performance on a novel test of multiluminance mobility [ ## Developmental Delay / Intellectual Disability Management Issues Children with LCA/EOSRD who have developmental delay should be referred to a developmental pediatrician and enrolled in a continuing program of care and support. Advice on developmental delay / intellectual disability management issues will vary from country to country, or even region to region within a country, depending on support services available. Overarching principles should include the following: Involving child development and educational specialists at the earliest available opportunity, often with specialist teachers / schools for the visually impaired Early referral to low vision services to access low visual aids, especially with improving technologies, such as the refreshable braille display As affected individuals grow older, identifying further assistance (including financial or employment assistance), which in some countries is available through certification/registration processes Some countries have registration services to record population data on the causes and effects of visual impairment. Note: The following information represents typical management recommendations for individuals with developmental delay / intellectual disability management issues in the United States. • Involving child development and educational specialists at the earliest available opportunity, often with specialist teachers / schools for the visually impaired • Early referral to low vision services to access low visual aids, especially with improving technologies, such as the refreshable braille display • As affected individuals grow older, identifying further assistance (including financial or employment assistance), which in some countries is available through certification/registration processes ## Motor Dysfunction Physical therapy is recommended to maximize mobility. Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • Physical therapy is recommended to maximize mobility. • Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## Social/Behavioral Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications (e.g., to treat attention-deficit/hyperactivity disorder) when necessary. ## Genetic Counseling for Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy Leber congenital amaurosis (LCA) / early-onset severe retinal dystrophy (EOSRD) is typically inherited in an autosomal recessive manner. Rarely, LCA/EOSRD is inherited in an autosomal dominant manner as a result of a heterozygous pathogenic variant in Note: In the estimated 30% of individuals with LCA/EOSRD in whom no molecular diagnosis is found, the mode of inheritance is most likely autosomal recessive with a small likelihood of autosomal dominant inheritance resulting from a The parents of an affected child are obligate heterozygotes (i.e., carriers of one LCA/EOSRD-causing allelic variant). 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. Some children diagnosed with autosomal dominant LCA/EOSRD have an affected parent. Most children diagnosed with autosomal dominant LCA/EOSRD have the disorder as the result of a Molecular genetic testing is recommended for the parents of a proband with an apparent If a parent of 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 LCA/EOSRD-causing allelic 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 LCA/EOSRD-causing allelic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. Once the LCA/EOSRD-causing allelic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. • The parents of an affected child are obligate heterozygotes (i.e., carriers of one LCA/EOSRD-causing allelic variant). • 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. • Some children diagnosed with autosomal dominant LCA/EOSRD have an affected parent. • Most children diagnosed with autosomal dominant LCA/EOSRD have the disorder as the result of a • Molecular genetic testing is recommended for the parents of a proband with an apparent • If a parent of 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 LCA/EOSRD-causing allelic 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 LCA/EOSRD-causing allelic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. ## Mode of Inheritance Leber congenital amaurosis (LCA) / early-onset severe retinal dystrophy (EOSRD) is typically inherited in an autosomal recessive manner. Rarely, LCA/EOSRD is inherited in an autosomal dominant manner as a result of a heterozygous pathogenic variant in Note: In the estimated 30% of individuals with LCA/EOSRD in whom no molecular diagnosis is found, the mode of inheritance is most likely autosomal recessive with a small likelihood of autosomal dominant inheritance resulting from a ## Autosomal Recessive Inheritance – Risk to Family Members The parents of an affected child are obligate heterozygotes (i.e., carriers of one LCA/EOSRD-causing allelic variant). 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 LCA/EOSRD-causing allelic variant). • 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. ## Autosomal Dominant Inheritance – Risk to Family Members Some children diagnosed with autosomal dominant LCA/EOSRD have an affected parent. Most children diagnosed with autosomal dominant LCA/EOSRD have the disorder as the result of a Molecular genetic testing is recommended for the parents of a proband with an apparent If a parent of 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 LCA/EOSRD-causing allelic 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 LCA/EOSRD-causing allelic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. • Some children diagnosed with autosomal dominant LCA/EOSRD have an affected parent. • Most children diagnosed with autosomal dominant LCA/EOSRD have the disorder as the result of a • Molecular genetic testing is recommended for the parents of a proband with an apparent • If a parent of 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 LCA/EOSRD-causing allelic 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 LCA/EOSRD-causing allelic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. ## Prenatal Testing and Preimplantation Genetic Testing Once the LCA/EOSRD-causing allelic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. ## Resources Ireland • • • • • • • • Ireland • ## Chapter Notes UCL Gene and Cell Therapy Group Casey Eye Institute Ophthalmic Genetics Service MM and NK are supported by grants from the National Institute for Health Research, the Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, the Medical Research Council, Fight for Sight, Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, the Wellcome Trust, the Macula Society, Retinitis Pigmentosa Fighting Blindness, and the Foundation Fighting Blindness. MEP is supported by grants from the Foundation Fighting Blindness. Casey Eye Institute is supported by an unrestricted grant from Research to Prevent Blindness and NIH P30 EY010572 grant. 23 March 2023 (aa/gm) Revision: 4 October 2018 (bp) Overview posted live 13 December 2017 (mm,nk) Original submission • 23 March 2023 (aa/gm) Revision: • 4 October 2018 (bp) Overview posted live • 13 December 2017 (mm,nk) Original submission ## Author Notes UCL Gene and Cell Therapy Group Casey Eye Institute Ophthalmic Genetics Service ## Acknowledgments MM and NK are supported by grants from the National Institute for Health Research, the Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, the Medical Research Council, Fight for Sight, Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, the Wellcome Trust, the Macula Society, Retinitis Pigmentosa Fighting Blindness, and the Foundation Fighting Blindness. MEP is supported by grants from the Foundation Fighting Blindness. Casey Eye Institute is supported by an unrestricted grant from Research to Prevent Blindness and NIH P30 EY010572 grant. ## Revision History 23 March 2023 (aa/gm) Revision: 4 October 2018 (bp) Overview posted live 13 December 2017 (mm,nk) Original submission • 23 March 2023 (aa/gm) Revision: • 4 October 2018 (bp) Overview posted live • 13 December 2017 (mm,nk) Original submission ## References ## Literature Cited	[]	4/10/2018		23/3/2023	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
lca	lca	[ "LCA", "LCA", "Aryl-hydrocarbon-interacting protein-like 1", "Centrosomal protein of 290 kDa", "Cone-rod homeobox protein", "Inosine-5'-monophosphate dehydrogenase 1", "Inward rectifier potassium channel 13", "IQ calmodulin-binding motif-containing protein 1", "Lebercilin", "Lecithin retinol acyltransferase", "Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1", "Protein crumbs homolog 1", "Protein RD3", "Retinal guanylyl cyclase 1", "Retinoid isomerohydrolase", "Retinol dehydrogenase 12", "Spermatogenesis-associated protein 7", "Tubby-related protein 1", "X-linked retinitis pigmentosa GTPase regulator-interacting protein 1", "AIPL1", "CEP290", "CRB1", "CRX", "GUCY2D", "IMPDH1", "IQCB1", "KCNJ13", "LCA5", "LRAT", "NMNAT1", "RD3", "RDH12", "RPE65", "RPGRIP1", "SPATA7", "TULP1", "Leber Congenital Amaurosis" ]	Leber Congenital Amaurosis – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY	Richard G Weleber, Peter J Francis, Karmen M Trzupek, Catie Beattie	Summary Leber congenital amaurosis (LCA), a severe dystrophy of the retina, typically becomes evident in the first year of life. Visual function is usually poor and often accompanied by nystagmus, sluggish or near-absent pupillary responses, photophobia, high hyperopia, and keratoconus. Visual acuity is rarely better than 20/400. A characteristic finding is Franceschetti's oculo-digital sign, comprising eye poking, pressing, and rubbing. The appearance of the fundus is extremely variable. While the retina may initially appear normal, a pigmentary retinopathy reminiscent of retinitis pigmentosa is frequently observed later in childhood. The electroretinogram (ERG) is characteristically "nondetectable" or severely subnormal. The diagnosis of LCA is established by clinical findings. Pathogenic variants in 17 genes are known to cause LCA: Most often LCA is inherited in an autosomal recessive manner. At conception, each sib of an individual with recessively inherited LCA has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members is possible if the pathogenic variants in the family are known. Prenatal testing for pregnancies at increased risk is possible through laboratories offering either testing for the gene of interest or custom testing. Rarely, LCA is inherited in an autosomal dominant manner as a result of a pathogenic variant in	## Diagnosis The form of congenital or early-infantile blindness known as Leber congenital amaurosis (LCA) was first defined by Theodor Leber in 1869 and 1871 on the basis of clinical findings [ Individuals with LCA also frequently exhibit the following: Sluggish or near-absent pupillary reactions reflecting the severe retinal dysfunction Nystagmus that is pendular or roving and present in all positions of gaze High hyperopia (>5 diopters), which is thought to result from impaired emmetropization (the ability of the eye to accommodate to visual stimuli) as a consequence of early-onset visual impairment Photophobia Keratoconus, a noninflammatory, self-limiting axial ectasia of the central cornea. Keratoconus can significantly interfere with vision in normal individuals but usually does not become a vision-limiting factor in LCA. Of note, three more specific retinal phenotypes can be observed: Preserved para-arteriolar retinal pigment epithelium (PPRPE) in individuals with "Translucent RPE," white dots, and a peculiar star-shaped maculopathy in individuals with A progressive macular atrophic lesion presenting in infancy or later in some individuals. Because of its sharply defined borders, this lesion has been at times called a “macular coloboma.” While it has been reported to occur with pathogenic variants in Molecular Genetic Testing Used in Leber Congenital Amaurosis See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Pathogenic variants in panel may vary. Testing that identifies exon or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. No deletions or duplications involving Exons sequenced may vary by laboratory. Whole-gene deletion reported [ • Sluggish or near-absent pupillary reactions reflecting the severe retinal dysfunction • Nystagmus that is pendular or roving and present in all positions of gaze • High hyperopia (>5 diopters), which is thought to result from impaired emmetropization (the ability of the eye to accommodate to visual stimuli) as a consequence of early-onset visual impairment • Photophobia • Keratoconus, a noninflammatory, self-limiting axial ectasia of the central cornea. Keratoconus can significantly interfere with vision in normal individuals but usually does not become a vision-limiting factor in LCA. • Preserved para-arteriolar retinal pigment epithelium (PPRPE) in individuals with • "Translucent RPE," white dots, and a peculiar star-shaped maculopathy in individuals with • A progressive macular atrophic lesion presenting in infancy or later in some individuals. Because of its sharply defined borders, this lesion has been at times called a “macular coloboma.” While it has been reported to occur with pathogenic variants in ## Clinical Diagnosis The form of congenital or early-infantile blindness known as Leber congenital amaurosis (LCA) was first defined by Theodor Leber in 1869 and 1871 on the basis of clinical findings [ Individuals with LCA also frequently exhibit the following: Sluggish or near-absent pupillary reactions reflecting the severe retinal dysfunction Nystagmus that is pendular or roving and present in all positions of gaze High hyperopia (>5 diopters), which is thought to result from impaired emmetropization (the ability of the eye to accommodate to visual stimuli) as a consequence of early-onset visual impairment Photophobia Keratoconus, a noninflammatory, self-limiting axial ectasia of the central cornea. Keratoconus can significantly interfere with vision in normal individuals but usually does not become a vision-limiting factor in LCA. Of note, three more specific retinal phenotypes can be observed: Preserved para-arteriolar retinal pigment epithelium (PPRPE) in individuals with "Translucent RPE," white dots, and a peculiar star-shaped maculopathy in individuals with A progressive macular atrophic lesion presenting in infancy or later in some individuals. Because of its sharply defined borders, this lesion has been at times called a “macular coloboma.” While it has been reported to occur with pathogenic variants in • Sluggish or near-absent pupillary reactions reflecting the severe retinal dysfunction • Nystagmus that is pendular or roving and present in all positions of gaze • High hyperopia (>5 diopters), which is thought to result from impaired emmetropization (the ability of the eye to accommodate to visual stimuli) as a consequence of early-onset visual impairment • Photophobia • Keratoconus, a noninflammatory, self-limiting axial ectasia of the central cornea. Keratoconus can significantly interfere with vision in normal individuals but usually does not become a vision-limiting factor in LCA. • Preserved para-arteriolar retinal pigment epithelium (PPRPE) in individuals with • "Translucent RPE," white dots, and a peculiar star-shaped maculopathy in individuals with • A progressive macular atrophic lesion presenting in infancy or later in some individuals. Because of its sharply defined borders, this lesion has been at times called a “macular coloboma.” While it has been reported to occur with pathogenic variants in ## Molecular Genetic Testing Molecular Genetic Testing Used in Leber Congenital Amaurosis See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Pathogenic variants in panel may vary. Testing that identifies exon or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. No deletions or duplications involving Exons sequenced may vary by laboratory. Whole-gene deletion reported [ ## Testing Strategy ## Clinical Characteristics Leber congenital amaurosis (LCA) has retinal, ocular, and extraocular features and occasionally, systemic associations [ "Macular coloboma"; not a true coloboma, but reflecting discrete chorioretinal degeneration and atrophy centered about the fovea "Bone-spicule" intraretinal pigment migration Widespread subretinal flecks resembling retinitis punctata albescens "Marbled" fundus Discrete pigmented nummular lesions at the level of the retinal pigment epithelium (RPE) Optic disc abnormalities: swelling, drusen formation, and peripapillary neovascularization Prior to the identification of A number of genotype-phenotype correlations appear to have emerged. Individuals with pathogenic variants in Extraretinal findings were described in a subset of individuals in Perrault’s study, and primarily included hypotonia and ataxia or intellectual disability and autistic behaviors. In fact, six of 40 families segregating The authors found that the presence of photophobia or night blindness at ages one and two years distinguished two groups: Those with photophobia constituted a cone-rod dystrophy class and were found to have pathogenic variants of Those with night blindness constituted a rod-cone dystrophy class and were found to have pathogenic variants of The birth prevalence of LCA is two to three per 100,000 births. The condition is the most common cause of inherited blindness in childhood and constitutes more than 5% of all retinal dystrophies. LCA accounts for the cause of blindness in more than 20% of children attending schools for the blind. LCA appears to be more prevalent when consanguinity is common [ • "Macular coloboma"; not a true coloboma, but reflecting discrete chorioretinal degeneration and atrophy centered about the fovea • "Bone-spicule" intraretinal pigment migration • Widespread subretinal flecks resembling retinitis punctata albescens • "Marbled" fundus • Discrete pigmented nummular lesions at the level of the retinal pigment epithelium (RPE) • Optic disc abnormalities: swelling, drusen formation, and peripapillary neovascularization • Those with photophobia constituted a cone-rod dystrophy class and were found to have pathogenic variants of • Those with night blindness constituted a rod-cone dystrophy class and were found to have pathogenic variants of ## Clinical Description Leber congenital amaurosis (LCA) has retinal, ocular, and extraocular features and occasionally, systemic associations [ "Macular coloboma"; not a true coloboma, but reflecting discrete chorioretinal degeneration and atrophy centered about the fovea "Bone-spicule" intraretinal pigment migration Widespread subretinal flecks resembling retinitis punctata albescens "Marbled" fundus Discrete pigmented nummular lesions at the level of the retinal pigment epithelium (RPE) Optic disc abnormalities: swelling, drusen formation, and peripapillary neovascularization Prior to the identification of • "Macular coloboma"; not a true coloboma, but reflecting discrete chorioretinal degeneration and atrophy centered about the fovea • "Bone-spicule" intraretinal pigment migration • Widespread subretinal flecks resembling retinitis punctata albescens • "Marbled" fundus • Discrete pigmented nummular lesions at the level of the retinal pigment epithelium (RPE) • Optic disc abnormalities: swelling, drusen formation, and peripapillary neovascularization ## Genotype-Phenotype Correlations A number of genotype-phenotype correlations appear to have emerged. Individuals with pathogenic variants in Extraretinal findings were described in a subset of individuals in Perrault’s study, and primarily included hypotonia and ataxia or intellectual disability and autistic behaviors. In fact, six of 40 families segregating The authors found that the presence of photophobia or night blindness at ages one and two years distinguished two groups: Those with photophobia constituted a cone-rod dystrophy class and were found to have pathogenic variants of Those with night blindness constituted a rod-cone dystrophy class and were found to have pathogenic variants of • Those with photophobia constituted a cone-rod dystrophy class and were found to have pathogenic variants of • Those with night blindness constituted a rod-cone dystrophy class and were found to have pathogenic variants of ## Prevalence The birth prevalence of LCA is two to three per 100,000 births. The condition is the most common cause of inherited blindness in childhood and constitutes more than 5% of all retinal dystrophies. LCA accounts for the cause of blindness in more than 20% of children attending schools for the blind. LCA appears to be more prevalent when consanguinity is common [ ## Genetically Related (Allelic) Disorders Different pathogenic variants within each of the LCA-associated genes are known to cause other retinal dystrophies, such as Meckel syndrome 4; an autosomal recessive condition characterized by renal cysts, CNS anomalies, hepatic abnormalities, and polydactyly. Senior-Løken syndrome 6; an autosomal recessive condition characterized by nephronophthisis and Leber congenital amaurosis. • Meckel syndrome 4; an autosomal recessive condition characterized by renal cysts, CNS anomalies, hepatic abnormalities, and polydactyly. • Senior-Løken syndrome 6; an autosomal recessive condition characterized by nephronophthisis and Leber congenital amaurosis. • Meckel syndrome 4; an autosomal recessive condition characterized by renal cysts, CNS anomalies, hepatic abnormalities, and polydactyly. • Senior-Løken syndrome 6; an autosomal recessive condition characterized by nephronophthisis and Leber congenital amaurosis. • Meckel syndrome 4; an autosomal recessive condition characterized by renal cysts, CNS anomalies, hepatic abnormalities, and polydactyly. • Senior-Løken syndrome 6; an autosomal recessive condition characterized by nephronophthisis and Leber congenital amaurosis. ## Differential Diagnosis Leber congenital amaurosis (LCA) typically presents as an isolated ocular anomaly without systemic involvement. Occasionally, the same or similar retinal findings can be seen as part of a systemic disorder. Systemic abnormalities including renal anomalies, deafness, skeletal abnormalities, microcephaly, neurodevelopmental delay, intellectual disability, or oculomotor apraxia should alert the clinician to consider syndromic disorders associated with early-onset retinal dystrophy. Systemic disorders to consider include the following: Juvenile nephronophthisis (medullary cystic renal disease) and Early-onset retinal dystrophy. See Cone-shaped digital epiphyses, Cerebellar hypoplasia, and Early-onset retinal dystrophy. Nephronophthisis (a juvenile-onset cystic kidney disease), Hypoplasia of the cerebellar vermis, Early-onset retinal dystrophy, and Either or both of the following: Episodic hyperpnea and/or apnea Atypical eye movements Zellweger syndrome (ZS) (OMIM Neonatal adrenoleukodystrophy (NALD) (OMIM Infantile Refsum disease (IRD) (OMIM ZS is the most severe and IRD the least severe. Children with ZS have retinal dystrophy, sensorineural hearing loss, developmental delay with hypotonia, and liver dysfunction; they usually die during the first year of life. The clinical courses of NALD and IRD are variable. Retinal degeneration is associated with congenital, liver, and renal abnormalities. In addition, an LCA-like retinal dystrophy has been documented in individuals with abetalipoproteinemia (OMIM In a child presenting without systemic involvement, other inherited retinal dystrophies may be considered. Compared to LCA, early-onset An intermediate category of retinal disease, presenting in early childhood with night blindness, variable degrees of central vision loss, and a severely abnormal but recordable ERG is now emerging. The authors favor the term "SECORD" ( Other retinal conditions that can be confused with Leber congenital amaurosis include congenital retinal disorders that are typically stationary, such as • Juvenile nephronophthisis (medullary cystic renal disease) and • Early-onset retinal dystrophy. • Cone-shaped digital epiphyses, • Cerebellar hypoplasia, and • Early-onset retinal dystrophy. • Nephronophthisis (a juvenile-onset cystic kidney disease), • Hypoplasia of the cerebellar vermis, • Early-onset retinal dystrophy, and • Either or both of the following: • Episodic hyperpnea and/or apnea • Atypical eye movements • Episodic hyperpnea and/or apnea • Atypical eye movements • Episodic hyperpnea and/or apnea • Atypical eye movements • Zellweger syndrome (ZS) (OMIM • Neonatal adrenoleukodystrophy (NALD) (OMIM • Infantile Refsum disease (IRD) (OMIM • In addition, an LCA-like retinal dystrophy has been documented in individuals with abetalipoproteinemia (OMIM • In a child presenting without systemic involvement, other inherited retinal dystrophies may be considered. Compared to LCA, early-onset • An intermediate category of retinal disease, presenting in early childhood with night blindness, variable degrees of central vision loss, and a severely abnormal but recordable ERG is now emerging. The authors favor the term "SECORD" ( • Other retinal conditions that can be confused with Leber congenital amaurosis include congenital retinal disorders that are typically stationary, such as ## Management To establish the extent of disease in an individual diagnosed with Leber congenital amaurosis (LCA), the following evaluations are recommended: Electroretinogram (ERG) to confirm the diagnosis and to assess retinal function Clinical genetic assessment to evaluate for the presence of systemic abnormalities Clinical genetics consultation Except for Affected individuals benefit from correction of refractive error, use of low-vision aids when possible, and optimal access to educational and work-related opportunities. Children should be discouraged from repeatedly poking and pressing on their eyes, although attempts to alter such behavior are not always successful. Affected individuals should be periodically seen for assessment of vision, trials of correction for refractive error, and when residual vision is present, assessment of the presence of amblyopia, glaucoma, or cataract. Rarely, vision appears to improve beyond expectations; in such cases, a repeat ERG is indicated. See In a naturally occurring Briard dog model of LCA resulting from mutation of Clinical and laboratory studies suggest that persons with Search • Electroretinogram (ERG) to confirm the diagnosis and to assess retinal function • Clinical genetic assessment to evaluate for the presence of systemic abnormalities • Clinical genetics consultation ## Evaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with Leber congenital amaurosis (LCA), the following evaluations are recommended: Electroretinogram (ERG) to confirm the diagnosis and to assess retinal function Clinical genetic assessment to evaluate for the presence of systemic abnormalities Clinical genetics consultation • Electroretinogram (ERG) to confirm the diagnosis and to assess retinal function • Clinical genetic assessment to evaluate for the presence of systemic abnormalities • Clinical genetics consultation ## Treatment of Manifestations Except for Affected individuals benefit from correction of refractive error, use of low-vision aids when possible, and optimal access to educational and work-related opportunities. ## Prevention of Secondary Complications Children should be discouraged from repeatedly poking and pressing on their eyes, although attempts to alter such behavior are not always successful. ## Surveillance Affected individuals should be periodically seen for assessment of vision, trials of correction for refractive error, and when residual vision is present, assessment of the presence of amblyopia, glaucoma, or cataract. Rarely, vision appears to improve beyond expectations; in such cases, a repeat ERG is indicated. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation In a naturally occurring Briard dog model of LCA resulting from mutation of Clinical and laboratory studies suggest that persons with Search ## Genetic Counseling Most often, Leber congenital amaurosis (LCA) is inherited in an autosomal recessive manner. Rarely, pathogenic variants in The parents of an affected child are obligate heterozygotes and therefore carry one mutated allele. Heterozygotes (carriers) are asymptomatic. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Heterozygotes (carriers) are asymptomatic. Carrier testing for at-risk family members is possible if the pathogenic variants in the family are known. Most children diagnosed as having autosomal dominant LCA have an affected parent. Occasionally a molecular diagnosis is made in the absence of family history. Such cases are the result of If one of the proband's parents is affected with LCA, the risk to sibs of inheriting the mutated allele is 50%. When neither parent of the proband is affected, the risk to sibs is negligible. 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 variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for Leber congenital amaurosis are possible. • The parents of an affected child are obligate heterozygotes and therefore carry one mutated allele. • Heterozygotes (carriers) are asymptomatic. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. • Heterozygotes (carriers) are asymptomatic. • Most children diagnosed as having autosomal dominant LCA have an affected parent. • Occasionally a molecular diagnosis is made in the absence of family history. Such cases are the result of • If one of the proband's parents is affected with LCA, the risk to sibs of inheriting the mutated allele is 50%. • When neither parent of the proband is affected, the risk to sibs is negligible. • 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 Most often, Leber congenital amaurosis (LCA) is inherited in an autosomal recessive manner. Rarely, pathogenic variants in ## Autosomal Recessive LCA – Risk to Family Members The parents of an affected child are obligate heterozygotes and therefore carry one mutated allele. Heterozygotes (carriers) are asymptomatic. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Heterozygotes (carriers) are asymptomatic. Carrier testing for at-risk family members is possible if the pathogenic variants in the family are known. • The parents of an affected child are obligate heterozygotes and therefore carry one mutated allele. • Heterozygotes (carriers) are asymptomatic. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. • Heterozygotes (carriers) are asymptomatic. ## Carrier Detection Carrier testing for at-risk family members is possible if the pathogenic variants in the family are known. ## Autosomal Dominant LCA – Risk to Family Members Most children diagnosed as having autosomal dominant LCA have an affected parent. Occasionally a molecular diagnosis is made in the absence of family history. Such cases are the result of If one of the proband's parents is affected with LCA, the risk to sibs of inheriting the mutated allele is 50%. When neither parent of the proband is affected, the risk to sibs is negligible. • Most children diagnosed as having autosomal dominant LCA have an affected parent. • Occasionally a molecular diagnosis is made in the absence of family history. Such cases are the result of • If one of the proband's parents is affected with LCA, the risk to sibs of inheriting the mutated allele is 50%. • When neither parent of the proband is affected, the risk to sibs is negligible. ## Related Genetic Counseling Issues The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for Leber congenital amaurosis are possible. ## Resources 2200 Wilson Boulevard Suite 650 Arlington VA 22201 11435 Cronhill Drive Owings Mills MD 21117-2220 200 East Wells Street (at Jernigan Place) Baltimore MD 21230 Retina Suisse Ausstellungsstrasse 36 Zurich CH-8005 Switzerland • • 2200 Wilson Boulevard • Suite 650 • Arlington VA 22201 • • • 11435 Cronhill Drive • Owings Mills MD 21117-2220 • • • 200 East Wells Street • (at Jernigan Place) • Baltimore MD 21230 • • • Retina Suisse • Ausstellungsstrasse 36 • Zurich CH-8005 • Switzerland • ## Molecular Genetics Leber Congenital Amaurosis: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Leber Congenital Amaurosis ( Variants listed in the table have been provided by the authors. Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions 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. 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. The aberrant splice product was reported in 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 ## Suggested Reading ## Chapter Notes Supported in part by Foundation Fighting Blindness, Research to Prevent Blindness, and the Grousbeck Family Foundation. 24 May 2018 (ma) Retired chapter: covered in 2 May 2013 (me) Comprehensive update posted live 30 March 2010 (me) Comprehensive update posted live 12 October 2006 (me) Comprehensive update posted live 9 November 2005 (rw) Revision: 7 July 2004 (me) Review posted live 30 December 2003 (rw, pf, kt) Original submission • 24 May 2018 (ma) Retired chapter: covered in • 2 May 2013 (me) Comprehensive update posted live • 30 March 2010 (me) Comprehensive update posted live • 12 October 2006 (me) Comprehensive update posted live • 9 November 2005 (rw) Revision: • 7 July 2004 (me) Review posted live • 30 December 2003 (rw, pf, kt) Original submission ## Acknowledgments Supported in part by Foundation Fighting Blindness, Research to Prevent Blindness, and the Grousbeck Family Foundation. ## Revision History 24 May 2018 (ma) Retired chapter: covered in 2 May 2013 (me) Comprehensive update posted live 30 March 2010 (me) Comprehensive update posted live 12 October 2006 (me) Comprehensive update posted live 9 November 2005 (rw) Revision: 7 July 2004 (me) Review posted live 30 December 2003 (rw, pf, kt) Original submission • 24 May 2018 (ma) Retired chapter: covered in • 2 May 2013 (me) Comprehensive update posted live • 30 March 2010 (me) Comprehensive update posted live • 12 October 2006 (me) Comprehensive update posted live • 9 November 2005 (rw) Revision: • 7 July 2004 (me) Review posted live • 30 December 2003 (rw, pf, kt) Original submission	[ "GM Acland, GD Aguirre, J Bennett, TS Aleman, AV Cideciyan, J Bennicelli, NS Dejneka, SE Pearce-Kelling, AM Maguire, K Palczewski, WW Hauswirth, SG Jacobson. Long-term restoration of rod and cone vision by single dose rAAV-mediated gene transfer to the retina in a canine model of childhood blindness.. Mol Ther 2005;12:1072-82", "MA Aldahmesh, M Al-Owain, F Alqahtani, S Hazzaa, FS Alkuraya. A null mutation in CABP4 causes Leber's congenital amaurosis-like phenotype.. Mol Vis. 2010;16:207-12", "T Araki, Y Sasaki, J. Milbrandt. Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration.. Science. 2004;305:1010-3", "JW Bainbridge, AJ Smith, SS Barker, S Robbie, R Henderson, K Balaggan, A Viswanathan, GE Holder, A Stockman, N Tyler, S Petersen-Jones, SS Bhattacharya, AJ Thrasher, FW Fitzke, BJ Carter, GS Rubin, AT Moore, RR Ali. Effect of gene therapy on visual function in Leber's congenital amaurosis.. N Engl J Med 2008;358:2231-9", "SJ Bowne, LS Sullivan, SE Mortimer, L Hedstrom, J Zhu, CJ Spellicy, AI Gire, D Hughbanks-Wheaton, DG Birch, RA Lewis, JR Heckenlively, SP Daiger. Spectrum and frequency of mutations in IMPDH1 associated with autosomal dominant retinitis pigmentosa and leber congenital amaurosis.. Invest Ophthalmol Vis Sci 2006;47:34-42", "PW Chiang, J Wang, Y Chen, Q Fu, J Zhong, X Yi. Exome sequencing identifies NMNAT1 mutations as a cause of Leber congenital amaurosis.. Nat Genet. 2012;44:972-4", "S Chen, QL Wang, S Xu, I Liu, LY Li, Y Wang, DJ Zack. Functional analysis of cone-rod homeobox (CRX) mutations associated with retinal dystrophy.. Hum Mol Genet 2002;11:873-84", "AV Cideciyan, TS Aleman, SL Boye, SB Schwartz, S Kaushal, AJ Roman, JJ Pang, A Sumaroka, EA Windsor, JM Wilson, TR Flotte, GA Fishman, E Heon, EM Stone, BJ Byrne, SG Jacobson, WW Hauswirth. Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics.. Proc Natl Acad Sci U S A 2008;105:15112-7", "FP Cremers, JA van den Hurk, AI den Hollander. Molecular genetics of Leber congenital amaurosis.. Hum Mol Genet 2002;11:1169-76", "AI den Hollander, JR Heckenlively, LI van den Born, YJ de Kok, SD van der Velde-Visser, U Kellner, B Jurklies, MJ van Schooneveld, A Blankenagel, K Rohrschneider, B Wissinger, JR Cruysberg, AF Deutman, HG Brunner, E Apfelstedt-Sylla, CB Hoyng, FP Cremers. Leber congenital amaurosis and retinitis pigmentosa with Coats-like exudative vasculopathy are associated with mutations in the crumbs homologue 1 (CRB1) gene.. Am J Hum Genet 2001;69:198-203", "AI den Hollander, RK Koenekoop, MD Mohamed, HH Arts, K Boldt, KV Towns, T Sedmak, M Beer, K Nagel-Wolfrum, M McKibbin, S Dharmaraj, I Lopez, L Ivings, GA Williams, K Springell, CG Woods, H Jafri, Y Rashid, TM Strom, B van der Zwaag, I Gosens, FF Kersten, E van Wijk, JA Veltman, MN Zonneveld, SE van Beersum, IH Maumenee, U Wolfrum, ME Cheetham, M Ueffing, FP Cremers, CF Inglehearn, R Roepman. Mutations in LCA5, encoding the ciliary protein lebercilin, cause Leber congenital amaurosis.. Nat Genet. 2007;39:889-95", "AI den Hollander, RK Koenekoop, S Yzer, I Lopez, ML Arends, KE Voesenek, MN Zonneveld, TM Strom, T Meitinger, HG Brunner, CB Hoyng, LI van den Born, K Rohrschneider, FP Cremers. Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis.. Am J Hum Genet 2006;79:556-61", "AI den Hollander, JB ten Brink, YJ de Kok, S van Soest, LI van den Born, MA van Driel, DJ van de Pol, AM Payne, SS Bhattacharya, U Kellner, CB Hoyng, A Westerveld, HG Brunner, EM Bleeker-Wagemakers, AF Deutman, JR Heckenlively, FP Cremers, AA Bergen. Mutations in a human homologue of Drosophila crumbs cause retinitis pigmentosa (RP12).. Nat Genet 1999;23:217-21", "S Dharmaraj, BP Leroy, MM Sohocki, RK Koenekoop, I Perrault, K Anwar, S Khaliq, RS Devi, DG Birch, E De Pool, N Izquierdo, L Van Maldergem, M Ismail, AM Payne, GE Holder, SS Bhattacharya, AC Bird, J Kaplan, IH Maumenee. The Phenotype of Leber Congenital Amaurosis in Patients With AIPL1 Mutations.. Arch Ophthalmol 2004;122:1029-37", "S Dharmaraj, Y Li, JM Robitaille, E Silva, D Zhu, TN Mitchell, LP Maltby, AB Baffoe-Bonnie, IH Maumenee. A novel locus for Leber congenital amaurosis maps to chromosome 6q.. Am J Hum Genet 2000a;66:319-26", "SR Dharmaraj, ER Silva, AL Pina, YY Li, JM Yang, CR Carter, MK Loyer, HK El-Hilali, EK Traboulsi, OK Sundin, DK Zhu, RK Koenekoop, IH Maumenee. Mutational analysis and clinical correlation in Leber congenital amaurosis.. Ophthalmic Genet 2000b;21:135-50", "M. Emanuelli, F. Carnevali, F. Saccucci, F. Pierella, A. Amici, N. Raffaelli, G. Magni. Molecular cloning, chromosomal localization, tissue mRNA levels, bacterial expression, and enzymatic properties of human NMN adenylyltransferase.. J. Biol. Chem. 2001;276:406-12", "MJ Falk, Q Zhang, E Nakamaru-Ogiso, C Kannabiran, Z Fonseca-Kelly, C Chakarova. NMNAT1 mutations cause Leber congenital amaurosis.. Nat Genet. 2012;44:1040-5", "E Fazzi, SG Signorini, B Scelsa, SM Bova, G Lanzi. Leber's congenital amaurosis: an update.. Eur J Paediatr Neurol 2003;7:13-22", "JS Friedman, B Chang, C Kannabiran, C Chakarova, HP Singh, S Jalali, NL Hawes, K Branham, M Othman, E Filippova, DA Thompson, AR Webster, S Andreasson, SG Jacobson, SS Bhattacharya, JR Heckenlively, A Swaroop. Premature truncation of novel protein, RD#, exhibiting subnuclear localization is associated with retinal degeneration.. Am J Hum Genet 2006;79:1059-70", "JA Galvin, GA Fishman, EM Stone, RK Koenekoop. Evaluation of genotype-phenotype associations in leber congenital amaurosis.. Retina 2005;25:919-29", "F Haeseleer, GF Jang, Y Imanishi, CA Driessen, M Matsumura, PS Nelson, K Palczewski. Dual-substrate specificity short chain retinol dehydrogenases from the vertebrate retina.. J Biol Chem 2002;277:45537-46", "SA Hagstrom, RF Watson, GJ Pauer, GH Grossman. Tulp1 is involved in specific photoreceptor protein transport pathways.. Adv Exp Med Biol. 2012;723:783-9", "A Hameed, A Abid, A Aziz, M Ismail, SQ Mehdi, S Khaliq. Evidence of RPGRIP1 gene mutations associated with recessive cone-rod dystrophy.. J Med Genet 2003;40:616-9", "A Hameed, S Khaliq, M Ismail, K Anwar, ND Ebenezer, T Jordan, SQ Mehdi, AM Payne, SS Bhattacharya. A novel locus for Leber congenital amaurosis (LCA4) with anterior keratoconus mapping to chromosome 17p13.. Invest Ophthalmol Vis Sci. 2000;41:629-33", "S Hanein, I Perrault, S Gerber, G Tanguy, F Barbet, D Ducroq, P Calvas, H Dollfus, C Hamel, T Lopponen, F Munier, L Santos, S Shalev, D Zafeiriou, JL Dufier, A Munnich, JM Rozet, J Kaplan. Leber congenital amaurosis: comprehensive survey of the genetic heterogeneity, refinement of the clinical definition, and genotype-phenotype correlations as a strategy for molecular diagnosis.. Hum Mutat 2004;23:306-17", "WW Hauswirth, TS Aleman, S Kaushal, AV Cideciyan, SB Schwartz, L Wang, TJ Conlon, SL Boye, TR Flotte, BJ Byrne, SG Jacobson. Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial.. Hum Gene Ther. 2008;19:979-90", "S Heegaard, T Rosenberg, M Preising, JU Prause, T Bek. An unusual retinal vascular morphology in connection with a novel AIPL1 mutation in Leber's congenital amaurosis.. Br J Ophthalmol 2003;87:980-3", "F Hildebrandt, W Zhou. Nephronophthisis-associated ciliopathies.. J Am Soc Nephrol. 2007;18:1855-71", "SG Jacobson, TS Aleman, AV Cideciyan, A Sumaroka, SB Schwartz, EAM Windsor, M Swider, W Herrera, EM Stone. Leber congenital amaurosis caused by Lebercilin (LCA5) mutation: retained photoreceptors adjacent to retinal disorganization.. Mol Vis 2009;15:1098-106", "SG Jacobson, AV Cideciyan, TS Aleman, MJ Pianta, A Sumaroka, SB Schwartz, EE Smilko, AH Milam, VC Sheffield, EM Stone. Crumbs homolog 1 (CRB1) mutations result in a thick human retina with abnormal lamination.. Hum Mol Genet 2003;12:1073-8", "SG Jacobson, AV Cideciyan, Y Huang, DB Hanna, CL Freund, LM Affatigato, RE Carr, DJ Zack, EM Stone, RR McInnes. Retinal degenerations with truncation mutations in the cone-rod homeobox (CRX) gene.. Invest Ophthalmol Vis Sci 1998;39:2417-26", "AR Janecke, DA Thompson, G Utermann, C Becker, CA Hubner, E Schmid, CL McHenry, AR Nair, F Ruschendorf, J Heckenlively, B Wissinger, P Nurnberg, A Gal. Mutations in RDH12 encoding a photoreceptor cell retinol dehydrogenase cause childhood-onset severe retinal dystrophy.. Nat Genet 2004;36:850-4", "K Kanaya, MM Sohocki, T Kamitani. Abolished interaction of NUB1 with mutant AIPL1 involved in Leber congenital amaurosis.. Biochem Biophys Res Commun 2004;317:768-73", "RK Koenekoop, GA Fishman, A Iannaccone, H Ezzeldin, ML Ciccarelli, A Baldi, JS Sunness, AJ Lotery, MM Jablonski, SJ Pittler, I Maumenee. Electroretinographic abnormalities in parents of patients with Leber congenital amaurosis who have heterozygous GUCY2D mutations.. Arch Ophthalmol 2002a;120:1325-30", "RK Koenekoop, M Loyer, O Dembinska, R Beneish. Visual improvement in Leber congenital amaurosis and the CRX genotype.. Ophthalmic Genet 2002b;23:49-59", "RK Koenekoop, H Wang, J Majewski, X Wang, I Lopez, H Ren. Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration.. Nat Genet. 2012;44:1035-9", "T Leber. Ueber retinitis pigmentosa und angeborene Amaurose.. Graefes Arch Clin Exp Ophthalmol 1869;15:1-25", "T Leber. Ueber hereditare und congenitalangelegte Schnervenleiden.. Graefes Arch Clin Exp Ophthalmol 1871;17:249-91", "B Lorenz, P Gyurus, M Preising, D Bremser, S Gu, M Andrassi, C Gerth, A Gal. Early-onset severe rod-cone dystrophy in young children with RPE65 mutations.. Invest Ophthalmol Vis Sci 2000;41:2735-42", "B Lorenz, E Poliakov, M Schambeck, C Friedburg, MN Preising, TM Redmond. A comprehensive clinical and biochemical functional study of a novel RPE65 hypomorphic mutation.. Invest Ophthalmol Vis Sci. 2008;49:5235-42", "AJ Lotery, SG Jacobson, GA Fishman, RG Weleber, AB Fulton, P Namperumalsamy, E Heon, AV Levin, S Grover, JR Rosenow, KK Kopp, VC Sheffield, EM Stone. Mutations in the CRB1 gene cause Leber congenital amaurosis.. Arch Ophthalmol 2001;119:415-20", "AJ Lotery, P Namperumalsamy, SG Jacobson, RG Weleber, GA Fishman, MA Musarella, CS Hoyt, E Heon, A Levin, J Jan, B Lam, RE Carr, A Franklin, S Radha, JL Andorf, VC Sheffield, EM Stone. Mutation analysis of 3 genes in patients with Leber congenital amaurosis.. Arch Ophthalmol 2000;118:538-43", "AM Maguire, F Simonelli, EA Pierce, EN Pugh, F Mingozzi, J Bennicelli, S Banfi, KA Marshall, F Testa, EM Surace, S Rossi, A Lyubarsky, VR Arruda, B Konkle, E Stone, J Sun, J Jacobs, L Dell'Osso, R Hertle, JX Ma, TM Redmond, X Zhu, B Hauck, O Zelenaia, KS Shindler, MG Maguire, JF Wright, NJ Volpe, JW McDonnell, A Auricchio, KA High, J Bennett. Safety and efficacy of gene transfer for Leber's congenital amaurosis.. N Engl J Med 2008;358:2240-8", "JK McBee, K Palczewski, W Baehr, DR Pepperberg. Confronting complexity: the interlink of phototransduction and retinoid metabolism in the vertebrate retina.. Prog Retin Eye Res 2001;20:469-529", "AH Milam, MR Barakat, N Gupta, L Rose, TS Aleman, MJ Pianta, AV Cideciyan, VC Sheffield, EM Stone, SG Jacobson. Clinicopathologic effects of mutant GUCY2D in Leber congenital amaurosis.. Ophthalmology 2003;110:549-58", "MD Mohamed, NC Topping, H Jafri, Y Raashed, MA McKibbin, CF Inglehearn. Progression of phenotype in Leber's congenital amaurosis with a mutation at the LCA5 locus.. Br J Ophthalmol 2003;87:473-5", "H Morimura, GA Fishman, SA Grover, AB Fulton, EL Berson, TP Dryja. Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or leber congenital amaurosis.. Proc Natl Acad Sci U S A 1998;95:3088-93", "EA Otto, J Helou, SJ Allen, JF O'Toole, EL Wise, S Ashraf, M Attanasio, W Zhou, MT Wolf, F Hildebrandt. Mutation analysis in nephronophthisis using a combined approach of homozygosity mapping, CEL I endonuclease cleavage, and direct sequencing.. Hum Mutat. 2008;29:418-26", "K Paunescu, B Wabbels, MN Preising, B Lorenz. Longitudinal and cross-sectional study of patients with early-onset severe retinal dystrophy associated with RPE65 mutations.. Graefes Arch Clin Exp Ophthalmol 2005;243:417-26", "ME Pennesi, NB Stover, EM Stone, PW Chiang, RG Weleber. Residual electroretinograms in young Leber congenital amaurosis patients with mutations of AIPL1. Invest Ophthalmol Vis Sci 2011;2011:8166-73", "I Perrault, N Delphin, S Hanein, S Gerber, JL Dufier, O Roche, S Defoort-Dhellemmes, H Dollfus, E Fazzi, A Munnich, J Kaplan, JM Rozet. Spectrum of NPHP6/CEP290 mutations in Leber congenital amaurosis and delineation of the associated phenotype.. Hum Mutat 2007;28:416", "I Perrault, S Hanein, S Gerber, F Barbet, D Ducroq, H Dollfus, C Hamel, JL Dufier, A Munnich, J Kaplan, JM Rozet. Retinal dehydrogenase 12 (RDH12) mutations in leber congenital amaurosis.. Am J Hum Genet 2004;75:639-46", "I Perrault, S Hanein, S Gerber, F Barbet, JL Dufier, A Munnich, JM Rozet, J Kaplan. Evidence of autosomal dominant Leber congenital amaurosis (LCA) underlain by a CRX heterozygous null allele.. J Med Genet 2003;40", "I Perrault, S Hanein, S Gerber, B Lebail, P Vlajnik, F Barbet, D Ducroq, JL Dufier, A Munnich, J Kaplan, JM Rozet. A novel mutation in the GUCY2D gene responsible for an early onset severe RP different from the usual GUCY2D-LCA phenotype.. Hum Mutat 2005;25:222", "I Perrault, S Hanein, X Zanlonghi, V Serre, M Nicouleau, S Defoort-Delhemmes. Mutations in NMNAT1 cause Leber congenital amaurosis with early-onset severe macular and optic atrophy.. Nat Genet. 2012;44:975-7", "I Perrault, JM Rozet, I Ghazi, C Leowski, M Bonnemaison, S Gerber, D Ducroq, A Cabot, E Souied, JL Dufier, A Munnich, J Kaplan. Different functional outcome of RetGC1 and RPE65 gene mutations in Leber congenital amaurosis.. Am J Hum Genet 1999;64:1225-8", "FB Porto, I Perrault, D Hicks, JM Rozet, N Hanoteau, S Hanein, J Kaplan, JA Sahel. Prenatal human ocular degeneration occurs in Leber's congenital amaurosis (LCA2).. J Gene Med 2002;4:390-6", "TM Redmond, E Poliakov, S Yu, JY Tsai, Z Lu, S Gentleman. Mutation of key residues of RPE65 abolishes its enzymatic role as isomerohydrolase in the visual cycle.. Proc Natl Acad Sci U S A 2005;102:13658-63", "C Rivolta, EL Berson, TP Dryja. Dominant Leber congenital amaurosis, cone-rod degeneration, and retinitis pigmentosa caused by mutant versions of the transcription factor CRX.. Hum Mutat 2001;18:488-98", "JM Rozet, I Perrault, S Gerber, S Hanein, F Barbet, D Ducroq, E Souied, A Munnich, J Kaplan. Complete abolition of the retinal-specific guanylyl cyclase (retGC-1) catalytic ability consistently leads to leber congenital amaurosis (LCA).. Invest Ophthalmol Vis Sci 2001;42:1190-2", "R Salomon, S Saunier, P Niaudet. Nephronophthisis.. Pediatr Nephrol. 2009;24:2333-44", "JA Sayer, EA Otto, JF O'Toole, G Nurnberg, MA Kennedy, C Becker, HC Hennies, J Helou, M Attanasio, BV Fausett, B Utsch, H Khanna, Y Liu, I Drummond, I Kawakami, T Kusakabe, M Tsuda, L Ma, H Lee, RG Larson, SJ Allen, CJ Wilkinson, EA Nigg, C Shou, C Lillo, DS Williams, B Hoppe, MJ Kemper, T Neuhaus, MA Parisi, IA Glass, M Petry, A Kispert, J Gloy, A Ganner, G Walz, X Zhu, D Goldman, P Nurnberg, A Swaroop, MR Leroux, F Hildebrandt. The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4.. Nat Genet 2006;38:674-81", "J Schuil, FM Meire, JW Delleman. Mental retardation in amaurosis congenita of Leber.. Neuropediatrics 1998;29:294-7", "PI Sergouniotis, AE Davidson, DS Mackay, Z Li, X Yang, V Plagnol, AT Moore, AR Webster. Recessive mutations in KCNJ13, encoding an inwardly rectifying potassium channel subunit, cause Leber congenital amaurosis.. Am. J. Hum. Genet. 2011;89:183-90", "R Sitorus, M Preising, B Lorenz. Causes of blindness at the \"Wiyata Guna\" School for the Blind, Indonesia.. Br J Ophthalmol 2003;87:1065-8", "MM Sohocki, SJ Bowne, LS Sullivan, S Blackshaw, CL Cepko, AM Payne, SS Bhattacharya, S Khaliq, S Qasim Mehdi, DG Birch, WR Harrison, FF Elder, JR Heckenlively, SP Daiger. Mutations in a new photoreceptor-pineal gene on 17p cause Leber congenital amaurosis.. Nat Genet 2000;24:79-83", "MM Sohocki, LS Sullivan, HA Mintz-Hittner, D Birch, JR Heckenlively, CL Freund, RR McInnes, SP Daiger. A range of clinical phenotypes associated with mutations in CRX, a photoreceptor transcription-factor gene.. Am J Hum Genet 1998;63:1307-15", "EM Stone. Leber congenital amaurosis - a model for efficient genetic testing of heterogeneous disorders: LXIV Edward Jackson Memorial Lecture.. Am J Ophthalmol. 2007;144:791-811", "A Swaroop, QL Wang, W Wu, J Cook, C Coats, S Xu, S Chen, DJ Zack, PA Sieving. Leber congenital amaurosis caused by a homozygous mutation (R90W) in the homeodomain of the retinal transcription factor CRX: direct evidence for the involvement of CRX in the development of photoreceptor function.. Hum Mol Genet 1999;8:299-305", "DA Thompson, AR Janecke, J Lange, KL Feathers, CA Hubner, CL McHenry, DW Stockton, G Rammesmayer, JR Lupski, G Antinolo, C Ayuso, M Baiget, P Gouras, JR Heckenlively, A den Hollander, SG Jacobson, RA Lewis, PA Sieving, B Wissinger, S Yzer, E Zrenner, G Utermann, A Gal. Retinal degeneration associated with RDH12 mutations results from decreased 11-cis retinal synthesis due to disruption of the visual cycle.. Hum Mol Genet 2005;14:3865-75", "DA Thompson, Y Li, CL McHenry, TJ Carlson, X Ding, PA Sieving, E Apfelstedt-Sylla, A Gal. Mutations in the gene encoding lecithin retinol acyltransferase are associated with early-onset severe retinal dystrophy.. Nat Genet 2001;28:123-4", "RT Tzekov, Y Liu, MM Sohocki, DJ Zack, SP Daiger, JR Heckenlively, DG Birch. Autosomal dominant retinal degeneration and bone loss in patients with a 12-bp deletion in the CRX gene.. Invest Ophthalmol Vis Sci 2001;42:1319-27", "J van der Spuy, JH Kim, YS Yu, A Szel, PJ Luthert, BJ Clark, ME Cheetham. The expression of the Leber congenital amaurosis protein AIPL1 coincides with rod and cone photoreceptor development.. Invest Ophthalmol Vis Sci 2003;44:5396-403", "H Wang, AI den Hollander, Y Moayedi, A Abulimiti, Y Li, RWJ Collin, CB Hoyng, I Lopez, M Bray, RA Lewis, JR Lupski, G Mardon, RK Koenekoop, R Chen. Mutations in SPATA7 cause Leber congenital amaurosis and juvenile retinitis pigmentosa.. Am J Hum Genet 2009;84:380-7", "RG Weleber. The dystrophic retina in multisystem disorders: the electroretinogram in neuronal ceroid lipofuscinoses.. Eye 1998;12:580-90", "RG Weleber, N Gupta, KM Trzupek, MS Wepner, DE Kurz, AH Milam. Electroretinographic and clinicopathologic correlations of retinal dysfunction in infantile neuronal ceroid lipofuscinosis (infantile Batten disease).. Mol Genet Metab 2004;83:128-37", "RG Weleber, M Michaelides, KM Trzupek, NB Stover, EM Stone. The phenotype of Severe Early Childhood Onset Retinal Dystrophy (SECORD) from mutation of RPE65 and differentiation from Leber congenital amaurosis.. Invest Ophthalmol Vis Sci 2011;52:292-302", "C Zeitz, B Kloeckener-Gruissem, U Forster, S Kohl, I Magyar, B Wissinger, G Matyas, FX Borruat, DF Schorderet, E Zrenner, FL Munier, W Berger. Mutations in CABP4, the gene encoding the Ca2+-binding protein 4, cause autosomal recessive night blindness.. Am J Hum Genet. 2006;79:657-67", "J Zernant, M Kulm, S Dharmaraj, AI den Hollander, I Perrault, MN Preising, B Lorenz, J Kaplan, FP Cremers, I Maumenee, RK Koenekoop, R Allikmets. Genotyping microarray (disease chip) for Leber congenital amaurosis: detection of modifier alleles.. Invest Ophthalmol Vis Sci 2005;46:3052-9", "Y Zhao, DH Hong, B Pawlyk, G Yue, M Adamian, M Grynberg, A Godzik, T Li. The retinitis pigmentosa GTPase regulator (RPGR)- interacting protein: subserving RPGR function and participating in disk morphogenesis.. Proc Natl Acad Sci U S A 2003;100:3965-70" ]	7/7/2004	2/5/2013	9/11/2005	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
lchad	lchad	[ "LCHAD deficiency (LCHADD)", "Long-Chain 3-Hydroxyacyl Coenzyme A Dehydrogenase Deficiency", "TFP Deficiency (TFPD)", "Mitochondrial Trifunctional Protein (MTP) Deficiency", "Trifunctional enzyme subunit alpha, mitochondrial", "Trifunctional enzyme subunit beta, mitochondrial", "HADHA", "HADHB", "Long-Chain Hydroxyacyl-CoA Dehydrogenase Deficiency / Trifunctional Protein Deficiency" ]	Long-Chain Hydroxyacyl-CoA Dehydrogenase Deficiency / Trifunctional Protein Deficiency	Pankaj Prasun, Mary Kate LoPiccolo, Ilona Ginevic	Summary Long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency and trifunctional protein (TFP) deficiency are caused by impairment of mitochondrial TFP. TFP has three enzymatic activities – long-chain enoyl-CoA hydratase, long-chain 3-hydroxyacyl-CoA dehydrogenase, and long-chain 3-ketoacyl-CoA thiolase. In individuals with LCHAD deficiency, there is isolated deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase, while deficiency of all three enzymes occurs in individuals with TFP deficiency. Individuals with TFP deficiency can present with a severe-to-mild phenotype, while individuals with LCHAD deficiency typically present with a severe-to-intermediate phenotype. Neonates with the severe phenotype present within a few days of birth with hypoglycemia, hepatomegaly, encephalopathy, and often cardiomyopathy. The intermediate phenotype is characterized by hypoketotic hypoglycemia precipitated by infection or fasting in infancy. The mild (late-onset) phenotype is characterized by myopathy and/or neuropathy. Long-term complications include peripheral neuropathy and retinopathy. The diagnosis of LCHAD/TFP deficiency is established in a proband with elevation of long-chain 3-hydroxyacylcarnitine species in plasma and/or increased excretion of 3-hydroxy-dicarboxylic acids in urine in combination with identification of biallelic pathogenic variants in Distinguishing LCHAD deficiency from TFP deficiency requires identification of isolated long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency on enzymatic assay in lymphocytes or skin fibroblasts. TFP deficiency is confirmed by the identification of deficiencies in all three TFP enzymatic activities (long-chain enoyl-CoA hydratase, long-chain 3-hydroxyacyl-CoA dehydrogenase, and long-chain 3-ketoacyl-CoA thiolase) in lymphocytes or skin fibroblasts. LCHAD/TFP deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an	Synonyms and Included Genes LCHAD deficiency (LCHADD) Long-chain 3-hydroxyacyl coenzyme A dehydrogenase deficiency TFP deficiency (TFPD) Mitochondrial trifunctional protein (MTP) deficiency • LCHAD deficiency (LCHADD) • Long-chain 3-hydroxyacyl coenzyme A dehydrogenase deficiency • TFP deficiency (TFPD) • Mitochondrial trifunctional protein (MTP) deficiency ## Diagnosis No consensus clinical diagnostic criteria for long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency or trifunctional protein (TFP) deficiency have been published. NBS for LCHAD/TFP deficiency is primarily based on quantification of the analytes 3-hydroxypalmitoyl carnitine (C16-OH) and 3-hydroxyoleoylcarnitine (C18:1-OH) on dried blood spots. C16-OH and C18:1-OH values above the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing including plasma acylcarnitine and urine organic acid profiles. If the follow-up biochemical testing supports the likelihood of LCHAD/TFP deficiency, additional testing is required to establish the diagnosis (see The following medical interventions need to begin immediately on receipt of an abnormal NBS result while additional testing is performed to determine whether this is a true positive NBS result and to establish a definitive diagnosis of LCHAD/TFP deficiency: Evaluation of the newborn to ascertain clinical status Education of the caregivers to avoid prolonged fasting and to monitor for decreased oral intake, vomiting, or lethargy Immediate intervention (to be considered if the newborn is not doing well clinically) possibly including admission to the hospital, fluid resuscitation, infusion of IV dextrose (10% or higher), and cardiac evaluation Supportive – but nonspecific – clinical findings, laboratory findings, and family history include the following. Hypoketotic hypoglycemia, hepatomegaly Cardiomyopathy Encephalopathy Episodic rhabdomyolysis Exercise intolerance and muscle weakness Peripheral neuropathy Retinopathy Nonspecific: Hypoglycemia (nonketotic or hypoketotic) with blood glucose often <45 mg/dL Urinalysis that demonstrates the absence of ketones in the setting of hypoglycemia Metabolic acidosis Lactic acidosis Hyperammonemia: blood ammonia level may be >200 µmol/L in newborns and >100 µmol/L after the neonatal period Elevated liver transaminases (AST, ALT) Elevated creatine kinase (CK), particularly in the late-onset myopathic form. A CK value greater than five times the upper limit of reference is suggestive of rhabdomyolysis (range 1,000-100,000 IU/L). A CK value of >15,000 IU/L at presentation increases the risk for acute kidney injury [ Specific: Note: Because elevations of these metabolites can be intermittent particularly in individuals with milder disease, follow-up testing is required to establish the diagnosis of LCHAD/TFP deficiency (see The diagnosis of LCHAD deficiency The diagnosis of TFP deficiency 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 [ Perform sequence analysis of If For an introduction to multigene panels click When the diagnosis of LCHAD/TFP deficiency has not been considered, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in LCHAD/TFP Deficiency LCHAD = long-chain hydroxyacyl-CoA dehydrogenase; TFP = trifunctional protein Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Data derived from the subscription-based professional view of Human Gene Mutation Database [ To date, large deletions and/or duplications have not been reported in individuals with LCHAD deficiency. Two large Two large • Evaluation of the newborn to ascertain clinical status • Education of the caregivers to avoid prolonged fasting and to monitor for decreased oral intake, vomiting, or lethargy • Immediate intervention (to be considered if the newborn is not doing well clinically) possibly including admission to the hospital, fluid resuscitation, infusion of IV dextrose (10% or higher), and cardiac evaluation • • Hypoketotic hypoglycemia, hepatomegaly • Cardiomyopathy • Encephalopathy • Hypoketotic hypoglycemia, hepatomegaly • Cardiomyopathy • Encephalopathy • • Episodic rhabdomyolysis • Exercise intolerance and muscle weakness • Peripheral neuropathy • Retinopathy • Episodic rhabdomyolysis • Exercise intolerance and muscle weakness • Peripheral neuropathy • Retinopathy • Hypoketotic hypoglycemia, hepatomegaly • Cardiomyopathy • Encephalopathy • Episodic rhabdomyolysis • Exercise intolerance and muscle weakness • Peripheral neuropathy • Retinopathy • Nonspecific: • Hypoglycemia (nonketotic or hypoketotic) with blood glucose often <45 mg/dL • Urinalysis that demonstrates the absence of ketones in the setting of hypoglycemia • Metabolic acidosis • Lactic acidosis • Hyperammonemia: blood ammonia level may be >200 µmol/L in newborns and >100 µmol/L after the neonatal period • Elevated liver transaminases (AST, ALT) • Elevated creatine kinase (CK), particularly in the late-onset myopathic form. A CK value greater than five times the upper limit of reference is suggestive of rhabdomyolysis (range 1,000-100,000 IU/L). A CK value of >15,000 IU/L at presentation increases the risk for acute kidney injury [ • Hypoglycemia (nonketotic or hypoketotic) with blood glucose often <45 mg/dL • Urinalysis that demonstrates the absence of ketones in the setting of hypoglycemia • Metabolic acidosis • Lactic acidosis • Hyperammonemia: blood ammonia level may be >200 µmol/L in newborns and >100 µmol/L after the neonatal period • Elevated liver transaminases (AST, ALT) • Elevated creatine kinase (CK), particularly in the late-onset myopathic form. A CK value greater than five times the upper limit of reference is suggestive of rhabdomyolysis (range 1,000-100,000 IU/L). A CK value of >15,000 IU/L at presentation increases the risk for acute kidney injury [ • Specific: • Hypoglycemia (nonketotic or hypoketotic) with blood glucose often <45 mg/dL • Urinalysis that demonstrates the absence of ketones in the setting of hypoglycemia • Metabolic acidosis • Lactic acidosis • Hyperammonemia: blood ammonia level may be >200 µmol/L in newborns and >100 µmol/L after the neonatal period • Elevated liver transaminases (AST, ALT) • Elevated creatine kinase (CK), particularly in the late-onset myopathic form. A CK value greater than five times the upper limit of reference is suggestive of rhabdomyolysis (range 1,000-100,000 IU/L). A CK value of >15,000 IU/L at presentation increases the risk for acute kidney injury [ • Perform sequence analysis of • If • Perform sequence analysis of • If • For an introduction to multigene panels click • Perform sequence analysis of • If ## Suggestive Findings NBS for LCHAD/TFP deficiency is primarily based on quantification of the analytes 3-hydroxypalmitoyl carnitine (C16-OH) and 3-hydroxyoleoylcarnitine (C18:1-OH) on dried blood spots. C16-OH and C18:1-OH values above the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing including plasma acylcarnitine and urine organic acid profiles. If the follow-up biochemical testing supports the likelihood of LCHAD/TFP deficiency, additional testing is required to establish the diagnosis (see The following medical interventions need to begin immediately on receipt of an abnormal NBS result while additional testing is performed to determine whether this is a true positive NBS result and to establish a definitive diagnosis of LCHAD/TFP deficiency: Evaluation of the newborn to ascertain clinical status Education of the caregivers to avoid prolonged fasting and to monitor for decreased oral intake, vomiting, or lethargy Immediate intervention (to be considered if the newborn is not doing well clinically) possibly including admission to the hospital, fluid resuscitation, infusion of IV dextrose (10% or higher), and cardiac evaluation Supportive – but nonspecific – clinical findings, laboratory findings, and family history include the following. Hypoketotic hypoglycemia, hepatomegaly Cardiomyopathy Encephalopathy Episodic rhabdomyolysis Exercise intolerance and muscle weakness Peripheral neuropathy Retinopathy Nonspecific: Hypoglycemia (nonketotic or hypoketotic) with blood glucose often <45 mg/dL Urinalysis that demonstrates the absence of ketones in the setting of hypoglycemia Metabolic acidosis Lactic acidosis Hyperammonemia: blood ammonia level may be >200 µmol/L in newborns and >100 µmol/L after the neonatal period Elevated liver transaminases (AST, ALT) Elevated creatine kinase (CK), particularly in the late-onset myopathic form. A CK value greater than five times the upper limit of reference is suggestive of rhabdomyolysis (range 1,000-100,000 IU/L). A CK value of >15,000 IU/L at presentation increases the risk for acute kidney injury [ Specific: Note: Because elevations of these metabolites can be intermittent particularly in individuals with milder disease, follow-up testing is required to establish the diagnosis of LCHAD/TFP deficiency (see • Evaluation of the newborn to ascertain clinical status • Education of the caregivers to avoid prolonged fasting and to monitor for decreased oral intake, vomiting, or lethargy • Immediate intervention (to be considered if the newborn is not doing well clinically) possibly including admission to the hospital, fluid resuscitation, infusion of IV dextrose (10% or higher), and cardiac evaluation • • Hypoketotic hypoglycemia, hepatomegaly • Cardiomyopathy • Encephalopathy • Hypoketotic hypoglycemia, hepatomegaly • Cardiomyopathy • Encephalopathy • • Episodic rhabdomyolysis • Exercise intolerance and muscle weakness • Peripheral neuropathy • Retinopathy • Episodic rhabdomyolysis • Exercise intolerance and muscle weakness • Peripheral neuropathy • Retinopathy • Hypoketotic hypoglycemia, hepatomegaly • Cardiomyopathy • Encephalopathy • Episodic rhabdomyolysis • Exercise intolerance and muscle weakness • Peripheral neuropathy • Retinopathy • Nonspecific: • Hypoglycemia (nonketotic or hypoketotic) with blood glucose often <45 mg/dL • Urinalysis that demonstrates the absence of ketones in the setting of hypoglycemia • Metabolic acidosis • Lactic acidosis • Hyperammonemia: blood ammonia level may be >200 µmol/L in newborns and >100 µmol/L after the neonatal period • Elevated liver transaminases (AST, ALT) • Elevated creatine kinase (CK), particularly in the late-onset myopathic form. A CK value greater than five times the upper limit of reference is suggestive of rhabdomyolysis (range 1,000-100,000 IU/L). A CK value of >15,000 IU/L at presentation increases the risk for acute kidney injury [ • Hypoglycemia (nonketotic or hypoketotic) with blood glucose often <45 mg/dL • Urinalysis that demonstrates the absence of ketones in the setting of hypoglycemia • Metabolic acidosis • Lactic acidosis • Hyperammonemia: blood ammonia level may be >200 µmol/L in newborns and >100 µmol/L after the neonatal period • Elevated liver transaminases (AST, ALT) • Elevated creatine kinase (CK), particularly in the late-onset myopathic form. A CK value greater than five times the upper limit of reference is suggestive of rhabdomyolysis (range 1,000-100,000 IU/L). A CK value of >15,000 IU/L at presentation increases the risk for acute kidney injury [ • Specific: • Hypoglycemia (nonketotic or hypoketotic) with blood glucose often <45 mg/dL • Urinalysis that demonstrates the absence of ketones in the setting of hypoglycemia • Metabolic acidosis • Lactic acidosis • Hyperammonemia: blood ammonia level may be >200 µmol/L in newborns and >100 µmol/L after the neonatal period • Elevated liver transaminases (AST, ALT) • Elevated creatine kinase (CK), particularly in the late-onset myopathic form. A CK value greater than five times the upper limit of reference is suggestive of rhabdomyolysis (range 1,000-100,000 IU/L). A CK value of >15,000 IU/L at presentation increases the risk for acute kidney injury [ ## Scenario 1: Abnormal Newborn Screening (NBS) Result NBS for LCHAD/TFP deficiency is primarily based on quantification of the analytes 3-hydroxypalmitoyl carnitine (C16-OH) and 3-hydroxyoleoylcarnitine (C18:1-OH) on dried blood spots. C16-OH and C18:1-OH values above the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing including plasma acylcarnitine and urine organic acid profiles. If the follow-up biochemical testing supports the likelihood of LCHAD/TFP deficiency, additional testing is required to establish the diagnosis (see The following medical interventions need to begin immediately on receipt of an abnormal NBS result while additional testing is performed to determine whether this is a true positive NBS result and to establish a definitive diagnosis of LCHAD/TFP deficiency: Evaluation of the newborn to ascertain clinical status Education of the caregivers to avoid prolonged fasting and to monitor for decreased oral intake, vomiting, or lethargy Immediate intervention (to be considered if the newborn is not doing well clinically) possibly including admission to the hospital, fluid resuscitation, infusion of IV dextrose (10% or higher), and cardiac evaluation • Evaluation of the newborn to ascertain clinical status • Education of the caregivers to avoid prolonged fasting and to monitor for decreased oral intake, vomiting, or lethargy • Immediate intervention (to be considered if the newborn is not doing well clinically) possibly including admission to the hospital, fluid resuscitation, infusion of IV dextrose (10% or higher), and cardiac evaluation ## Scenario 2: Symptomatic Individual Supportive – but nonspecific – clinical findings, laboratory findings, and family history include the following. Hypoketotic hypoglycemia, hepatomegaly Cardiomyopathy Encephalopathy Episodic rhabdomyolysis Exercise intolerance and muscle weakness Peripheral neuropathy Retinopathy Nonspecific: Hypoglycemia (nonketotic or hypoketotic) with blood glucose often <45 mg/dL Urinalysis that demonstrates the absence of ketones in the setting of hypoglycemia Metabolic acidosis Lactic acidosis Hyperammonemia: blood ammonia level may be >200 µmol/L in newborns and >100 µmol/L after the neonatal period Elevated liver transaminases (AST, ALT) Elevated creatine kinase (CK), particularly in the late-onset myopathic form. A CK value greater than five times the upper limit of reference is suggestive of rhabdomyolysis (range 1,000-100,000 IU/L). A CK value of >15,000 IU/L at presentation increases the risk for acute kidney injury [ Specific: Note: Because elevations of these metabolites can be intermittent particularly in individuals with milder disease, follow-up testing is required to establish the diagnosis of LCHAD/TFP deficiency (see • • Hypoketotic hypoglycemia, hepatomegaly • Cardiomyopathy • Encephalopathy • Hypoketotic hypoglycemia, hepatomegaly • Cardiomyopathy • Encephalopathy • • Episodic rhabdomyolysis • Exercise intolerance and muscle weakness • Peripheral neuropathy • Retinopathy • Episodic rhabdomyolysis • Exercise intolerance and muscle weakness • Peripheral neuropathy • Retinopathy • Hypoketotic hypoglycemia, hepatomegaly • Cardiomyopathy • Encephalopathy • Episodic rhabdomyolysis • Exercise intolerance and muscle weakness • Peripheral neuropathy • Retinopathy • Nonspecific: • Hypoglycemia (nonketotic or hypoketotic) with blood glucose often <45 mg/dL • Urinalysis that demonstrates the absence of ketones in the setting of hypoglycemia • Metabolic acidosis • Lactic acidosis • Hyperammonemia: blood ammonia level may be >200 µmol/L in newborns and >100 µmol/L after the neonatal period • Elevated liver transaminases (AST, ALT) • Elevated creatine kinase (CK), particularly in the late-onset myopathic form. A CK value greater than five times the upper limit of reference is suggestive of rhabdomyolysis (range 1,000-100,000 IU/L). A CK value of >15,000 IU/L at presentation increases the risk for acute kidney injury [ • Hypoglycemia (nonketotic or hypoketotic) with blood glucose often <45 mg/dL • Urinalysis that demonstrates the absence of ketones in the setting of hypoglycemia • Metabolic acidosis • Lactic acidosis • Hyperammonemia: blood ammonia level may be >200 µmol/L in newborns and >100 µmol/L after the neonatal period • Elevated liver transaminases (AST, ALT) • Elevated creatine kinase (CK), particularly in the late-onset myopathic form. A CK value greater than five times the upper limit of reference is suggestive of rhabdomyolysis (range 1,000-100,000 IU/L). A CK value of >15,000 IU/L at presentation increases the risk for acute kidney injury [ • Specific: • Hypoglycemia (nonketotic or hypoketotic) with blood glucose often <45 mg/dL • Urinalysis that demonstrates the absence of ketones in the setting of hypoglycemia • Metabolic acidosis • Lactic acidosis • Hyperammonemia: blood ammonia level may be >200 µmol/L in newborns and >100 µmol/L after the neonatal period • Elevated liver transaminases (AST, ALT) • Elevated creatine kinase (CK), particularly in the late-onset myopathic form. A CK value greater than five times the upper limit of reference is suggestive of rhabdomyolysis (range 1,000-100,000 IU/L). A CK value of >15,000 IU/L at presentation increases the risk for acute kidney injury [ ## Establishing the Diagnosis The diagnosis of LCHAD deficiency The diagnosis of TFP deficiency 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 [ Perform sequence analysis of If For an introduction to multigene panels click When the diagnosis of LCHAD/TFP deficiency has not been considered, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in LCHAD/TFP Deficiency LCHAD = long-chain hydroxyacyl-CoA dehydrogenase; TFP = trifunctional protein Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Data derived from the subscription-based professional view of Human Gene Mutation Database [ To date, large deletions and/or duplications have not been reported in individuals with LCHAD deficiency. Two large Two large • Perform sequence analysis of • If • Perform sequence analysis of • If • For an introduction to multigene panels click • Perform sequence analysis of • If ## Molecular Genetic Testing Approaches Perform sequence analysis of If For an introduction to multigene panels click When the diagnosis of LCHAD/TFP deficiency has not been considered, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in LCHAD/TFP Deficiency LCHAD = long-chain hydroxyacyl-CoA dehydrogenase; TFP = trifunctional protein Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Data derived from the subscription-based professional view of Human Gene Mutation Database [ To date, large deletions and/or duplications have not been reported in individuals with LCHAD deficiency. Two large Two large • Perform sequence analysis of • If • Perform sequence analysis of • If • For an introduction to multigene panels click • Perform sequence analysis of • If ## Biochemical Testing Approaches ## Clinical Characteristics Long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency and trifunctional protein (TFP) deficiency are caused by impairment of mitochondrial TFP. TFP has three enzymatic activities – long-chain enoyl-CoA hydratase, long-chain 3-hydroxyacyl-CoA dehydrogenase, and long-chain 3-ketoacyl-CoA thiolase. Deficiency of the enzyme long-chain 3-hydroxyacyl-CoA dehydrogenase occurs in individuals with LCHAD deficiency, while deficiency of all three enzymes occurs in individuals with TFP deficiency. LCHAD and TFP deficiency are disorders of long-chain fatty acid oxidation, which typically present with recurrent episodes of hypoketotic hypoglycemia precipitated by fasting or illness. In addition, the other characteristic manifestations of long-chain fatty acid oxidation defects (FAODs) such as cardiomyopathy, liver dysfunction, or rhabdomyolysis may be present. However, peripheral neuropathy and retinopathy are unique complications of these disorders not seen in other FAODs. The clinical presentation represents a continuous spectrum of severity ranging from severe neonatal-onset to mild late-onset forms. Individuals with LCHAD deficiency usually present with a severe-to-intermediate phenotype, while individuals with TFP deficiency typically present with a severe-to-mild phenotype. LCHAD/TFP Deficiency: Frequency of Select Features LCHAD = long-chain hydroxyacyl-CoA dehydrogenase; TFP = trifunctional protein Frequencies are approximations from data published prior to the implementation of newborn screening (NBS) [den Boer ME et al 2002, den Boer ME et al 2003, The neonatal-onset (severe/cardiac) presentation is more common in individuals with TFP deficiency than in those with LCHAD deficiency. The main manifestations are the following: Individuals with the intermediate or moderate severity phenotype present later in infancy. This is the most common presentation in LCHAD deficiency and relatively uncommon in TFP deficiency. The classic presentation is acute metabolic decompensation precipitated by fasting or infection. The metabolic decompensation is characterized by hypoketotic hypoglycemia often associated with lactic acidosis, elevated liver enzymes, and high creatine kinase (CK). Infants may present with vomiting, lethargy, poor feeding, and hepatomegaly. Associated baseline findings including muscle weakness, feeding difficulties, and hypotonia may be present. Other manifestations of this form (more common in previously untreated individuals): cardiomyopathy (dilated or hypertrophic), long QT intervals, liver cirrhosis, cholestasis, developmental delays, and failure to thrive. Cardiomyopathy may be present at baseline or dilated cardiomyopathy may first appear during metabolic crisis even in previously treated individuals. Prompt diagnosis and initiation of treatment is crucial for reversal of cardiomyopathy and favorable outcome. Newborn screening has enabled presymptomatic diagnosis and thus improved outcome. Individuals with the mild phenotype usually present after infancy with neuromuscular symptoms. The isolated neuromyopathic presentation is typical of mild TFP deficiency and rare in LCHAD deficiency. However, infants with LCHAD deficiency with the intermediate/hepatic phenotype may present later with neuromyopathic symptoms. The common manifestations are the following: Long-term complications in those with the intermediate and late-onset phenotypes include the following: Stage 1. Normal to diffuse hypopigmentation of the fundus Stage 2. Pigment clumping in the fovea Stage 3. Macular pallor and migration of pigmentary changes toward the periphery Stage 4. Atrophy of the posterior fundus and further peripheral migration of pigmentary changes Visual impairment is present from stage 3 onward. Hence, retinopathy may be missed if fundal imaging and electroretinogram are not done. Approximately half of individuals with LCHAD deficiency have evidence of retinopathy by age two years. Early diagnosis and treatment can slow the progress but may not prevent this complication [ Rare manifestations in individuals with LCHAD/TFP deficiency include hypoparathyroidism, neonatal respiratory distress syndrome, and necrotizing enterocolitis [ Pregnancy complications such as HELLP ( Although clinical manifestations of The incidence of LCHAD deficiency on NBS data from Australia, Germany, and the US was estimated at 1:250,000; TFP deficiency incidence was estimated at 1:750,000 [ The carrier frequency of the most common LCHAD deficiency is especially frequent in the Pomerania region of Poland near the Baltic Sea, partly as a result of a high carrier frequency (1:73) of • The metabolic decompensation is characterized by hypoketotic hypoglycemia often associated with lactic acidosis, elevated liver enzymes, and high creatine kinase (CK). • Infants may present with vomiting, lethargy, poor feeding, and hepatomegaly. • Associated baseline findings including muscle weakness, feeding difficulties, and hypotonia may be present. • Other manifestations of this form (more common in previously untreated individuals): cardiomyopathy (dilated or hypertrophic), long QT intervals, liver cirrhosis, cholestasis, developmental delays, and failure to thrive. Cardiomyopathy may be present at baseline or dilated cardiomyopathy may first appear during metabolic crisis even in previously treated individuals. • Prompt diagnosis and initiation of treatment is crucial for reversal of cardiomyopathy and favorable outcome. Newborn screening has enabled presymptomatic diagnosis and thus improved outcome. • Stage 1. Normal to diffuse hypopigmentation of the fundus • Stage 2. Pigment clumping in the fovea • Stage 3. Macular pallor and migration of pigmentary changes toward the periphery • Stage 4. Atrophy of the posterior fundus and further peripheral migration of pigmentary changes • Visual impairment is present from stage 3 onward. Hence, retinopathy may be missed if fundal imaging and electroretinogram are not done. Approximately half of individuals with LCHAD deficiency have evidence of retinopathy by age two years. Early diagnosis and treatment can slow the progress but may not prevent this complication [ • Stage 1. Normal to diffuse hypopigmentation of the fundus • Stage 2. Pigment clumping in the fovea • Stage 3. Macular pallor and migration of pigmentary changes toward the periphery • Stage 4. Atrophy of the posterior fundus and further peripheral migration of pigmentary changes • Stage 1. Normal to diffuse hypopigmentation of the fundus • Stage 2. Pigment clumping in the fovea • Stage 3. Macular pallor and migration of pigmentary changes toward the periphery • Stage 4. Atrophy of the posterior fundus and further peripheral migration of pigmentary changes ## Clinical Description Long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency and trifunctional protein (TFP) deficiency are caused by impairment of mitochondrial TFP. TFP has three enzymatic activities – long-chain enoyl-CoA hydratase, long-chain 3-hydroxyacyl-CoA dehydrogenase, and long-chain 3-ketoacyl-CoA thiolase. Deficiency of the enzyme long-chain 3-hydroxyacyl-CoA dehydrogenase occurs in individuals with LCHAD deficiency, while deficiency of all three enzymes occurs in individuals with TFP deficiency. LCHAD and TFP deficiency are disorders of long-chain fatty acid oxidation, which typically present with recurrent episodes of hypoketotic hypoglycemia precipitated by fasting or illness. In addition, the other characteristic manifestations of long-chain fatty acid oxidation defects (FAODs) such as cardiomyopathy, liver dysfunction, or rhabdomyolysis may be present. However, peripheral neuropathy and retinopathy are unique complications of these disorders not seen in other FAODs. The clinical presentation represents a continuous spectrum of severity ranging from severe neonatal-onset to mild late-onset forms. Individuals with LCHAD deficiency usually present with a severe-to-intermediate phenotype, while individuals with TFP deficiency typically present with a severe-to-mild phenotype. LCHAD/TFP Deficiency: Frequency of Select Features LCHAD = long-chain hydroxyacyl-CoA dehydrogenase; TFP = trifunctional protein Frequencies are approximations from data published prior to the implementation of newborn screening (NBS) [den Boer ME et al 2002, den Boer ME et al 2003, The neonatal-onset (severe/cardiac) presentation is more common in individuals with TFP deficiency than in those with LCHAD deficiency. The main manifestations are the following: Individuals with the intermediate or moderate severity phenotype present later in infancy. This is the most common presentation in LCHAD deficiency and relatively uncommon in TFP deficiency. The classic presentation is acute metabolic decompensation precipitated by fasting or infection. The metabolic decompensation is characterized by hypoketotic hypoglycemia often associated with lactic acidosis, elevated liver enzymes, and high creatine kinase (CK). Infants may present with vomiting, lethargy, poor feeding, and hepatomegaly. Associated baseline findings including muscle weakness, feeding difficulties, and hypotonia may be present. Other manifestations of this form (more common in previously untreated individuals): cardiomyopathy (dilated or hypertrophic), long QT intervals, liver cirrhosis, cholestasis, developmental delays, and failure to thrive. Cardiomyopathy may be present at baseline or dilated cardiomyopathy may first appear during metabolic crisis even in previously treated individuals. Prompt diagnosis and initiation of treatment is crucial for reversal of cardiomyopathy and favorable outcome. Newborn screening has enabled presymptomatic diagnosis and thus improved outcome. Individuals with the mild phenotype usually present after infancy with neuromuscular symptoms. The isolated neuromyopathic presentation is typical of mild TFP deficiency and rare in LCHAD deficiency. However, infants with LCHAD deficiency with the intermediate/hepatic phenotype may present later with neuromyopathic symptoms. The common manifestations are the following: Long-term complications in those with the intermediate and late-onset phenotypes include the following: Stage 1. Normal to diffuse hypopigmentation of the fundus Stage 2. Pigment clumping in the fovea Stage 3. Macular pallor and migration of pigmentary changes toward the periphery Stage 4. Atrophy of the posterior fundus and further peripheral migration of pigmentary changes Visual impairment is present from stage 3 onward. Hence, retinopathy may be missed if fundal imaging and electroretinogram are not done. Approximately half of individuals with LCHAD deficiency have evidence of retinopathy by age two years. Early diagnosis and treatment can slow the progress but may not prevent this complication [ Rare manifestations in individuals with LCHAD/TFP deficiency include hypoparathyroidism, neonatal respiratory distress syndrome, and necrotizing enterocolitis [ Pregnancy complications such as HELLP ( • The metabolic decompensation is characterized by hypoketotic hypoglycemia often associated with lactic acidosis, elevated liver enzymes, and high creatine kinase (CK). • Infants may present with vomiting, lethargy, poor feeding, and hepatomegaly. • Associated baseline findings including muscle weakness, feeding difficulties, and hypotonia may be present. • Other manifestations of this form (more common in previously untreated individuals): cardiomyopathy (dilated or hypertrophic), long QT intervals, liver cirrhosis, cholestasis, developmental delays, and failure to thrive. Cardiomyopathy may be present at baseline or dilated cardiomyopathy may first appear during metabolic crisis even in previously treated individuals. • Prompt diagnosis and initiation of treatment is crucial for reversal of cardiomyopathy and favorable outcome. Newborn screening has enabled presymptomatic diagnosis and thus improved outcome. • Stage 1. Normal to diffuse hypopigmentation of the fundus • Stage 2. Pigment clumping in the fovea • Stage 3. Macular pallor and migration of pigmentary changes toward the periphery • Stage 4. Atrophy of the posterior fundus and further peripheral migration of pigmentary changes • Visual impairment is present from stage 3 onward. Hence, retinopathy may be missed if fundal imaging and electroretinogram are not done. Approximately half of individuals with LCHAD deficiency have evidence of retinopathy by age two years. Early diagnosis and treatment can slow the progress but may not prevent this complication [ • Stage 1. Normal to diffuse hypopigmentation of the fundus • Stage 2. Pigment clumping in the fovea • Stage 3. Macular pallor and migration of pigmentary changes toward the periphery • Stage 4. Atrophy of the posterior fundus and further peripheral migration of pigmentary changes • Stage 1. Normal to diffuse hypopigmentation of the fundus • Stage 2. Pigment clumping in the fovea • Stage 3. Macular pallor and migration of pigmentary changes toward the periphery • Stage 4. Atrophy of the posterior fundus and further peripheral migration of pigmentary changes ## Neonatal Onset (Severe/Cardiac Phenotype) The neonatal-onset (severe/cardiac) presentation is more common in individuals with TFP deficiency than in those with LCHAD deficiency. The main manifestations are the following: ## Infantile Onset (Intermediate/Hepatic Phenotype) Individuals with the intermediate or moderate severity phenotype present later in infancy. This is the most common presentation in LCHAD deficiency and relatively uncommon in TFP deficiency. The classic presentation is acute metabolic decompensation precipitated by fasting or infection. The metabolic decompensation is characterized by hypoketotic hypoglycemia often associated with lactic acidosis, elevated liver enzymes, and high creatine kinase (CK). Infants may present with vomiting, lethargy, poor feeding, and hepatomegaly. Associated baseline findings including muscle weakness, feeding difficulties, and hypotonia may be present. Other manifestations of this form (more common in previously untreated individuals): cardiomyopathy (dilated or hypertrophic), long QT intervals, liver cirrhosis, cholestasis, developmental delays, and failure to thrive. Cardiomyopathy may be present at baseline or dilated cardiomyopathy may first appear during metabolic crisis even in previously treated individuals. Prompt diagnosis and initiation of treatment is crucial for reversal of cardiomyopathy and favorable outcome. Newborn screening has enabled presymptomatic diagnosis and thus improved outcome. • The metabolic decompensation is characterized by hypoketotic hypoglycemia often associated with lactic acidosis, elevated liver enzymes, and high creatine kinase (CK). • Infants may present with vomiting, lethargy, poor feeding, and hepatomegaly. • Associated baseline findings including muscle weakness, feeding difficulties, and hypotonia may be present. • Other manifestations of this form (more common in previously untreated individuals): cardiomyopathy (dilated or hypertrophic), long QT intervals, liver cirrhosis, cholestasis, developmental delays, and failure to thrive. Cardiomyopathy may be present at baseline or dilated cardiomyopathy may first appear during metabolic crisis even in previously treated individuals. • Prompt diagnosis and initiation of treatment is crucial for reversal of cardiomyopathy and favorable outcome. Newborn screening has enabled presymptomatic diagnosis and thus improved outcome. ## Late Onset (Mild/Neuromyopathic Phenotype) Individuals with the mild phenotype usually present after infancy with neuromuscular symptoms. The isolated neuromyopathic presentation is typical of mild TFP deficiency and rare in LCHAD deficiency. However, infants with LCHAD deficiency with the intermediate/hepatic phenotype may present later with neuromyopathic symptoms. The common manifestations are the following: ## Long-Term Complications Long-term complications in those with the intermediate and late-onset phenotypes include the following: Stage 1. Normal to diffuse hypopigmentation of the fundus Stage 2. Pigment clumping in the fovea Stage 3. Macular pallor and migration of pigmentary changes toward the periphery Stage 4. Atrophy of the posterior fundus and further peripheral migration of pigmentary changes Visual impairment is present from stage 3 onward. Hence, retinopathy may be missed if fundal imaging and electroretinogram are not done. Approximately half of individuals with LCHAD deficiency have evidence of retinopathy by age two years. Early diagnosis and treatment can slow the progress but may not prevent this complication [ • Stage 1. Normal to diffuse hypopigmentation of the fundus • Stage 2. Pigment clumping in the fovea • Stage 3. Macular pallor and migration of pigmentary changes toward the periphery • Stage 4. Atrophy of the posterior fundus and further peripheral migration of pigmentary changes • Visual impairment is present from stage 3 onward. Hence, retinopathy may be missed if fundal imaging and electroretinogram are not done. Approximately half of individuals with LCHAD deficiency have evidence of retinopathy by age two years. Early diagnosis and treatment can slow the progress but may not prevent this complication [ • Stage 1. Normal to diffuse hypopigmentation of the fundus • Stage 2. Pigment clumping in the fovea • Stage 3. Macular pallor and migration of pigmentary changes toward the periphery • Stage 4. Atrophy of the posterior fundus and further peripheral migration of pigmentary changes • Stage 1. Normal to diffuse hypopigmentation of the fundus • Stage 2. Pigment clumping in the fovea • Stage 3. Macular pallor and migration of pigmentary changes toward the periphery • Stage 4. Atrophy of the posterior fundus and further peripheral migration of pigmentary changes ## Other Rare manifestations in individuals with LCHAD/TFP deficiency include hypoparathyroidism, neonatal respiratory distress syndrome, and necrotizing enterocolitis [ ## Pregnancy Complications Pregnancy complications such as HELLP ( ## Genotype-Phenotype Correlations Although clinical manifestations of ## Prevalence The incidence of LCHAD deficiency on NBS data from Australia, Germany, and the US was estimated at 1:250,000; TFP deficiency incidence was estimated at 1:750,000 [ The carrier frequency of the most common LCHAD deficiency is especially frequent in the Pomerania region of Poland near the Baltic Sea, partly as a result of a high carrier frequency (1:73) of ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Genetic Disorders of Interest in the Differential Diagnosis of LCHAD/TFP Deficiency Severe early-onset form: cardiomyopathy & multiorgan failure Intermediate form: intermittent hypoketotic hypoglycemia Late-onset myopathic form: recurrent rhabdomyolysis Lethal neonatal form: hypoglycemia, liver failure, cardiomyopathy Severe infantile hepatocardiomuscular form: intermittent hypoketotic hypoglycemia, liver failure, cardiomyopathy Late-onset myopathic form: recurrent rhabdomyolysis Congenital anomalies (cystic/dysplastic kidneys, neuronal migration defects) may be present in lethal neonatal form of CPT II deficiency. CPT II deficiency is not assoc w/peripheral neuropathy or retinopathy. Severe neonatal form: hypoglycemia, metabolic acidosis, lactic acidosis, hyperammonemia, hepatomegaly, cardiomyopathy Late-onset form: recurrent metabolic decompensation consisting of hypoglycemia & metabolic acidosis, recurrent rhabdomyolysis Congenital anomalies may be present in severe neonatal form of MADD. Peripheral neuropathy has been described in MADD, but retinopathy has not been assoc w/MADD. Severe neonatal form: hypoglycemia, hyperammonemia, liver failure, ↑ CK, cardiomyopathy Late-onset form (rare): recurrent metabolic decompensation consisting of hypoketotic hypoglycemia CK = creatine kinase; LCHAD = long-chain hydroxyacyl-CoA dehydrogenase; TFP = trifunctional protein The disorders listed in These disorders can usually be differentiated with acylcarnitine profile testing. In addition to the above-mentioned conditions, mitochondrial respiratory chain disorders should be considered in the differential diagnosis of long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) / trifunctional protein (TFP) deficiency. The common manifestations of LCHAD/TFP deficiency – such as cardiomyopathy, skeletal myopathy, hypotonia, peripheral neuropathy, and retinopathy – are also very commonly seen in mitochondrial respiratory chain disorders. See • Severe early-onset form: cardiomyopathy & multiorgan failure • Intermediate form: intermittent hypoketotic hypoglycemia • Late-onset myopathic form: recurrent rhabdomyolysis • Lethal neonatal form: hypoglycemia, liver failure, cardiomyopathy • Severe infantile hepatocardiomuscular form: intermittent hypoketotic hypoglycemia, liver failure, cardiomyopathy • Late-onset myopathic form: recurrent rhabdomyolysis • Congenital anomalies (cystic/dysplastic kidneys, neuronal migration defects) may be present in lethal neonatal form of CPT II deficiency. • CPT II deficiency is not assoc w/peripheral neuropathy or retinopathy. • Severe neonatal form: hypoglycemia, metabolic acidosis, lactic acidosis, hyperammonemia, hepatomegaly, cardiomyopathy • Late-onset form: recurrent metabolic decompensation consisting of hypoglycemia & metabolic acidosis, recurrent rhabdomyolysis • Congenital anomalies may be present in severe neonatal form of MADD. • Peripheral neuropathy has been described in MADD, but retinopathy has not been assoc w/MADD. • Severe neonatal form: hypoglycemia, hyperammonemia, liver failure, ↑ CK, cardiomyopathy • Late-onset form (rare): recurrent metabolic decompensation consisting of hypoketotic hypoglycemia ## Management A brief outline of treatment recommendations for long-chain fatty acid oxidation defects including long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) / trifunctional protein (TFP) deficiency has been published [ To establish the extent of disease and needs in an individual diagnosed with LCHAD/TFP deficiency, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with LCHAD/TFP Deficiency Blood gas – arterial or venous (e.g., w/i-STAT Glucose, liver transaminases (AST, ALT) Electrolytes w/bicarbonate, BUN, creatinine CK CBC w/differential & addl eval when infection is suspected Community or Social work involvement for parental support; Home nursing referral. ALT = alanine transaminase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CBC = complete blood count; CK = creatine kinase; LCHAD = long-chain hydroxyacyl-CoA dehydrogenase; MOI = mode of inheritance; TFP = trifunctional protein Medical geneticist, certified genetic counselor, certified advanced genetic nurse Management by multidisciplinary specialists including a metabolic physician / biochemical geneticist, specialist metabolic dietitian, cardiologist, neurologist, ophthalmologist, and developmental pediatrician is recommended. Treatment of Manifestations in Individuals with LCHAD/TFP Deficiency Birth-age 3 mos: frequent feeds (every 2-3 hrs) Age 4-12 mos: feeding interval can be ↑ to every 4 hrs if tolerated by 6 mos. From age 6 to 12 mos, daytime feeding interval every 4 hrs; overnight fasting can be gradually ↑ to 6-8 hrs by 12 mos. Age 1-3 yrs: daytime feeding interval 4 hrs; overnight fasting up to 10 hrs may be attempted Age 3+ yrs: overnight fasting up to 12 hrs may be attempted ↓ feeding interval by half during periods of illness. After age 1 yr, if preprandial hypoglycemia remains an issue, consider overnight feedings or 1 gm/kg of uncooked cornstarch at bedtime to ensure sufficient glucose supply overnight. Low-fat diet recommended Goal: provide 30% of energy needs from fat incl 7%-15% from long-chain fat & 15%-25% from MCT Approved by FDA in 2020 for treatment of long-chain FAODs; can be used as an alternative to MCT to provide up to 35% of daily calorie intake. Triheptanoin treatment can ↓ frequency of hospitalizations & rhabdomyolysis Adverse effects are mainly gastrointestinal & transient (e.g., abdominal pain, diarrhea). Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. CoA = coenzyme A; DD/ID = developmental delay /intellectual disability; FAOD = fatty acid oxidation disorders; FTT = failure to thrive; LCHAD = long-chain hydroxyacyl-CoA dehydrogenase; MCT = medium-chain triglyceride; OT = occupational therapy; PT = physical therapy; TFP = trifunctional protein Emergency Outpatient Treatment in Individuals with LCHAD/TFP Deficiency ↓ fasting interval by 1/2 of non-sick-day duration. Encourage intake of sugary drinks (e.g., Gatorade™, juice). If there is ↓ oral intake, vomiting, or lethargy, start acute inpatient treatment (see Low threshold for starting inpatient mgmt for infants & young children LCHAD = long-chain hydroxyacyl-CoA dehydrogenase; TFP = trifunctional protein Parents or local hospitals should immediately inform the designated metabolic center if: (1) temperature rises >38.5° C; (2) persistent vomiting/diarrhea or other symptoms of intercurrent illness develop; or (3) new neurologic symptoms occur. Avoid ondansetron and other medications known to prolong QT intervals in individuals with cardiomyopathy and/or long QT intervals. Acute manifestations (e.g., lethargy, encephalopathy, intractable vomiting, seizures, severe myalgia, red-colored urine) often occur in the setting of intercurrent illness and/or inadequate caloric intake as a result of poor appetite or prolonged fasting, and should be managed with generous caloric and intravenous fluid support in a hospital setting. Suspected infection should be identified and treated immediately. Acute Inpatient Treatment in Individuals with LCHAD/TFP Deficiency IV fluid w/high dextrose content (≥10%) to maintain blood glucose >100 mg/dL. Starting fluid at 1.5x maintenance usually achieves this goal. Glucose infusion rate of 8-12 mg/kg/min is usually needed for young children. High-dose glucose is needed to avoid catabolism. If there is hyperglycemia, start insulin infusion rather than reducing glucose infusion rate. For severe metabolic acidosis (pH <7.10), initiate bicarbonate therapy. A common formula for bicarbonate dose: bicarbonate (mEq) = 0.5 x weight (kg) x [desired bicarbonate − measured bicarbonate] Give 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 is needed for severe metabolic acidosis. Hyperammonemia improves w/reversal of catabolism. High-dose glucose infusion w/insulin infusion is helpful in achieving this goal. If severe hyperammonemia & altered mental status persists after above measures, consider extracorporeal toxin removal procedures such as hemodialysis & hemofiltration. Start IV fluid containing 10% dextrose & electrolytes as needed at 2x maintenance (in children) to provide adequate hydration & calories & ensure urine output of >3 mL/kg/hr to prevent acute renal failure. For adults, start IV fluid at 400 mL/hour; tailor to maintain urine output of ~200 mL/hr. If there is acute renal failure at presentation, consult nephrologist for hemodialysis. Avoid treatment of rhabdomyolysis by glucose-free hypotonic IV fluid such as 0.45 normal saline, as it will promote catabolism & worsen rhabdomyolysis. If hyperglycemia develops due to high dextrose infusion, start insulin infusion. IV = intravenous; LCHAD = long-chain hydroxyacyl-CoA dehydrogenase; TFP = trifunctional protein Monitor blood glucose levels every 1-2 hours initially. Intralipid administration is contraindicated; supplemental calories should be provided in the form of carbohydrates. 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. Triheptanoin was found to be useful in management of cardiomyopathy in both chronic and acute settings [ Avoidance of fasting and supplementation with medium-chain triglycerides (MCT) or triheptanoin remains the mainstay of treatment. Early diagnosis and strict dietary therapy may prevent or delay the onset or slow the progression of long-term complications [ Education of parents and caregivers is critical to ensure diligent observation and timely initiation of treatment in the setting of intercurrent illness or other catabolic stressors. Prompt administration of high dextrose-containing intravenous fluids is essential to avoid complications such as hypoglycemia, liver failure, rhabdomyolysis, encephalopathy, and coma. Written protocols for emergency treatment (see Sample Emergency Management Protocol for Individuals with LCHAD/TFP Deficiency Start IV fluid immediately even if not clinically dehydrated with 10% dextrose & appropriate electrolytes at 1.5x maintenance rate. It is imperative to prevent or reverse catabolism immediately. Correct metabolic acidosis by giving sodium bicarbonate if acidosis is severe (pH <7.10 or bicarbonate <10mEq/L). Do not wait for results of laboratory evaluation before starting IV fluids with glucose. Monitor blood glucose levels every 1-2 hours initially and maintain glucose levels at >100 mg/dL. Blood gas – arterial or venous (e.g., w/i-STAT Glucose, liver transaminases (AST, ALT) Electrolytes with bicarbonate, BUN, creatinine CK CBC with differential & additional evaluation when infection is suspected EKG, echocardiography Plasma free & total carnitine Plasma acylcarnitine profile Urine organic acids ALT = alanine transaminase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CBC = complete blood count; CK = creatine kinase; IV = intravenous; LCHAD = long-chain hydroxyacyl-CoA dehydrogenase; TFP = trifunctional protein There are no current published guidelines for surveillance. In addition to regular evaluations by a metabolic specialist and metabolic dietician, the evaluations in Recommended Surveillance for Individuals with LCHAD/TFP Deficiency <1 yr: weekly to monthly 1-7 yrs: every 1-6 mos >7 yrs: every 6-12 mos <1 yr: every 3 mos 1-7 yrs: every 3-6 mos >7 yrs: every 6-12 mos Neuropsychological testing using age-appropriate standardized assessment batteries Standardized quality of life assessment tools for affected persons & parents/caregivers ALT = alanine transaminase; AST = aspartate aminotransferase; CK = creatine kinase; NCV = nerve conduction velocity test; EMG = electromyography; ERG = electroretinography; LCHAD = long-chain hydroxyacyl-CoA dehydrogenase; TFP = trifunctional protein Affected individuals are at risk of developing essential fatty acid deficiency as a result of a diet restricted in long-chain fat. Avoid the following: Fasting, including periods of preparation and recovery from planned surgery or anesthesia Inadequate caloric provision during stressors, especially when fasting is involved (surgery or procedure requiring fasting/anesthesia) Inadequate calories following vaccination Note: Vaccination is safe. Dehydration (risk for rhabdomyolysis and acute renal failure) High-fat diet including ketogenic or carbohydrate-restricted diets for the purpose of weight loss, such as Atkins diet Administration of intravenous intralipids during an acute metabolic crisis Anesthetics that contain high doses of long-chain fatty acids (e.g., propofol, etomidate) are avoided in long-chain fatty acid oxidation defects. However, a retrospective analysis revealed no adverse events with propofol for short-duration procedures in individuals with LCHAD/TFP deficiency [ If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs. If the pathogenic variants in the family are not known, obtain a plasma acylcarnitine profile, plasma free and total carnitine, and urine organic acid profile. * The following medical interventions need to begin immediately on receipt of an abnormal NBS result while additional testing is performed to determine whether the abnormal screen represents a true positive NBS result and to establish a definitive diagnosis of LCHAD/TFP deficiency: Evaluation of the newborn to ascertain clinical status Education of the caregivers to avoid prolonged fasting and to monitor for decreased oral intake, vomiting, or lethargy Immediate intervention (to be considered if the newborn is not doing well clinically) possibly including admission to the hospital, fluid resuscitation, infusion of IV dextrose (≥10%), and cardiac evaluation See Labor and postpartum periods are catabolic states and place the mother at higher risk for rhabdomyolysis and myoglobinuria. A successful pregnancy in a female with LCHAD deficiency has been reported [ Maternal complications such as HELLP syndrome and acute fatty liver of pregnancy are seen in an estimated 15%-25% of pregnancies in women carrying a fetus affected with LCHAD/TFP deficiency [ See Search • Blood gas – arterial or venous (e.g., w/i-STAT • Glucose, liver transaminases (AST, ALT) • Electrolytes w/bicarbonate, BUN, creatinine • CK • CBC w/differential & addl eval when infection is suspected • Community or • Social work involvement for parental support; • Home nursing referral. • Birth-age 3 mos: frequent feeds (every 2-3 hrs) • Age 4-12 mos: feeding interval can be ↑ to every 4 hrs if tolerated by 6 mos. From age 6 to 12 mos, daytime feeding interval every 4 hrs; overnight fasting can be gradually ↑ to 6-8 hrs by 12 mos. • Age 1-3 yrs: daytime feeding interval 4 hrs; overnight fasting up to 10 hrs may be attempted • Age 3+ yrs: overnight fasting up to 12 hrs may be attempted • ↓ feeding interval by half during periods of illness. • After age 1 yr, if preprandial hypoglycemia remains an issue, consider overnight feedings or 1 gm/kg of uncooked cornstarch at bedtime to ensure sufficient glucose supply overnight. • Low-fat diet recommended • Goal: provide 30% of energy needs from fat incl 7%-15% from long-chain fat & 15%-25% from MCT • Approved by FDA in 2020 for treatment of long-chain FAODs; can be used as an alternative to MCT to provide up to 35% of daily calorie intake. • Triheptanoin treatment can ↓ frequency of hospitalizations & rhabdomyolysis • Adverse effects are mainly gastrointestinal & transient (e.g., abdominal pain, diarrhea). • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • ↓ fasting interval by 1/2 of non-sick-day duration. • Encourage intake of sugary drinks (e.g., Gatorade™, juice). • If there is ↓ oral intake, vomiting, or lethargy, start acute inpatient treatment (see • Low threshold for starting inpatient mgmt for infants & young children • IV fluid w/high dextrose content (≥10%) to maintain blood glucose >100 mg/dL. • Starting fluid at 1.5x maintenance usually achieves this goal. • Glucose infusion rate of 8-12 mg/kg/min is usually needed for young children. • High-dose glucose is needed to avoid catabolism. • If there is hyperglycemia, start insulin infusion rather than reducing glucose infusion rate. • For severe metabolic acidosis (pH <7.10), initiate bicarbonate therapy. • A common formula for bicarbonate dose: bicarbonate (mEq) = 0.5 x weight (kg) x [desired bicarbonate − measured bicarbonate] • Give 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 is needed for severe metabolic acidosis. • Hyperammonemia improves w/reversal of catabolism. • High-dose glucose infusion w/insulin infusion is helpful in achieving this goal. • If severe hyperammonemia & altered mental status persists after above measures, consider extracorporeal toxin removal procedures such as hemodialysis & hemofiltration. • Start IV fluid containing 10% dextrose & electrolytes as needed at 2x maintenance (in children) to provide adequate hydration & calories & ensure urine output of >3 mL/kg/hr to prevent acute renal failure. • For adults, start IV fluid at 400 mL/hour; tailor to maintain urine output of ~200 mL/hr. • If there is acute renal failure at presentation, consult nephrologist for hemodialysis. • Avoid treatment of rhabdomyolysis by glucose-free hypotonic IV fluid such as 0.45 normal saline, as it will promote catabolism & worsen rhabdomyolysis. • If hyperglycemia develops due to high dextrose infusion, start insulin infusion. • Start IV fluid immediately even if not clinically dehydrated with 10% dextrose & appropriate electrolytes at 1.5x maintenance rate. It is imperative to prevent or reverse catabolism immediately. • Correct metabolic acidosis by giving sodium bicarbonate if acidosis is severe (pH <7.10 or bicarbonate <10mEq/L). • Do not wait for results of laboratory evaluation before starting IV fluids with glucose. • Monitor blood glucose levels every 1-2 hours initially and maintain glucose levels at >100 mg/dL. • Blood gas – arterial or venous (e.g., w/i-STAT • Glucose, liver transaminases (AST, ALT) • Electrolytes with bicarbonate, BUN, creatinine • CK • CBC with differential & additional evaluation when infection is suspected • EKG, echocardiography • Plasma free & total carnitine • Plasma acylcarnitine profile • Urine organic acids • <1 yr: weekly to monthly • 1-7 yrs: every 1-6 mos • >7 yrs: every 6-12 mos • <1 yr: every 3 mos • 1-7 yrs: every 3-6 mos • >7 yrs: every 6-12 mos • Neuropsychological testing using age-appropriate standardized assessment batteries • Standardized quality of life assessment tools for affected persons & parents/caregivers • Fasting, including periods of preparation and recovery from planned surgery or anesthesia • Inadequate caloric provision during stressors, especially when fasting is involved (surgery or procedure requiring fasting/anesthesia) • Inadequate calories following vaccination • Note: Vaccination is safe. • Dehydration (risk for rhabdomyolysis and acute renal failure) • High-fat diet including ketogenic or carbohydrate-restricted diets for the purpose of weight loss, such as Atkins diet • Administration of intravenous intralipids during an acute metabolic crisis • If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs. • If the pathogenic variants in the family are not known, obtain a plasma acylcarnitine profile, plasma free and total carnitine, and urine organic acid profile. • Evaluation of the newborn to ascertain clinical status • Education of the caregivers to avoid prolonged fasting and to monitor for decreased oral intake, vomiting, or lethargy • Immediate intervention (to be considered if the newborn is not doing well clinically) possibly including admission to the hospital, fluid resuscitation, infusion of IV dextrose (≥10%), and cardiac evaluation ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with LCHAD/TFP deficiency, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with LCHAD/TFP Deficiency Blood gas – arterial or venous (e.g., w/i-STAT Glucose, liver transaminases (AST, ALT) Electrolytes w/bicarbonate, BUN, creatinine CK CBC w/differential & addl eval when infection is suspected Community or Social work involvement for parental support; Home nursing referral. ALT = alanine transaminase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CBC = complete blood count; CK = creatine kinase; LCHAD = long-chain hydroxyacyl-CoA dehydrogenase; MOI = mode of inheritance; TFP = trifunctional protein Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Blood gas – arterial or venous (e.g., w/i-STAT • Glucose, liver transaminases (AST, ALT) • Electrolytes w/bicarbonate, BUN, creatinine • CK • CBC w/differential & addl eval when infection is suspected • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Management by multidisciplinary specialists including a metabolic physician / biochemical geneticist, specialist metabolic dietitian, cardiologist, neurologist, ophthalmologist, and developmental pediatrician is recommended. Treatment of Manifestations in Individuals with LCHAD/TFP Deficiency Birth-age 3 mos: frequent feeds (every 2-3 hrs) Age 4-12 mos: feeding interval can be ↑ to every 4 hrs if tolerated by 6 mos. From age 6 to 12 mos, daytime feeding interval every 4 hrs; overnight fasting can be gradually ↑ to 6-8 hrs by 12 mos. Age 1-3 yrs: daytime feeding interval 4 hrs; overnight fasting up to 10 hrs may be attempted Age 3+ yrs: overnight fasting up to 12 hrs may be attempted ↓ feeding interval by half during periods of illness. After age 1 yr, if preprandial hypoglycemia remains an issue, consider overnight feedings or 1 gm/kg of uncooked cornstarch at bedtime to ensure sufficient glucose supply overnight. Low-fat diet recommended Goal: provide 30% of energy needs from fat incl 7%-15% from long-chain fat & 15%-25% from MCT Approved by FDA in 2020 for treatment of long-chain FAODs; can be used as an alternative to MCT to provide up to 35% of daily calorie intake. Triheptanoin treatment can ↓ frequency of hospitalizations & rhabdomyolysis Adverse effects are mainly gastrointestinal & transient (e.g., abdominal pain, diarrhea). Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. CoA = coenzyme A; DD/ID = developmental delay /intellectual disability; FAOD = fatty acid oxidation disorders; FTT = failure to thrive; LCHAD = long-chain hydroxyacyl-CoA dehydrogenase; MCT = medium-chain triglyceride; OT = occupational therapy; PT = physical therapy; TFP = trifunctional protein Emergency Outpatient Treatment in Individuals with LCHAD/TFP Deficiency ↓ fasting interval by 1/2 of non-sick-day duration. Encourage intake of sugary drinks (e.g., Gatorade™, juice). If there is ↓ oral intake, vomiting, or lethargy, start acute inpatient treatment (see Low threshold for starting inpatient mgmt for infants & young children LCHAD = long-chain hydroxyacyl-CoA dehydrogenase; TFP = trifunctional protein Parents or local hospitals should immediately inform the designated metabolic center if: (1) temperature rises >38.5° C; (2) persistent vomiting/diarrhea or other symptoms of intercurrent illness develop; or (3) new neurologic symptoms occur. Avoid ondansetron and other medications known to prolong QT intervals in individuals with cardiomyopathy and/or long QT intervals. Acute manifestations (e.g., lethargy, encephalopathy, intractable vomiting, seizures, severe myalgia, red-colored urine) often occur in the setting of intercurrent illness and/or inadequate caloric intake as a result of poor appetite or prolonged fasting, and should be managed with generous caloric and intravenous fluid support in a hospital setting. Suspected infection should be identified and treated immediately. Acute Inpatient Treatment in Individuals with LCHAD/TFP Deficiency IV fluid w/high dextrose content (≥10%) to maintain blood glucose >100 mg/dL. Starting fluid at 1.5x maintenance usually achieves this goal. Glucose infusion rate of 8-12 mg/kg/min is usually needed for young children. High-dose glucose is needed to avoid catabolism. If there is hyperglycemia, start insulin infusion rather than reducing glucose infusion rate. For severe metabolic acidosis (pH <7.10), initiate bicarbonate therapy. A common formula for bicarbonate dose: bicarbonate (mEq) = 0.5 x weight (kg) x [desired bicarbonate − measured bicarbonate] Give 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 is needed for severe metabolic acidosis. Hyperammonemia improves w/reversal of catabolism. High-dose glucose infusion w/insulin infusion is helpful in achieving this goal. If severe hyperammonemia & altered mental status persists after above measures, consider extracorporeal toxin removal procedures such as hemodialysis & hemofiltration. Start IV fluid containing 10% dextrose & electrolytes as needed at 2x maintenance (in children) to provide adequate hydration & calories & ensure urine output of >3 mL/kg/hr to prevent acute renal failure. For adults, start IV fluid at 400 mL/hour; tailor to maintain urine output of ~200 mL/hr. If there is acute renal failure at presentation, consult nephrologist for hemodialysis. Avoid treatment of rhabdomyolysis by glucose-free hypotonic IV fluid such as 0.45 normal saline, as it will promote catabolism & worsen rhabdomyolysis. If hyperglycemia develops due to high dextrose infusion, start insulin infusion. IV = intravenous; LCHAD = long-chain hydroxyacyl-CoA dehydrogenase; TFP = trifunctional protein Monitor blood glucose levels every 1-2 hours initially. Intralipid administration is contraindicated; supplemental calories should be provided in the form of carbohydrates. 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. Triheptanoin was found to be useful in management of cardiomyopathy in both chronic and acute settings [ • Birth-age 3 mos: frequent feeds (every 2-3 hrs) • Age 4-12 mos: feeding interval can be ↑ to every 4 hrs if tolerated by 6 mos. From age 6 to 12 mos, daytime feeding interval every 4 hrs; overnight fasting can be gradually ↑ to 6-8 hrs by 12 mos. • Age 1-3 yrs: daytime feeding interval 4 hrs; overnight fasting up to 10 hrs may be attempted • Age 3+ yrs: overnight fasting up to 12 hrs may be attempted • ↓ feeding interval by half during periods of illness. • After age 1 yr, if preprandial hypoglycemia remains an issue, consider overnight feedings or 1 gm/kg of uncooked cornstarch at bedtime to ensure sufficient glucose supply overnight. • Low-fat diet recommended • Goal: provide 30% of energy needs from fat incl 7%-15% from long-chain fat & 15%-25% from MCT • Approved by FDA in 2020 for treatment of long-chain FAODs; can be used as an alternative to MCT to provide up to 35% of daily calorie intake. • Triheptanoin treatment can ↓ frequency of hospitalizations & rhabdomyolysis • Adverse effects are mainly gastrointestinal & transient (e.g., abdominal pain, diarrhea). • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • ↓ fasting interval by 1/2 of non-sick-day duration. • Encourage intake of sugary drinks (e.g., Gatorade™, juice). • If there is ↓ oral intake, vomiting, or lethargy, start acute inpatient treatment (see • Low threshold for starting inpatient mgmt for infants & young children • IV fluid w/high dextrose content (≥10%) to maintain blood glucose >100 mg/dL. • Starting fluid at 1.5x maintenance usually achieves this goal. • Glucose infusion rate of 8-12 mg/kg/min is usually needed for young children. • High-dose glucose is needed to avoid catabolism. • If there is hyperglycemia, start insulin infusion rather than reducing glucose infusion rate. • For severe metabolic acidosis (pH <7.10), initiate bicarbonate therapy. • A common formula for bicarbonate dose: bicarbonate (mEq) = 0.5 x weight (kg) x [desired bicarbonate − measured bicarbonate] • Give 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 is needed for severe metabolic acidosis. • Hyperammonemia improves w/reversal of catabolism. • High-dose glucose infusion w/insulin infusion is helpful in achieving this goal. • If severe hyperammonemia & altered mental status persists after above measures, consider extracorporeal toxin removal procedures such as hemodialysis & hemofiltration. • Start IV fluid containing 10% dextrose & electrolytes as needed at 2x maintenance (in children) to provide adequate hydration & calories & ensure urine output of >3 mL/kg/hr to prevent acute renal failure. • For adults, start IV fluid at 400 mL/hour; tailor to maintain urine output of ~200 mL/hr. • If there is acute renal failure at presentation, consult nephrologist for hemodialysis. • Avoid treatment of rhabdomyolysis by glucose-free hypotonic IV fluid such as 0.45 normal saline, as it will promote catabolism & worsen rhabdomyolysis. • If hyperglycemia develops due to high dextrose infusion, start insulin infusion. ## Prevention of Primary Manifestations Avoidance of fasting and supplementation with medium-chain triglycerides (MCT) or triheptanoin remains the mainstay of treatment. Early diagnosis and strict dietary therapy may prevent or delay the onset or slow the progression of long-term complications [ Education of parents and caregivers is critical to ensure diligent observation and timely initiation of treatment in the setting of intercurrent illness or other catabolic stressors. Prompt administration of high dextrose-containing intravenous fluids is essential to avoid complications such as hypoglycemia, liver failure, rhabdomyolysis, encephalopathy, and coma. Written protocols for emergency treatment (see Sample Emergency Management Protocol for Individuals with LCHAD/TFP Deficiency Start IV fluid immediately even if not clinically dehydrated with 10% dextrose & appropriate electrolytes at 1.5x maintenance rate. It is imperative to prevent or reverse catabolism immediately. Correct metabolic acidosis by giving sodium bicarbonate if acidosis is severe (pH <7.10 or bicarbonate <10mEq/L). Do not wait for results of laboratory evaluation before starting IV fluids with glucose. Monitor blood glucose levels every 1-2 hours initially and maintain glucose levels at >100 mg/dL. Blood gas – arterial or venous (e.g., w/i-STAT Glucose, liver transaminases (AST, ALT) Electrolytes with bicarbonate, BUN, creatinine CK CBC with differential & additional evaluation when infection is suspected EKG, echocardiography Plasma free & total carnitine Plasma acylcarnitine profile Urine organic acids ALT = alanine transaminase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CBC = complete blood count; CK = creatine kinase; IV = intravenous; LCHAD = long-chain hydroxyacyl-CoA dehydrogenase; TFP = trifunctional protein • Start IV fluid immediately even if not clinically dehydrated with 10% dextrose & appropriate electrolytes at 1.5x maintenance rate. It is imperative to prevent or reverse catabolism immediately. • Correct metabolic acidosis by giving sodium bicarbonate if acidosis is severe (pH <7.10 or bicarbonate <10mEq/L). • Do not wait for results of laboratory evaluation before starting IV fluids with glucose. • Monitor blood glucose levels every 1-2 hours initially and maintain glucose levels at >100 mg/dL. • Blood gas – arterial or venous (e.g., w/i-STAT • Glucose, liver transaminases (AST, ALT) • Electrolytes with bicarbonate, BUN, creatinine • CK • CBC with differential & additional evaluation when infection is suspected • EKG, echocardiography • Plasma free & total carnitine • Plasma acylcarnitine profile • Urine organic acids ## Surveillance There are no current published guidelines for surveillance. In addition to regular evaluations by a metabolic specialist and metabolic dietician, the evaluations in Recommended Surveillance for Individuals with LCHAD/TFP Deficiency <1 yr: weekly to monthly 1-7 yrs: every 1-6 mos >7 yrs: every 6-12 mos <1 yr: every 3 mos 1-7 yrs: every 3-6 mos >7 yrs: every 6-12 mos Neuropsychological testing using age-appropriate standardized assessment batteries Standardized quality of life assessment tools for affected persons & parents/caregivers ALT = alanine transaminase; AST = aspartate aminotransferase; CK = creatine kinase; NCV = nerve conduction velocity test; EMG = electromyography; ERG = electroretinography; LCHAD = long-chain hydroxyacyl-CoA dehydrogenase; TFP = trifunctional protein Affected individuals are at risk of developing essential fatty acid deficiency as a result of a diet restricted in long-chain fat. • <1 yr: weekly to monthly • 1-7 yrs: every 1-6 mos • >7 yrs: every 6-12 mos • <1 yr: every 3 mos • 1-7 yrs: every 3-6 mos • >7 yrs: every 6-12 mos • Neuropsychological testing using age-appropriate standardized assessment batteries • Standardized quality of life assessment tools for affected persons & parents/caregivers ## Agents/Circumstances to Avoid Avoid the following: Fasting, including periods of preparation and recovery from planned surgery or anesthesia Inadequate caloric provision during stressors, especially when fasting is involved (surgery or procedure requiring fasting/anesthesia) Inadequate calories following vaccination Note: Vaccination is safe. Dehydration (risk for rhabdomyolysis and acute renal failure) High-fat diet including ketogenic or carbohydrate-restricted diets for the purpose of weight loss, such as Atkins diet Administration of intravenous intralipids during an acute metabolic crisis Anesthetics that contain high doses of long-chain fatty acids (e.g., propofol, etomidate) are avoided in long-chain fatty acid oxidation defects. However, a retrospective analysis revealed no adverse events with propofol for short-duration procedures in individuals with LCHAD/TFP deficiency [ • Fasting, including periods of preparation and recovery from planned surgery or anesthesia • Inadequate caloric provision during stressors, especially when fasting is involved (surgery or procedure requiring fasting/anesthesia) • Inadequate calories following vaccination • Note: Vaccination is safe. • Dehydration (risk for rhabdomyolysis and acute renal failure) • High-fat diet including ketogenic or carbohydrate-restricted diets for the purpose of weight loss, such as Atkins diet • Administration of intravenous intralipids during an acute metabolic crisis ## Evaluation of Relatives at Risk If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs. If the pathogenic variants in the family are not known, obtain a plasma acylcarnitine profile, plasma free and total carnitine, and urine organic acid profile. * The following medical interventions need to begin immediately on receipt of an abnormal NBS result while additional testing is performed to determine whether the abnormal screen represents a true positive NBS result and to establish a definitive diagnosis of LCHAD/TFP deficiency: Evaluation of the newborn to ascertain clinical status Education of the caregivers to avoid prolonged fasting and to monitor for decreased oral intake, vomiting, or lethargy Immediate intervention (to be considered if the newborn is not doing well clinically) possibly including admission to the hospital, fluid resuscitation, infusion of IV dextrose (≥10%), and cardiac evaluation See • If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs. • If the pathogenic variants in the family are not known, obtain a plasma acylcarnitine profile, plasma free and total carnitine, and urine organic acid profile. • Evaluation of the newborn to ascertain clinical status • Education of the caregivers to avoid prolonged fasting and to monitor for decreased oral intake, vomiting, or lethargy • Immediate intervention (to be considered if the newborn is not doing well clinically) possibly including admission to the hospital, fluid resuscitation, infusion of IV dextrose (≥10%), and cardiac evaluation ## Pregnancy Management Labor and postpartum periods are catabolic states and place the mother at higher risk for rhabdomyolysis and myoglobinuria. A successful pregnancy in a female with LCHAD deficiency has been reported [ Maternal complications such as HELLP syndrome and acute fatty liver of pregnancy are seen in an estimated 15%-25% of pregnancies in women carrying a fetus affected with LCHAD/TFP deficiency [ See ## Therapies Under Investigation Search ## Genetic Counseling Long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency and trifunctional protein (TFP) deficiency are inherited in an autosomal recessive manner. The parents of an affected child are presumed to be heterozygous for an Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are not at risk of developing LCHAD/TFP deficiency. However, pregnant female carriers may be at risk of developing HELLP syndrome and acute fatty liver of pregnancy if the fetus has LCHAD/TFP deficiency (see If both parents are known to be heterozygous for an Significant intrafamilial clinical variability may be observed between sibs who inherit the same biallelic Heterozygotes (carriers) are not at risk of developing LCHAD/TFP deficiency. However, pregnant female carriers may be at risk of developing HELLP syndrome and acute fatty liver of pregnancy if the fetus has LCHAD/TFP deficiency (see Molecular genetic carrier testing for at-risk relatives requires prior identification of the Note: Because biochemical analysis is usually normal in carriers, biochemical testing is not reliable for the detection of carriers. 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. Pregnant females who are heterozygous for 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 • 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 not at risk of developing LCHAD/TFP deficiency. However, pregnant female carriers may be at risk of developing HELLP syndrome and acute fatty liver of pregnancy if the fetus has LCHAD/TFP deficiency (see • 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 • Significant intrafamilial clinical variability may be observed between sibs who inherit the same biallelic • Heterozygotes (carriers) are not at risk of developing LCHAD/TFP deficiency. However, pregnant female carriers may be at risk of developing HELLP syndrome and acute fatty liver of pregnancy if the fetus has LCHAD/TFP deficiency (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. • Pregnant females who are heterozygous for an ## Mode of Inheritance Long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency and trifunctional protein (TFP) deficiency are inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected child are presumed to be heterozygous for an Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are not at risk of developing LCHAD/TFP deficiency. However, pregnant female carriers may be at risk of developing HELLP syndrome and acute fatty liver of pregnancy if the fetus has LCHAD/TFP deficiency (see If both parents are known to be heterozygous for an Significant intrafamilial clinical variability may be observed between sibs who inherit the same biallelic Heterozygotes (carriers) are not at risk of developing LCHAD/TFP deficiency. However, pregnant female carriers may be at risk of developing HELLP syndrome and acute fatty liver of pregnancy if the fetus has LCHAD/TFP deficiency (see • 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 not at risk of developing LCHAD/TFP deficiency. However, pregnant female carriers may be at risk of developing HELLP syndrome and acute fatty liver of pregnancy if the fetus has LCHAD/TFP deficiency (see • 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 • Significant intrafamilial clinical variability may be observed between sibs who inherit the same biallelic • Heterozygotes (carriers) are not at risk of developing LCHAD/TFP deficiency. However, pregnant female carriers may be at risk of developing HELLP syndrome and acute fatty liver of pregnancy if the fetus has LCHAD/TFP deficiency (see ## Carrier Detection Molecular genetic carrier testing for at-risk relatives requires prior identification of the Note: Because biochemical analysis is usually normal in carriers, biochemical testing is not reliable for the detection of carriers. ## 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. Pregnant females who are heterozygous for an • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • Pregnant females who are heterozygous for 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 TEMPLE (Tools Enabling Metabolic Parents LEarning) United Kingdom United Kingdom Health Resources & Services Administration • • TEMPLE (Tools Enabling Metabolic Parents LEarning) • United Kingdom • • • • • • • • • • • • • • • United Kingdom • • • Health Resources & Services Administration • ## Molecular Genetics Long-Chain Hydroxyacyl-CoA Dehydrogenase Deficiency / Trifunctional Protein Deficiency: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Long-Chain Hydroxyacyl-CoA Dehydrogenase Deficiency / Trifunctional Protein Deficiency ( Mitochondrial fatty acid oxidation (beta-oxidation) is the primary pathway of energy production from fatty acids. Fatty acid undergoes repeated cycles of four steps inside mitochondria that result in the shortening of fatty acid by two carbon atoms and production of acetyl-coenzyme A (CoA), reduced nicotinamide adenine dinucleotide (NADH), and reduced flavin adenine dinucleotide (FADH Mitochondrial TFP is an octamer composed of four alpha subunits (encoded by In addition, the alpha subunit of TFP participates in cardiolipin remodeling, and TFP physically interacts with mitochondrial respiratory chain complex 1 [ Notable LCHAD = long-chain hydroxyacyl-CoA dehydrogenase Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis Mitochondrial fatty acid oxidation (beta-oxidation) is the primary pathway of energy production from fatty acids. Fatty acid undergoes repeated cycles of four steps inside mitochondria that result in the shortening of fatty acid by two carbon atoms and production of acetyl-coenzyme A (CoA), reduced nicotinamide adenine dinucleotide (NADH), and reduced flavin adenine dinucleotide (FADH Mitochondrial TFP is an octamer composed of four alpha subunits (encoded by In addition, the alpha subunit of TFP participates in cardiolipin remodeling, and TFP physically interacts with mitochondrial respiratory chain complex 1 [ Notable LCHAD = long-chain hydroxyacyl-CoA dehydrogenase Variants listed in the table have been provided by the authors. ## Chapter Notes Dr Pankaj Prasun is faculty in the Division of Medical Genetics of the Department of Genetics and Genomics at the Icahn School of Medicine at Mount Sinai, New York. He is also the director of the Mitochondrial Medicine Program and has published a textbook on mitochondrial medicine. PANKAJ PRASUN, MDDivision of Medical GeneticsDepartment of Genetics and Genomics Icahn School of Medicine at Mount SinaiOne Gustave L. Levy PlaceNew York, NY, 10029, USAEmail: 1 September 2022 (sw) Review posted live 16 December 2021 (pp) Original submission • 1 September 2022 (sw) Review posted live • 16 December 2021 (pp) Original submission ## Author Notes Dr Pankaj Prasun is faculty in the Division of Medical Genetics of the Department of Genetics and Genomics at the Icahn School of Medicine at Mount Sinai, New York. He is also the director of the Mitochondrial Medicine Program and has published a textbook on mitochondrial medicine. PANKAJ PRASUN, MDDivision of Medical GeneticsDepartment of Genetics and Genomics Icahn School of Medicine at Mount SinaiOne Gustave L. Levy PlaceNew York, NY, 10029, USAEmail: ## Revision History 1 September 2022 (sw) Review posted live 16 December 2021 (pp) Original submission • 1 September 2022 (sw) Review posted live • 16 December 2021 (pp) Original submission ## References ## Literature Cited Mitochondrial fatty acid oxidation (beta-oxidation), the primary pathway of energy production from fatty acids Activated long-chain fatty acyl-coenzyme A (CoA) is transported from the cytoplasm across the mitochondrial membrane by the carnitine shuttle. It then enters the cycle of beta-oxidation with a dehydrogenation reaction by very long-chain acyl-CoA dehydrogenase (VLCAD), producing reduced flavin adenine dinucleotide (FADH TFP is embedded in the inner mitochondrial membrane and catalyzes the final three of the four steps of long-chain fatty acid beta-oxidation. It comprises four alpha and four beta subunits, encoded by	[ "S Aradhya, R Lewis, T Bonaga, N Nwokekeh, A Stafford, B Boggs, K Hruska, N Smaoui, JG Compton, G Richard, S Suchy. Exon-level array CGH in a large clinical cohort demonstrates increased sensitivity of diagnostic testing for Mendelian disorders.. Genet Med. 2012;14:594-603", "KR Blish, JA Ibdah. Maternal heterozygosity for a mitochondrial trifunctional protein mutation as a cause for liver disease in pregnancy.. Med Hypotheses. 2005;64:96-100", "R Bo, K Yamada, H Kobayashi, P Jamiyan, Y Hasegawa, T Taketani, S Fukuda, I Hata, Y Niida, Y Shigematsu, K Iijima, S Yamaguchi. Clinical and molecular investigation of 14 Japanese patients with complete TFP deficiency: a comparison with Caucasian cases.. J Hum Genet. 2017;62:809-14", "X Bosch, E Poch, JM Grau. Rhabdomyolysis and acute kidney injury.. N Engl J Med 2009;361:62-72", "A Boutron, C Acquaviva, C Vianey-Saban, P de Lonlay, HO de Baulny, N Guffon, D Dobbelaere, F Feillet, F Labarthe, D Lamireau, A Cano, TB de Villemeur, A Munnich, JM Saudubray, D Rabier, O Rigal, M Brivet. Comprehensive cDNA study and quantitative analysis of mutant HADHA and HADHB transcripts in a French cohort of 52 patients with mitochondrial trifunctional protein deficiency.. Mol Genet Metab. 2011;103:341-8", "C Bursle, R Weintraub, C Ward, R Justo, J Cardinal, D Coman. Mitochondrial trifunctional protein deficiency: severe cardiomyopathy and cardiac transplantation.. JIMD Rep. 2018;40:91-5", "I De Biase, KS Viau, A Liu, T Yuzyuk, LD Botto, M Pasquali, N Longo. Diagnosis, treatment, and clinical outcome of patients with mitochondrial trifunctional protein/long-chain 3-hydroxy acyl-CoA dehydrogenase deficiency.. JIMD Rep. 2017;31:63-71", "ME den Boer, C Dionisi-Vici, A Chakrapani, AO van Thuijl, RJ Wanders, FA Wijburg. Mitochondrial trifunctional protein deficiency: a severe fatty acid oxidation disorder with cardiac and neurologic involvement.. J Pediatr. 2003;142:684-9", "ME den Boer, RJ Wanders, AA Morris, L Ijlst, HS Heymans, FA Wijburg. Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: clinical presentation and follow-up of 50 patients.. Pediatrics. 2002;109:99-104", "EF Diekman, CC Boelen, BH Prinsen, L Ijlst, M Duran, TJ de Koning, HR Waterham, RJ Wanders, FA Wijburg, G Visser. Necrotizing enterocolitis and respiratory distress syndrome as first clinical presentation of mitochondrial trifunctional protein deficiency.. JIMD Rep. 2013;7:1-6", "F Djouadi, F Habarou, C Le Bachelier, S Ferdinandusse, D Schlemmer, JF Benoist, A Boutron, BS Andresen, G Visser, P de Lonlay, S Olpin, T Fukao, S Yamaguchi, AW Strauss, RJ Wanders, J Bastin. Mitochondrial trifunctional protein deficiency in human cultured fibroblasts: effects of bezafibrate.. J Inherit Metab Dis. 2016;39:47-58", "S Dulz, Y Atiskova, P Engel, J Wildner, K Tsiakas, R Santer. Retained visual function in a subset of patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD).. Ophthalmic Genet. 2021;42:23-27", "G Elizondo, D Matern, J Vockley, CO Harding, MB Gillingham. Effects of fasting, feeding and exercise on plasma acylcarnitines among subjects with CPT2D, VLCADD and LCHADD/TFPD.. Mol Genet Metab. 2020;131:90-7", "KT Fahnehjelm, Y Liu, D Olsson, U Amrén, CB Haglind, G Holmström, M Halldin, S Andreasson, A Nordenström. Most patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency develop pathological or subnormal retinal function.. Acta Paediatr. 2016;105:1451-60", "AL Fletcher, ME Pennesi, CO Harding, RG Weleber, MB Gillingham. Observations regarding retinopathy in mitochondrial trifunctional protein deficiencies.. Mol Genet Metab. 2012;106:18-24", "H Fraser, J Geppert, R Johnson, S Johnson, M Connock, A Clarke, S Taylor-Phillips, C Stinton. Evaluation of earlier versus later dietary management in long-chain 3-hydroxyacyl-CoA dehydrogenase or mitochondrial trifunctional protein deficiency: a systematic review.. Orphanet J Rare Dis. 2019;14:258", "MB Gillingham, SB Heitner, J Martin, S Rose, A Goldstein, AH El-Gharbawy, S Deward, MR Lasarev, J Pollaro, JP DeLany, LJ Burchill, B Goodpaster, J Shoemaker, D Matern, CO Harding, J Vockley. Triheptanoin versus trioctanoin for long-chain fatty acid oxidation disorders: a double blinded, randomized controlled trial.. J Inherit Metab Dis. 2017;40:831-43", "SC Grünert, M Eckenweiler, D Haas, M Lindner, K Tsiakas, R Santer, S Tucci, U Spiekerkoetter. The spectrum of peripheral neuropathy in disorders of the mitochondrial trifunctional protein.. J Inherit Metab Dis. 2021;44:893-902", "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", "L Ijlst, JP Ruiter, JM Hoovers, ME Jakobs, RJ Wanders. Common missense mutation G1528C in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Characterization and expression of the mutant protein, mutation analysis on genomic DNA and chromosomal localization of the mitochondrial trifunctional protein alpha subunit gene.. J Clin Invest. 1996;98:1028-33", "T Immonen, E Ahola, J Toppila, R Lapatto, T Tyni, L Lauronen. Peripheral neuropathy in patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency - a follow-up EMG study of 12 patients.. Eur J Paediatr Neurol. 2016a;20:38-44", "T Immonen, M Turanlahti, A Paganus, P Keskinen, T Tyni, R Lapatto. Earlier diagnosis and strict diets improve the survival rate and clinical course of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency.. Acta Paediatr. 2016b;105:549-54", "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", "K Joost, K Ounap, R Zordania, ML Uudelepp, RK Olsen, K Kall, K Kilk, U Soomets, T Kahre. Prevalence of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency in Estonia.. JIMD Rep. 2012;2:79-85", "D Karall, M Brunner-Krainz, K Kogelnig, V Konstantopoulou, EM Maier, D Möslinger, B Plecko, W Sperl, B Volkmar, S Scholl-Bürgi. Clinical outcome, biochemical and therapeutic follow-up in 14 Austrian patients with long-chain 3-hydroxy acyl CoA dehydrogenase deficiency (LCHADD).. Orphanet J Rare Dis. 2015;10:21", "T Kobayashi, S Minami, A Mitani, Y Tanizaki, M Booka, T Okutani, S Yamaguchi, K Ino. Acute fatty liver of pregnancy associated with fetal mitochondrial trifunctional protein deficiency.. J Obstet Gynaecol Res. 2015;41:799-802", "M Lindner, GF Hoffmann, D Matern. Newborn screening for disorders of fatty-acid oxidation: experience and recommendations from an expert meeting.. J Inherit Metab Dis. 2010;33:521-6", "JM Martin, MB Gillingham, CO Harding. Use of propofol for short duration procedures in children with long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) or trifunctional protein (TFP) deficiencies.. Mol Genet Metab. 2014;112:139-42", "JW Miklas, E Clark, S Levy, D Detraux, A Leonard, K Beussman, MR Showalter, AT Smith, P Hofsteen, X Yang, J Macadangdang, T Manninen, D Raftery, A Madan, A Suomalainen, DH Kim, CE Murry, O Fiehn, NJ Sniadecki, Y Wang, H Ruohola-Baker. TFPa/HADHA is required for fatty acid beta-oxidation and cardiolipin re-modeling in human cardiomyocytes.. Nat Commun. 2019;10:4671", "B Nedoszytko, A Siemińska, D Strapagiel, S Dąbrowski, M Słomka, M Sobalska-Kwapis, B Marciniak, J Wierzba, J Skokowski, M Fijałkowski, R Nowicki, L Kalinowski. High prevalence of carriers of variant c.1528G>C of HADHA gene causing long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) in the population of adult Kashubians from North Poland.. PLoS One. 2017;12", "JG Okun, S Kölker, A Schulze, D Kohlmüller, K Olgemöller, M Lindner, GF Hoffmann, RJ Wanders, E Mayatepek. A method for quantitative acylcarnitine profiling in human skin fibroblasts using unlabelled palmitic acid: diagnosis of fatty acid oxidation disorders and differentiation between biochemical phenotypes of MCAD deficiency.. Biochim Biophys Acta. 2002;1584:91-8", "D Piekutowska-Abramczuk, RK Olsen, J Wierzba, E Popowska, D Jurkiewicz, E Ciara, M Ołtarzewski, W Gradowska, J Sykut-Cegielska, M Krajewska-Walasek, BS Andresen, N Gregersen, E Pronicka. A comprehensive HADHA c.1528G>C frequency study reveals high prevalence of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency in Poland.. J Inherit Metab Dis. 2010;33:S373-7", "J Purevsuren, T Fukao, Y Hasegawa, H Kobayashi, H Li, Y Mushimoto, S Fukuda, S Yamaguchi. Clinical and molecular aspects of Japanese patients with mitochondrial trifunctional protein deficiency.. Mol Genet Metab. 2009;98:372-7", "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", "CR Roe, H Brunengraber. Anaplerotic treatment of long-chain fat oxidation disorders with triheptanoin: review of 15 years experience.. Mol Genet Metab. 2015;116:260-8", "E Sklirou, AN Alodaib, SF Dobrowolski, AA Mohsen, J Vockley. Physiological perspectives on the use of triheptanoin as anaplerotic therapy for long chain fatty acid oxidation disorders.. Front Genet. 2021;11", "U Spiekerkoetter, Z Khuchua, Z Yue, MJ Bennett, AW Strauss. General mitochondrial trifunctional protein (TFP) deficiency as a result of either alpha- or beta-subunit mutations exhibits similar phenotypes because mutations in either subunit alter TFP complex expression and subunit turnover.. Pediatr Res. 2004;55:190-6", "U Spiekerkoetter, M Lindner, R Santer, M Grotzke, MR Baumgartner, H Boehles, A Das, C Haase, JB Hennermann, D Karall, H de Klerk, I Knerr, HG Koch, B Plecko, W Röschinger, KO Schwab, D Scheible, FA Wijburg, J Zschocke, E Mayatepek, U Wendel. Treatment recommendations in long-chain fatty acid oxidation defects: consensus from a workshop.. J Inherit Metab Dis. 2009;32:498-505", "U Spiekerkoetter, B Sun, Z Khuchua, MJ Bennett, AW Strauss. Molecular and phenotypic heterogeneity in mitochondrial trifunctional protein deficiency due to beta-subunit mutations.. Hum Mutat. 2003;21:598-607", "D Steinmann, J Knab, HJ Priebe. Perioperative management of a child with long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency.. Paediatr Anaesth. 2010;20:371-3", "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 Suyama, M Shimura, T Fushimi, N Kuranobu, K Ichimoto, A Matsunaga, M Takayanagi, K Murayama. Efficacy of bezafibrate in two patients with mitochondrial trifunctional protein deficiency.. Mol Genet Metab Rep. 2020;24", "HS Szugye. Pediatric rhabdomyolysis.. Pediatr Rev. 2020;41:265-75", "WA Taylor, EM Mejia, RW Mitchell, PC Choy, GC Sparagna, GM Hatch. Human trifunctional protein alpha links cardiolipin remodeling to beta-oxidation.. PLoS One. 2012;7", "T Tyni, T Kivelä, M Lappi, P Summanen, E Nikoskelainen, H Pihko. Ophthalmologic findings in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency caused by the G1528C mutation: a new type of hereditary metabolic chorioretinopathy.. Ophthalmology. 1998;105:810-24", "T Tyni, H. Pihko. Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency.. Acta Paediatr. 1999;88:237-45", "T Tyni, J Rapola, A Palotie, H Pihko. Hypoparathyroidism in a patient with long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency caused by the G1528C mutation.. J Pediatr. 1997;131:766-8", "DC van Eerd, IA Brussé, VF Adriaens, RT Mankowski, SF Praet, M Michels, M Langeveld. Management of an LCHADD patient during pregnancy and high intensity exercise.. JIMD Rep. 2017;32:95-100", "P van Vliet, AE Berden, MKM van Schie, JA Bakker, C Heringhaus, IFM de Coo, M Langeveld, MA Schroijen, MS Arbous. Peripheral neuropathy, episodic rhabdomyolysis, and hypoparathyroidism in a patient with mitochondrial trifunctional protein deficiency.. JIMD Rep. 2018;38:101-105", "J Vockley, B Burton, G Berry, N Longo, J Phillips, A Sanchez-Valle, K Chapman, P Tanpaiboon, S Grunewald, E Murphy, X Lu, J. Cataldo. Effects of triheptanoin (UX007) in patients with long-chain fatty acid oxidation disorders: Results from an open-label, long-term extension study.. J Inherit Metab Dis. 2021;44:253-63", "J Vockley, J Charrow, J Ganesh, M Eswara, GA Diaz, E McCracken, R Conway, GM Enns, J Starr, R Wang, JE Abdenur, J Sanchez-de-Toledo, DL Marsden. Triheptanoin treatment in patients with pediatric cardiomyopathy associated with long chain-fatty acid oxidation disorders.. Mol Genet Metab. 2016;119:223-31", "J Wang, H Zhan, FY Li, AN Pursley, ES Schmitt, LJ Wong. Targeted array CGH as a valuable molecular diagnostic approach: experience in the diagnosis of mitochondrial and metabolic disorders.. Mol Genet Metab. 2012;106:221-30", "Y Wang, J Palmfeldt, N Gregersen, AM Makhov, JF Conway, M Wang, SP McCalley, S Basu, H Alharbi, C St Croix, MJ Calderon, S Watkins, J Vockley. Mitochondrial fatty acid oxidation and the electron transport chain comprise a multifunctional mitochondrial protein complex.. J Biol Chem. 2019;294:12380-91", "CJ Wei, XZ Chang, L Ge, XN Fu, YB Fan, JY Liu, S Wang, HL Li, YL Yang, H Xiong. Multisystem involvement in Chinese patients with neuromyopathic phenotype of mitochondrial trifunctional protein deficiency.. Chin Med J (Engl) 2020;133:1358-60", "T Zöggeler, K Stock, M Jörg-Streller, J Spenger, V Konstantopoulou, M Hufgard-Leitner, S Scholl-Bürgi, D Karall. Long-term experience with triheptanoin in 12 Austrian patients with long-chain fatty acid oxidation disorders.. Orphanet J Rare Dis. 2021;16:28" ]	1/9/2022			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
lds	lds	[ "Forkhead box protein C2", "FOXC2", "Lymphedema-Distichiasis Syndrome" ]	Lymphedema-Distichiasis Syndrome	Sahar Mansour, Glen W Brice, Steve Jeffery, Peter Mortimer	Summary Lymphedema-distichiasis syndrome (referred to as LDS in this The clinical diagnosis of LDS is established in a proband with either lymphedema and distichiasis, distichiasis and a family history of lower-limb lymphedema, or lower-limb lymphedema and a family history of distichiasis. If clinical findings are not diagnostic, the identification of a heterozygous LDS is inherited in an autosomal dominant manner. Approximately 75% of affected individuals have an affected parent; about 25% have a	## Diagnosis Lymphedema-distichiasis syndrome (LDS) Other less frequent findings: Congenital heart disease including bicuspid aortic valves Cleft palate ± Pierre Robin sequence Renal anomalies Spinal extradural arachnoid cysts Nonimmune hydrops fetalis Antenatal hydrothoraces Neck webbing The clinical diagnosis of LDS Distichiasis and lymphedema (although a young child may have no evidence of lymphedema) Distichiasis and a family history of lower-limb lymphedema Lower-limb lymphedema and a family history of distichiasis If clinical findings are not diagnostic, the identification of a heterozygous pathogenic variant in 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 LDS can be specific to this condition, individuals with the distinctive findings described in When the phenotypic findings suggest the diagnosis of LDS, molecular genetic testing approaches can include For an introduction to multigene panels click When the diagnosis of LDS is not considered because an individual has atypical phenotypic features, If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Lymphedema-Distichiasis Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click 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 data on detection rate of gene-targeted deletion/duplication analysis are available. • Other less frequent findings: • Congenital heart disease including bicuspid aortic valves • Cleft palate ± Pierre Robin sequence • Renal anomalies • Spinal extradural arachnoid cysts • Nonimmune hydrops fetalis • Antenatal hydrothoraces • Neck webbing • Congenital heart disease including bicuspid aortic valves • Cleft palate ± Pierre Robin sequence • Renal anomalies • Spinal extradural arachnoid cysts • Nonimmune hydrops fetalis • Antenatal hydrothoraces • Neck webbing • Congenital heart disease including bicuspid aortic valves • Cleft palate ± Pierre Robin sequence • Renal anomalies • Spinal extradural arachnoid cysts • Nonimmune hydrops fetalis • Antenatal hydrothoraces • Neck webbing • Distichiasis and lymphedema (although a young child may have no evidence of lymphedema) • Distichiasis and a family history of lower-limb lymphedema • Lower-limb lymphedema and a family history of distichiasis • For an introduction to multigene panels click ## Suggestive Findings Lymphedema-distichiasis syndrome (LDS) Other less frequent findings: Congenital heart disease including bicuspid aortic valves Cleft palate ± Pierre Robin sequence Renal anomalies Spinal extradural arachnoid cysts Nonimmune hydrops fetalis Antenatal hydrothoraces Neck webbing • Other less frequent findings: • Congenital heart disease including bicuspid aortic valves • Cleft palate ± Pierre Robin sequence • Renal anomalies • Spinal extradural arachnoid cysts • Nonimmune hydrops fetalis • Antenatal hydrothoraces • Neck webbing • Congenital heart disease including bicuspid aortic valves • Cleft palate ± Pierre Robin sequence • Renal anomalies • Spinal extradural arachnoid cysts • Nonimmune hydrops fetalis • Antenatal hydrothoraces • Neck webbing • Congenital heart disease including bicuspid aortic valves • Cleft palate ± Pierre Robin sequence • Renal anomalies • Spinal extradural arachnoid cysts • Nonimmune hydrops fetalis • Antenatal hydrothoraces • Neck webbing ## Establishing the Diagnosis The clinical diagnosis of LDS Distichiasis and lymphedema (although a young child may have no evidence of lymphedema) Distichiasis and a family history of lower-limb lymphedema Lower-limb lymphedema and a family history of distichiasis If clinical findings are not diagnostic, the identification of a heterozygous pathogenic variant in 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 LDS can be specific to this condition, individuals with the distinctive findings described in When the phenotypic findings suggest the diagnosis of LDS, molecular genetic testing approaches can include For an introduction to multigene panels click When the diagnosis of LDS is not considered because an individual has atypical phenotypic features, If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Lymphedema-Distichiasis Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click 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 data on detection rate of gene-targeted deletion/duplication analysis are available. • Distichiasis and lymphedema (although a young child may have no evidence of lymphedema) • Distichiasis and a family history of lower-limb lymphedema • Lower-limb lymphedema and a family history of distichiasis • For an introduction to multigene panels click ## Option 1 When the phenotypic findings suggest the diagnosis of LDS, 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 LDS is not considered because an individual has atypical phenotypic features, If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Lymphedema-Distichiasis Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click 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 data on detection rate of gene-targeted deletion/duplication analysis are available. ## Clinical Characteristics Lymphedema-distichiasis syndrome (LDS) is characterized by lymphedema with onset in late childhood or puberty and is confined to the lower limbs and/or genitalia. Varicose veins are a frequent association and may develop before the onset of the lymphedema. Distichiasis, which may be present at birth, can be associated with ocular problems such as corneal irritation, recurrent conjunctivitis, and photophobia. Congenital ptosis involving one or both eyes may be present. Other less common findings include congenital heart disease, cleft palate, webbed neck, and renal anomalies. Severity varies within and between families, with some affected neonates presenting with hydrops fetalis. Lymphedema is confined to the lower limbs, is often asymmetric, and can be unilateral. The severity of the lymphedema varies within families. Males develop edema at a significantly earlier age and have more problems with cellulitis than females. Sixty-five percent of males in one series complained of recurrent cellulitis in the edematous leg, compared to 25% of females [ Whereas primary lymphedema is usually associated with hypoplasia or aplasia of the lymphatic vessels, LDS is associated with an increased number of lymphatic vessels and inguinal lymph nodes [ Isotope lymphoscintigraphy can be used to demonstrate that the swelling is caused by lymphedema. Radioactive colloid is injected into the toe web spaces and uptake in the ilioinguinal nodes is measured at intervals. Low uptake can be demonstrated in most affected individuals in association with dermal backflow, indicating lymph reflux into the lower limbs. This technique replaces lymphangiography (x-ray after injection of dye into the lymphatic vessels in the foot). About 75% of affected individuals have ocular problems related to distichiasis, including corneal irritation, recurrent conjunctivitis, and photophobia. About 25% of individuals have no symptoms from distichiasis and are thus not aware of it. Therefore, any individual with primary lymphedema of the lower limbs should be examined carefully for the presence of distichiasis. In one family, distichiasis was associated with a pathogenic variant in Nonimmune hydrops fetalis or antenatal hydrothoraces have been reported as a rare complication of LDS. Hydrops fetalis can be caused by lymphatic abnormalities [ Spinal extradural arachnoid cyst (SEDAC) is a cyst in the spinal canal that protrudes into the epidural space from a defect in the dura mater. Thus, SEDAC caused by a heterozygous Renal anomalies include hydronephrosis, ectopic kidney, and renal agenesis, which may be detected by antenatal ultrasound examination [ Other abnormalities include scoliosis, neck webbing, uterine anomalies, strabismus, and synophrys. Neonatal chylothorax has been reported in one case in association with congenital heart disease [ No genotype-phenotype correlations for the major clinical signs have been reported. Approximately 80% of individuals with lymphedema-distichiasis syndrome have lymphedema by early adulthood (age 30 years), although a few individuals may develop lymphedema later. Approximately 94% of affected individuals have distichiasis. In all families with Lymphedema and ptosis, once described as a separate entity, is thought to be the same as lymphedema-distichiasis syndrome [ The prevalence of lymphedema-distichiasis syndrome is not known; it is a well-recognized and relatively frequent cause of autosomal dominant primary lymphedema. • Nonimmune hydrops fetalis or antenatal hydrothoraces have been reported as a rare complication of LDS. Hydrops fetalis can be caused by lymphatic abnormalities [ • Spinal extradural arachnoid cyst (SEDAC) is a cyst in the spinal canal that protrudes into the epidural space from a defect in the dura mater. Thus, SEDAC caused by a heterozygous • Renal anomalies include hydronephrosis, ectopic kidney, and renal agenesis, which may be detected by antenatal ultrasound examination [ ## Clinical Description Lymphedema-distichiasis syndrome (LDS) is characterized by lymphedema with onset in late childhood or puberty and is confined to the lower limbs and/or genitalia. Varicose veins are a frequent association and may develop before the onset of the lymphedema. Distichiasis, which may be present at birth, can be associated with ocular problems such as corneal irritation, recurrent conjunctivitis, and photophobia. Congenital ptosis involving one or both eyes may be present. Other less common findings include congenital heart disease, cleft palate, webbed neck, and renal anomalies. Severity varies within and between families, with some affected neonates presenting with hydrops fetalis. Lymphedema is confined to the lower limbs, is often asymmetric, and can be unilateral. The severity of the lymphedema varies within families. Males develop edema at a significantly earlier age and have more problems with cellulitis than females. Sixty-five percent of males in one series complained of recurrent cellulitis in the edematous leg, compared to 25% of females [ Whereas primary lymphedema is usually associated with hypoplasia or aplasia of the lymphatic vessels, LDS is associated with an increased number of lymphatic vessels and inguinal lymph nodes [ Isotope lymphoscintigraphy can be used to demonstrate that the swelling is caused by lymphedema. Radioactive colloid is injected into the toe web spaces and uptake in the ilioinguinal nodes is measured at intervals. Low uptake can be demonstrated in most affected individuals in association with dermal backflow, indicating lymph reflux into the lower limbs. This technique replaces lymphangiography (x-ray after injection of dye into the lymphatic vessels in the foot). About 75% of affected individuals have ocular problems related to distichiasis, including corneal irritation, recurrent conjunctivitis, and photophobia. About 25% of individuals have no symptoms from distichiasis and are thus not aware of it. Therefore, any individual with primary lymphedema of the lower limbs should be examined carefully for the presence of distichiasis. In one family, distichiasis was associated with a pathogenic variant in Nonimmune hydrops fetalis or antenatal hydrothoraces have been reported as a rare complication of LDS. Hydrops fetalis can be caused by lymphatic abnormalities [ Spinal extradural arachnoid cyst (SEDAC) is a cyst in the spinal canal that protrudes into the epidural space from a defect in the dura mater. Thus, SEDAC caused by a heterozygous Renal anomalies include hydronephrosis, ectopic kidney, and renal agenesis, which may be detected by antenatal ultrasound examination [ Other abnormalities include scoliosis, neck webbing, uterine anomalies, strabismus, and synophrys. Neonatal chylothorax has been reported in one case in association with congenital heart disease [ • Nonimmune hydrops fetalis or antenatal hydrothoraces have been reported as a rare complication of LDS. Hydrops fetalis can be caused by lymphatic abnormalities [ • Spinal extradural arachnoid cyst (SEDAC) is a cyst in the spinal canal that protrudes into the epidural space from a defect in the dura mater. Thus, SEDAC caused by a heterozygous • Renal anomalies include hydronephrosis, ectopic kidney, and renal agenesis, which may be detected by antenatal ultrasound examination [ ## Genotype-Phenotype Correlations No genotype-phenotype correlations for the major clinical signs have been reported. ## Penetrance Approximately 80% of individuals with lymphedema-distichiasis syndrome have lymphedema by early adulthood (age 30 years), although a few individuals may develop lymphedema later. Approximately 94% of affected individuals have distichiasis. In all families with ## Nomenclature Lymphedema and ptosis, once described as a separate entity, is thought to be the same as lymphedema-distichiasis syndrome [ ## Prevalence The prevalence of lymphedema-distichiasis syndrome is not known; it is a well-recognized and relatively frequent cause of autosomal dominant primary lymphedema. ## Genetically Related (Allelic) Disorders No other phenotypes are known to be associated with ## Differential Diagnosis Disorders to Consider in the Differential Diagnosis of Lymphedema-Distichiasis Syndrome (LDS) Typically congenital-onset lymphedema (very rarely presents later) Absence of distichiasis Absence of distichiasis Loss of hair Telangiectasia, particularly in the palms Absence of distichiasis Small head circumference May be associated w/chorioretinopathy &/or ID Absence of distichiasis Very slow-growing nails w/transverse overcurvature & hardening of the nail plate Absence of distichiasis Myelodysplasia Immunodeficiency Absence of distichiasis Lagophthalmos (inability to fully close eyes) Cleft lip & palate Atrial septal defect Oligodontia Absence of lymphedema AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked The presence of lymphatic vessels on lymphoscintigraphy in LDS contrasts with other causes of primary lymphedema, including Milroy disease and Meige disease, which show aplasia or hypoplasia of the lymphatic vessels. Inheritance is said to be autosomal dominant; most affected individuals represent simplex cases (i.e., a single occurrence in a family) [ Nail changes are different from the typically discolored nails often associated with chronic lymphedema. Distichiasis should also be clinically distinguished from trichiasis, a more common condition in which lashes arise normally from the anterior lamella of the eyelids but are misdirected. The misdirected lashes can cause symptoms similar to distichiasis (e.g., corneal irritation and photophobia). • Typically congenital-onset lymphedema (very rarely presents later) • Absence of distichiasis • Absence of distichiasis • Loss of hair • Telangiectasia, particularly in the palms • Absence of distichiasis • Small head circumference • May be associated w/chorioretinopathy &/or ID • Absence of distichiasis • Very slow-growing nails w/transverse overcurvature & hardening of the nail plate • Absence of distichiasis • Myelodysplasia • Immunodeficiency • Absence of distichiasis • Lagophthalmos (inability to fully close eyes) • Cleft lip & palate • Atrial septal defect • Oligodontia • Absence of lymphedema ## Management To establish the extent of disease and needs of in an individual diagnosed with lymphedema-distichiasis syndrome (LDS), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Lymphedema-Distichiasis Syndrome Slit lamp eval for distichiasis & related problems of corneal irritation, recurrent conjunctivitis, & photophobia Assess for ptosis. Assess for strabismus. Echocardiogram Further eval if clinical evidence suggests arrhythmias Cysts can result in fluctuating symptoms (e.g., when enlarged, they may compress the root or cord & result in pain or weakness). Spinal MRI if symptomatic Conservative management of symptomatic distichiasis with lubrication or epilation (plucking), or more definitive management with cryotherapy, electrolysis, or lid splitting [ Surgery for ptosis if clinically indicated (e.g., obscured vision, cosmetic appearance) The following are appropriate: Prevention of secondary cellulitis in areas with lymphedema, particularly as cellulitis may aggravate the degree of edema. Prophylactic antibiotics (e.g., penicillin V 500 mg/day) are recommended for recurrent cellulitis. Prompt treatment of early cellulitis with appropriate antibiotics. It may be necessary to give the first few doses intravenously if there is severe systemic upset. Prevention of foot infections (particularly athlete's foot / infected eczema) by treatment with appropriate creams/ointments Note: (1) Diuretics are not effective in the treatment of lymphedema. (2) Cosmetic surgery is often associated with disappointing results. See Recommended Surveillance for Individuals with Lymphedema-Distichiasis Syndrome See See Edema may be exacerbated during pregnancy, but often improves after delivery. The patient should continue compression and bandage treatment as long as possible but this should be adapted to the patient's needs (e.g., thigh-length compression garments instead of tights). See Search • Slit lamp eval for distichiasis & related problems of corneal irritation, recurrent conjunctivitis, & photophobia • Assess for ptosis. • Assess for strabismus. • Echocardiogram • Further eval if clinical evidence suggests arrhythmias • Cysts can result in fluctuating symptoms (e.g., when enlarged, they may compress the root or cord & result in pain or weakness). • Spinal MRI if symptomatic • Conservative management of symptomatic distichiasis with lubrication or epilation (plucking), or more definitive management with cryotherapy, electrolysis, or lid splitting [ • Surgery for ptosis if clinically indicated (e.g., obscured vision, cosmetic appearance) • Prevention of secondary cellulitis in areas with lymphedema, particularly as cellulitis may aggravate the degree of edema. Prophylactic antibiotics (e.g., penicillin V 500 mg/day) are recommended for recurrent cellulitis. • Prompt treatment of early cellulitis with appropriate antibiotics. It may be necessary to give the first few doses intravenously if there is severe systemic upset. • Prevention of foot infections (particularly athlete's foot / infected eczema) by treatment with appropriate creams/ointments ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs of in an individual diagnosed with lymphedema-distichiasis syndrome (LDS), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Lymphedema-Distichiasis Syndrome Slit lamp eval for distichiasis & related problems of corneal irritation, recurrent conjunctivitis, & photophobia Assess for ptosis. Assess for strabismus. Echocardiogram Further eval if clinical evidence suggests arrhythmias Cysts can result in fluctuating symptoms (e.g., when enlarged, they may compress the root or cord & result in pain or weakness). Spinal MRI if symptomatic • Slit lamp eval for distichiasis & related problems of corneal irritation, recurrent conjunctivitis, & photophobia • Assess for ptosis. • Assess for strabismus. • Echocardiogram • Further eval if clinical evidence suggests arrhythmias • Cysts can result in fluctuating symptoms (e.g., when enlarged, they may compress the root or cord & result in pain or weakness). • Spinal MRI if symptomatic ## Treatment of Manifestations Conservative management of symptomatic distichiasis with lubrication or epilation (plucking), or more definitive management with cryotherapy, electrolysis, or lid splitting [ Surgery for ptosis if clinically indicated (e.g., obscured vision, cosmetic appearance) The following are appropriate: Prevention of secondary cellulitis in areas with lymphedema, particularly as cellulitis may aggravate the degree of edema. Prophylactic antibiotics (e.g., penicillin V 500 mg/day) are recommended for recurrent cellulitis. Prompt treatment of early cellulitis with appropriate antibiotics. It may be necessary to give the first few doses intravenously if there is severe systemic upset. Prevention of foot infections (particularly athlete's foot / infected eczema) by treatment with appropriate creams/ointments Note: (1) Diuretics are not effective in the treatment of lymphedema. (2) Cosmetic surgery is often associated with disappointing results. See • Conservative management of symptomatic distichiasis with lubrication or epilation (plucking), or more definitive management with cryotherapy, electrolysis, or lid splitting [ • Surgery for ptosis if clinically indicated (e.g., obscured vision, cosmetic appearance) • Prevention of secondary cellulitis in areas with lymphedema, particularly as cellulitis may aggravate the degree of edema. Prophylactic antibiotics (e.g., penicillin V 500 mg/day) are recommended for recurrent cellulitis. • Prompt treatment of early cellulitis with appropriate antibiotics. It may be necessary to give the first few doses intravenously if there is severe systemic upset. • Prevention of foot infections (particularly athlete's foot / infected eczema) by treatment with appropriate creams/ointments ## Surveillance Recommended Surveillance for Individuals with Lymphedema-Distichiasis Syndrome See ## Evaluation of Relatives at Risk See ## Pregnancy Management Edema may be exacerbated during pregnancy, but often improves after delivery. The patient should continue compression and bandage treatment as long as possible but this should be adapted to the patient's needs (e.g., thigh-length compression garments instead of tights). See ## Therapies Under Investigation Search ## Genetic Counseling Lymphedema-distichiasis syndrome (LDS) is inherited in an autosomal dominant manner. Most individuals diagnosed with LDS have an affected parent. A proband with LDS may have the disorder as the result of a If the The family history of some individuals diagnosed with LDS may appear to be negative because of failure to recognize the disorder in family members as a result of variable expressivity. 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%. Manifestations of the disorder in sibs who inherit a If the parents are clinically unaffected and/or the proband has a known The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Fetal echocardiography at 16 to 20 weeks' gestation is recommended because of the increased risk for congenital heart disease. Additional fetal scans may be warranted because of the increased risk for cleft palate. An additional scan in the third trimester is recommended because of the increased risk of hydrothoraces or hydrops fetalis. • Most individuals diagnosed with LDS have an affected parent. • A proband with LDS may have the disorder as the result of a • If the • The family history of some individuals diagnosed with LDS may appear to be negative because of failure to recognize the disorder in family members as a result of variable expressivity. 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%. Manifestations of the disorder in sibs who inherit a • If the parents are clinically unaffected and/or the proband has a known • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • Fetal echocardiography at 16 to 20 weeks' gestation is recommended because of the increased risk for congenital heart disease. • Additional fetal scans may be warranted because of the increased risk for cleft palate. • An additional scan in the third trimester is recommended because of the increased risk of hydrothoraces or hydrops fetalis. ## Mode of Inheritance Lymphedema-distichiasis syndrome (LDS) is inherited in an autosomal dominant manner. ## Risk to Family Members Most individuals diagnosed with LDS have an affected parent. A proband with LDS may have the disorder as the result of a If the The family history of some individuals diagnosed with LDS may appear to be negative because of failure to recognize the disorder in family members as a result of variable expressivity. 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%. Manifestations of the disorder in sibs who inherit a If the parents are clinically unaffected and/or the proband has a known • Most individuals diagnosed with LDS have an affected parent. • A proband with LDS may have the disorder as the result of a • If the • The family history of some individuals diagnosed with LDS may appear to be negative because of failure to recognize the disorder in family members as a result of variable expressivity. 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%. Manifestations of the disorder in sibs who inherit a • If the parents are clinically unaffected and/or the proband has a known ## 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 Fetal echocardiography at 16 to 20 weeks' gestation is recommended because of the increased risk for congenital heart disease. Additional fetal scans may be warranted because of the increased risk for cleft palate. An additional scan in the third trimester is recommended because of the increased risk of hydrothoraces or hydrops fetalis. • Fetal echocardiography at 16 to 20 weeks' gestation is recommended because of the increased risk for congenital heart disease. • Additional fetal scans may be warranted because of the increased risk for cleft palate. • An additional scan in the third trimester is recommended because of the increased risk of hydrothoraces or hydrops fetalis. ## Resources Lymphatic Education and Research Network 261 Madison Avenue 9th Floor New York NY 10016 St. Luke's Crypt Sydney Street London SW3 6NH United Kingdom 116 New Montgomery Street Suite 235 San Francisco CA 94105 • • Lymphatic Education and Research Network • 261 Madison Avenue • 9th Floor • New York NY 10016 • • • St. Luke's Crypt • Sydney Street • London SW3 6NH • United Kingdom • • • 116 New Montgomery Street • Suite 235 • San Francisco CA 94105 • • • • • ## Molecular Genetics Lymphedema-Distichiasis Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Lymphedema-Distichiasis Syndrome ( ## Molecular Pathogenesis ## References ## Literature Cited ## Chapter Notes 4 April 2019 (bp) Comprehensive update posted live 24 May 2012 (me) Comprehensive update posted live 2 August 2007 (me) Comprehensive update posted live 4 January 2007 (sm) Revision: 16 June 2006 (cd) Revision: prenatal testing clinically available 6 March 2006 (cd) Revision: FOXC2 testing clinically available 29 March 2005 (me) Review posted live 13 September 2004 (sm) Original submission • 4 April 2019 (bp) Comprehensive update posted live • 24 May 2012 (me) Comprehensive update posted live • 2 August 2007 (me) Comprehensive update posted live • 4 January 2007 (sm) Revision: • 16 June 2006 (cd) Revision: prenatal testing clinically available • 6 March 2006 (cd) Revision: FOXC2 testing clinically available • 29 March 2005 (me) Review posted live • 13 September 2004 (sm) Original submission ## Revision History 4 April 2019 (bp) Comprehensive update posted live 24 May 2012 (me) Comprehensive update posted live 2 August 2007 (me) Comprehensive update posted live 4 January 2007 (sm) Revision: 16 June 2006 (cd) Revision: prenatal testing clinically available 6 March 2006 (cd) Revision: FOXC2 testing clinically available 29 March 2005 (me) Review posted live 13 September 2004 (sm) Original submission • 4 April 2019 (bp) Comprehensive update posted live • 24 May 2012 (me) Comprehensive update posted live • 2 August 2007 (me) Comprehensive update posted live • 4 January 2007 (sm) Revision: • 16 June 2006 (cd) Revision: prenatal testing clinically available • 6 March 2006 (cd) Revision: FOXC2 testing clinically available • 29 March 2005 (me) Review posted live • 13 September 2004 (sm) Original submission	[ "C Bellini, G Donarini, D Paladini, MG Calevo, T Bellini, LA Ramenghi, RC Hennekam. Etiology of non-immune hydrops fetalis: an update.. Am J Med Genet A. 2015;167A:1082-8", "G Brice. Diagnostic difficulties in lympedema distichiasis.. Pediatr Dermatol 2003;20:89", "G Brice, S Mansour, R Bell, JR Collin, AH Child, AF Brady, M Sarfarazi, KG Burnand, S Jeffery, P Mortimer, VA Murday. Analysis of the phenotypic abnormalities in lymphoedema-distichiasis syndrome in 74 patients with FOXC2 mutations or linkage to 16q24.. J Med Genet 2002;39:478-83", "BP Brooks, SL Dagenais, CC Nelson, MW Glynn, MS Caulder, CA Downs, TW Glover. Mutation of the FOXC2 gene in familial distichiasis.. J AAPOS 2003;7:354-7", "MG Butler, SL Dagenais, JL Garcia-Perez, P Brouillard, M Vikkula, P Strouse, JW Innis, TW Glover. Microcephaly, intellectual impairment, bilateral vesicoureteral reflux, distichiasis, and glomuvenous malformations associated with a 16q24.3 contiguous gene deletion and a Glomulin mutation.. Am J Med Genet A. 2012;158A:839-49", "E Chen, SK Larabell, JM Daniels, S Goldstein. Distichiasis-lymphedema syndrome: tetralogy of Fallot, chylothorax, and neonatal death.. Am J Med Genet 1996;66:273-5", "RF Dale. Primary lymphoedema when found with distichiasis is of the type defined as bilateral hyperplasia by lymphography.. J Med Genet 1987;24:170-1", "G de Bruyn, A Casaer, K Devolder, G Van Acker, H Logghe, K Devriendt, L Cornette. Hydrops fetalis and pulmonary lymphangiectasia due to FOXC2 mutation: an autosomal dominant hereditary lymphedema syndrome with variable expression.. Eur J Pediatr. 2012;171:447-50", "RP Erickson, SL Dagenais, MS Caulder, CA Downs, G Herman, MC Jones, WS Kerstjens-Frederikse, AC Lidral, M McDonald, CC Nelson, M Witte, TW Glover. Clinical heterogeneity in lymphoedema-distichiasis with FOXC2 truncating mutations.. J Med Genet 2001;38:761-6", "DN Finegold, MA Kimak, EC Lawrence, KL Levinson, EM Cherniske, BR Pober, JW Dunlap, RE Ferrell. Truncating mutations in FOXC2 cause multiple lymphedema syndromes.. Hum Mol Genet 2001;10:1185-9", "SR Hoque, S Mansour, PS Mortimer. Yellow nail syndrome: not a genetic disorder? Eleven new cases and a review of the literature.. Br J Dermatol. 2007;156:1230-4", "KE Inman, CD Caiaffa, KR Melton, LL Sandell, A Achilleos, T Kume, PA Trainor. Foxc2 is required for proper cardiac neural crest cell migration, outflow tract septation, and ventricle expansion.. Dev Dyn. 2018;247:1286-96", "GE Jones, AK Richmond, O Navti, HA Mousa, S Abbs, E Thompson, S Mansour, PC Vasudevan. Renal anomalies and lymphedema distichiasis syndrome. A rare association?. Am J Med Genet A. 2017;173:2251-6", "IN Kanaan, N Sakati, F Otaibi. Type I congenital multiple intraspinal extradural cysts associated with distichiasis and lymphedema syndrome.. Surg Neurol 2006;65:162-6", "O Lyons, P Saha, C Seet, A Kuchta, A Arnold, S Grover, V Rashbrook, A Sabine, G Vizcay-Barrena, A Patel, F Ludwinski, S Padayachee, T Kume, BR Kwak, G Brice, S Mansour, P Ostergaard, P Mortimer, S Jeffery, N Brown, T Makinen, TV Petrova, B Modarai, A Smith. Human venous valve disease caused by mutations in FOXC2 and GJC2.. J Exp Med. 2017;214:2437-52", "RH Mellor, G Brice, AW Stanton, J French, A Smith, S Jeffery, JR Levick, KG Burnand, PS Mortimer. Mutations in FOXC2 are strongly associated with primary valve failure in veins of the lower limb.. Circulation 2007;115:1912-20", "MY Ng, T Andrew, TD Spector, S Jeffery. Linkage to the FOXC2 region of chromosome 16 for varicose veins in otherwise healthy, unselected sibling pairs.. J Med Genet 2005;42:235-9", "BA O'Donnell, JR Collin. Distichiasis: management with cryotherapy to the posterior lamella.. Br J Ophthalmol 1993;77:289-92", "Y Ogura, S Yabuki, A Iida, I Kou, M Nakajima, H Kano, M Shiina, S Kikuchi, Y Toyama, K Ogata, M Nakamura, M Matsumoto, S. Ikegawa. FOXC2 mutations in familial and sporadic spinal extradural arachnoid cyst.. PLoS One. 2013;8", "P Papoff, M Castori, L Manganaro, F Midulla, C Moretti, P Cascone. Early mandibular distraction to relieve Robin severe airway obstruction in two siblings with lymphedema-distichiasis syndrome.. J Maxillofac Oral Surg. 2016;15:384-9", "TV Petrova, T Karpanen, C Norrmen, R Mellor, T Tamakoshi, D Finegold, R Ferrell, D Kerjaschki, P Mortimer, S Yla-Herttuala, N Miura, K Alitalo. Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis.. Nat Med 2004;10:974-81", "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", "T Rezaie, R Ghoroghchian, R Bell, G Brice, A Hasan, K Burnand, S Vernon, S Mansour, P Mortimer, S Jeffery, A Child, M. Sarfarazi. Primary non-syndromic lymphoedema (Meige disease) is not caused by mutations in FOXC2.. Eur J Hum Genet. 2008;16:300-4", "JL Rosbotham, GW Brice, AH Child, TO Nunan, PS Mortimer, KG Burnand. Distichiasis-lymphoedema: clinical features, venous function and lymphoscintigraphy.. Br J Dermatol 2000;142:148-52", "C Sargent, J Bauer, M Khalil, P Filmore, M Bernas, M Witte, MP Pearson, RP Erickson. A five generation family with a novel mutation in FOXC2 and lymphedema worsening to hydrops in the youngest generation.. Am J Med Genet A. 2014;164A:2802-7" ]	29/3/2005	4/4/2019	4/1/2007	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
legius	legius	[ "Neurofibromatosis Type 1-Like Syndrome", "Neurofibromatosis Type 1-Like Syndrome", "Sprouty-related, EVH1 domain-containing protein 1", "SPRED1", "Legius Syndrome" ]	Legius Syndrome	Eric Legius, David Stevenson	Summary Legius syndrome is characterized by multiple café au lait macules without neurofibromas or other tumor manifestations of neurofibromatosis type 1 (NF1). Additional clinical manifestations reported commonly include intertriginous freckling, lipomas, macrocephaly, and learning disabilities / attention-deficit/hyperactivity disorder (ADHD) / developmental delays. Current knowledge of the natural history of Legius syndrome is based on the clinical manifestations of fewer than 300 individuals with a molecularly confirmed diagnosis; better delineation of the clinical manifestations and natural history of Legius syndrome will likely occur as more affected individuals are identified. The diagnosis of Legius syndrome is established in a proband with suggestive findings and a heterozygous pathogenic variant in Legius syndrome is inherited in an autosomal dominant manner. Many affected individuals have an affected parent. Each child of an individual with Legius syndrome has a 50% chance of inheriting the pathogenic variant and developing clinical features of the disorder. Preimplantation genetic testing or prenatal testing for pregnancies at increased risk is possible if the	## Diagnosis Legius syndrome Has pigmentary dysplasia consisting of café au lait macules, with or without intertriginous freckling; and Lacks the nonpigmentary clinical diagnostic manifestations of The diagnostic criteria for Legius syndrome are met if at least two of the following criteria are present: Five or more café au lait macules bilaterally distributed and no other NF1-related diagnostic criteria except for axillary or inguinal freckling A heterozygous pathogenic (or likely pathogenic) variant in A parent with the diagnosis of Legius syndrome by the above criteria 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 A For an introduction to multigene panels click Note: Opinions differ on the appropriate approach when clinical information and family history cannot distinguish between NF1 and Legius syndrome. This is the case in individuals with only café au lait macules with or without freckling but no other signs of NF1. The assessment of pros and cons of molecular testing requires consideration of the circumstances unique to each individual, including (but not limited to) the following: Clinical findings and family history Age of the individual Differences in recommended clinical management when the diagnosis of NF1 or Legius syndrome is established with certainty vs when the diagnosis of neither can be established with confidence Psychological burden of a diagnosis or lack thereof Costs of testing and surveillance Odds of identifying a diagnosis of NF1 vs Legius syndrome in those with phenotype limited to pigmentary findings For various approaches, see Molecular Genetic Testing Used in Legius 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 Of individuals evaluated for NF1 without an identifiable 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. Sequence analysis in combination with deletion/duplication analysis should identify the majority of individuals, although it is estimated that approximately 1% could have deep intronic variants that could be missed; however, this has not been reported. • Has pigmentary dysplasia consisting of café au lait macules, with or without intertriginous freckling; and • Lacks the nonpigmentary clinical diagnostic manifestations of • Five or more café au lait macules bilaterally distributed and no other NF1-related diagnostic criteria except for axillary or inguinal freckling • A heterozygous pathogenic (or likely pathogenic) variant in • A parent with the diagnosis of Legius syndrome by the above criteria • A • For an introduction to multigene panels click • Clinical findings and family history • Age of the individual • Differences in recommended clinical management when the diagnosis of NF1 or Legius syndrome is established with certainty vs when the diagnosis of neither can be established with confidence • Psychological burden of a diagnosis or lack thereof • Costs of testing and surveillance • Odds of identifying a diagnosis of NF1 vs Legius syndrome in those with phenotype limited to pigmentary findings ## Suggestive Findings Legius syndrome Has pigmentary dysplasia consisting of café au lait macules, with or without intertriginous freckling; and Lacks the nonpigmentary clinical diagnostic manifestations of • Has pigmentary dysplasia consisting of café au lait macules, with or without intertriginous freckling; and • Lacks the nonpigmentary clinical diagnostic manifestations of ## Establishing the Diagnosis The diagnostic criteria for Legius syndrome are met if at least two of the following criteria are present: Five or more café au lait macules bilaterally distributed and no other NF1-related diagnostic criteria except for axillary or inguinal freckling A heterozygous pathogenic (or likely pathogenic) variant in A parent with the diagnosis of Legius syndrome by the above criteria 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 A For an introduction to multigene panels click Note: Opinions differ on the appropriate approach when clinical information and family history cannot distinguish between NF1 and Legius syndrome. This is the case in individuals with only café au lait macules with or without freckling but no other signs of NF1. The assessment of pros and cons of molecular testing requires consideration of the circumstances unique to each individual, including (but not limited to) the following: Clinical findings and family history Age of the individual Differences in recommended clinical management when the diagnosis of NF1 or Legius syndrome is established with certainty vs when the diagnosis of neither can be established with confidence Psychological burden of a diagnosis or lack thereof Costs of testing and surveillance Odds of identifying a diagnosis of NF1 vs Legius syndrome in those with phenotype limited to pigmentary findings For various approaches, see Molecular Genetic Testing Used in Legius 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 Of individuals evaluated for NF1 without an identifiable 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. Sequence analysis in combination with deletion/duplication analysis should identify the majority of individuals, although it is estimated that approximately 1% could have deep intronic variants that could be missed; however, this has not been reported. • Five or more café au lait macules bilaterally distributed and no other NF1-related diagnostic criteria except for axillary or inguinal freckling • A heterozygous pathogenic (or likely pathogenic) variant in • A parent with the diagnosis of Legius syndrome by the above criteria • A • For an introduction to multigene panels click • Clinical findings and family history • Age of the individual • Differences in recommended clinical management when the diagnosis of NF1 or Legius syndrome is established with certainty vs when the diagnosis of neither can be established with confidence • Psychological burden of a diagnosis or lack thereof • Costs of testing and surveillance • Odds of identifying a diagnosis of NF1 vs Legius syndrome in those with phenotype limited to pigmentary findings ## Clinical Characteristics Of note, the phenotype of Legius syndrome is based on the reports of relatively few (<300) individuals, in which the primary focus was on individuals with the overlapping pigmentary manifestations of Legius Syndrome: Frequency of Select Features The cognitive issues in individuals with Legius syndrome are likely milder than those observed in NF1. A study of 15 individuals with Legius syndrome by Hearing loss in four individuals [ Seizures in six individuals [ Polydactyly in three individuals [ Scoliosis in five individuals [ Pulmonic valve stenosis in three individuals [ No genotype-phenotype correlations have been identified. The vast majority of individuals with Some very young children may not have developed café au lait macules yet, and in older individuals the café au lait macules may have faded away. Some adolescents or young adults show only two or three café au lait macules, and the syndrome may be underdiagnosed. The majority of individuals with The prevalence of Legius syndrome is estimated at 1:46,000-1:75,000 based on the fraction of children with a • Hearing loss in four individuals [ • Seizures in six individuals [ • Polydactyly in three individuals [ • Scoliosis in five individuals [ • Pulmonic valve stenosis in three individuals [ ## Clinical Description Of note, the phenotype of Legius syndrome is based on the reports of relatively few (<300) individuals, in which the primary focus was on individuals with the overlapping pigmentary manifestations of Legius Syndrome: Frequency of Select Features The cognitive issues in individuals with Legius syndrome are likely milder than those observed in NF1. A study of 15 individuals with Legius syndrome by Hearing loss in four individuals [ Seizures in six individuals [ Polydactyly in three individuals [ Scoliosis in five individuals [ Pulmonic valve stenosis in three individuals [ • Hearing loss in four individuals [ • Seizures in six individuals [ • Polydactyly in three individuals [ • Scoliosis in five individuals [ • Pulmonic valve stenosis in three individuals [ ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been identified. ## Penetrance The vast majority of individuals with Some very young children may not have developed café au lait macules yet, and in older individuals the café au lait macules may have faded away. Some adolescents or young adults show only two or three café au lait macules, and the syndrome may be underdiagnosed. ## Nomenclature The majority of individuals with ## Prevalence The prevalence of Legius syndrome is estimated at 1:46,000-1:75,000 based on the fraction of children with a ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Of primary importance in the clinical delineation of Legius syndrome is establishing the absence of other manifestations associated with the large number of other syndromes with multiple café au lait macules (most notably Disorders with Multiple Café au Lait Macules of Interest in the Differential Diagnosis of Legius Syndrome AD = autosomal dominant; AR = autosomal recessive; CMMRD = constitutional mismatch repair deficiency; MOI = mode of inheritance; XL = X-linked Genes associated with RASopathies are grouped together in this table to avoid redundancy. See the linked At least one individual with Legius syndrome was previously diagnosed as having Noonan syndrome [ Noonan syndrome is most often inherited in an autosomal dominant manner. Noonan syndrome caused by pathogenic variants in Listed genes represent the most common genetic causes; see ## Management To establish the extent of disease and needs of an individual with Legius syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Legius Syndrome Incl motor, adaptive, cognitive, & speech/language eval Eval for early intervention / special education ADHD = attention-deficit/hyperactivity disorder; MOI = mode of inheritance Geneticist, certified genetic counselor, or certified advanced genetic nurse Treatment of Manifestations in Individuals with Legius Syndrome Adjuvant therapies incl PT, OT, & speech therapy for persons w/identified developmental delays Individualized education plans for learning disorders & school performance issues ADHD = attention-deficit/hyperactivity disorder; OT = occupational therapy; PT = physical therapy Recommended Surveillance for Individuals with Legius Syndrome ADHD = attention-deficit/hyperactivity disorder Although vascular abnormalities have been reported in a few individuals with Legius syndrome, hypertension has not been reported. However, given the prevalence of vascular abnormalities and hypertension in NF1, it would seem appropriate to have regular blood pressure monitoring at each physician visit. See Search • Incl motor, adaptive, cognitive, & speech/language eval • Eval for early intervention / special education • Adjuvant therapies incl PT, OT, & speech therapy for persons w/identified developmental delays • Individualized education plans for learning disorders & school performance issues ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual with Legius syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Legius Syndrome Incl motor, adaptive, cognitive, & speech/language eval Eval for early intervention / special education ADHD = attention-deficit/hyperactivity disorder; MOI = mode of inheritance Geneticist, certified genetic counselor, or certified advanced genetic nurse • Incl motor, adaptive, cognitive, & speech/language eval • Eval for early intervention / special education ## Treatment of Manifestations Treatment of Manifestations in Individuals with Legius Syndrome Adjuvant therapies incl PT, OT, & speech therapy for persons w/identified developmental delays Individualized education plans for learning disorders & school performance issues ADHD = attention-deficit/hyperactivity disorder; OT = occupational therapy; PT = physical therapy • Adjuvant therapies incl PT, OT, & speech therapy for persons w/identified developmental delays • Individualized education plans for learning disorders & school performance issues ## Surveillance Recommended Surveillance for Individuals with Legius Syndrome ADHD = attention-deficit/hyperactivity disorder Although vascular abnormalities have been reported in a few individuals with Legius syndrome, hypertension has not been reported. However, given the prevalence of vascular abnormalities and hypertension in NF1, it would seem appropriate to have regular blood pressure monitoring at each physician visit. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Legius syndrome is inherited in an autosomal dominant manner. Many individuals diagnosed with Legius syndrome have an affected parent. Some individuals diagnosed with Legius syndrome 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 * Misattributed parentage can also be explored as an alternative explanation for an apparent The family history of some individuals diagnosed with Legius syndrome 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 Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic/germline mosaicism for the pathogenic variant and may be mildly/minimally affected. (Segmental distribution of café au lait macules as a result of somatic mosaicism for a If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. All sibs who inherit a pathogenic 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. 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 Legius syndrome have an affected parent. • Some individuals diagnosed with Legius syndrome 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 • * Misattributed parentage can also be explored as an alternative explanation for an apparent • The family history of some individuals diagnosed with Legius syndrome 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 • Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic/germline mosaicism for the pathogenic variant and may be mildly/minimally affected. (Segmental distribution of café au lait macules as a result of somatic mosaicism for a • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. • All sibs who inherit a pathogenic • 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 Legius syndrome is inherited in an autosomal dominant manner. ## Risk to Family Members Many individuals diagnosed with Legius syndrome have an affected parent. Some individuals diagnosed with Legius syndrome 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 * Misattributed parentage can also be explored as an alternative explanation for an apparent The family history of some individuals diagnosed with Legius syndrome 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 Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic/germline mosaicism for the pathogenic variant and may be mildly/minimally affected. (Segmental distribution of café au lait macules as a result of somatic mosaicism for a If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. All sibs who inherit a pathogenic If the proband has a known If the parents have not been tested for the • Many individuals diagnosed with Legius syndrome have an affected parent. • Some individuals diagnosed with Legius syndrome 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 • * Misattributed parentage can also be explored as an alternative explanation for an apparent • The family history of some individuals diagnosed with Legius syndrome 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 • Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic/germline mosaicism for the pathogenic variant and may be mildly/minimally affected. (Segmental distribution of café au lait macules as a result of somatic mosaicism for a • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. • All sibs who inherit a pathogenic • If the proband has a known • If the parents have not been tested for the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom • • • • • • United Kingdom • ## Molecular Genetics Legius Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Legius Syndrome ( N-terminal EVH-1 domain Central KIT binding domain C-terminal SPRY domain Spred1 belongs to a family of proteins that are negative regulators of the Ras/ERK pathway. Spred1 negatively regulates the Ras/ERK pathway by inhibiting Raf1 kinase activation [ Disease-associated variants result in Spred1 proteins incapable of inhibiting Raf1 kinase activation, resulting in attenuated inhibition of downstream Raf-MEK-ERK signaling [ • N-terminal EVH-1 domain • Central KIT binding domain • C-terminal SPRY domain ## Molecular Pathogenesis N-terminal EVH-1 domain Central KIT binding domain C-terminal SPRY domain Spred1 belongs to a family of proteins that are negative regulators of the Ras/ERK pathway. Spred1 negatively regulates the Ras/ERK pathway by inhibiting Raf1 kinase activation [ Disease-associated variants result in Spred1 proteins incapable of inhibiting Raf1 kinase activation, resulting in attenuated inhibition of downstream Raf-MEK-ERK signaling [ • N-terminal EVH-1 domain • Central KIT binding domain • C-terminal SPRY domain ## Chapter Notes John Carey, MDLudwine Messiaen, PhDTalia Muram, MD Eric Legius, MD, PhD (2020-present)Rong Mao, MD; University of Utah (2010-2020)Talia Muram-Zborovski, MD, University of Utah (2010-2015)David Stevenson, MD (2010-present)David Viskochil, MD, PhD; University of Utah (2010-2020) 6 August 2020 (sw) Comprehensive update posted live 15 January 2015 (me) Comprehensive update posted live 12 May 2011 (cd) Revision: Testing Strategy 14 October 2010 (me) Review posted live 29 April 2010 (ds) Original submission • 6 August 2020 (sw) Comprehensive update posted live • 15 January 2015 (me) Comprehensive update posted live • 12 May 2011 (cd) Revision: Testing Strategy • 14 October 2010 (me) Review posted live • 29 April 2010 (ds) Original submission ## Acknowledgments John Carey, MDLudwine Messiaen, PhDTalia Muram, MD ## Author History Eric Legius, MD, PhD (2020-present)Rong Mao, MD; University of Utah (2010-2020)Talia Muram-Zborovski, MD, University of Utah (2010-2015)David Stevenson, MD (2010-present)David Viskochil, MD, PhD; University of Utah (2010-2020) ## Revision History 6 August 2020 (sw) Comprehensive update posted live 15 January 2015 (me) Comprehensive update posted live 12 May 2011 (cd) Revision: Testing Strategy 14 October 2010 (me) Review posted live 29 April 2010 (ds) Original submission • 6 August 2020 (sw) Comprehensive update posted live • 15 January 2015 (me) Comprehensive update posted live • 12 May 2011 (cd) Revision: Testing Strategy • 14 October 2010 (me) Review posted live • 29 April 2010 (ds) Original submission ## References ## Literature Cited	[ "J Ablain, M Xu, H Rothschild, RC Jordan, JK Mito, BH Daniels, CF Bell, NM Joseph, H Wu, BC Bastian, LI Zon, I Yeh. Human tumor genomics and zebrafish modeling identify. Science. 2018;362:1055-60", "E Benelli, I Bruno, C Belcaro, A Ventura, I. Berti. Legius syndrome: case report and review of literature.. Ital J Pediatr. 2015;41:8", "H Brems, M Chmara, M Sahbatou, E Denayer, K Taniguchi, R Kato, R Somers, L Messiaen, S De Schepper, JP Fryns, J Cools, P Marynen, G Thomas, A Yoshimura, E Legius. Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype.. Nat Genet 2007;39:1120-6", "H Brems, E Pasmant, R Van Minkelen, K Wimmer, M Upadhyaya, E Legius, L Messiaen. Review and update of SPRED1 mutations causing Legius syndrome.. Hum Mutat. 2012;33:1538-46", "E Castellanos, I Rosas, A Negro, B Gel, A Alibés, N Baena, M Pineda, G Pi, G Pintos, H Salvador, C Lázaro, I Blanco, L Vilageliu, H Brems, D Grinberg, E Legius, E Serra. Mutational spectrum by phenotype: panel-based NGS testing of patients with clinical suspicion of RASopathy and children with multiple café-au-lait macules.. Clin Genet. 2020;97:264-75", "E Denayer, M Chmara, H Brems, AM Kievit, Y van Bever, AM Van den Ouweland, R Van Minkelen, A de Goede-Bolder, R Oostenbrink, P Lakeman, E Beert, T Ishizaki, T Mori, K Keymolen, J Van den Ende, E Mangold, S Peltonen, G Brice, J Rankin, KY Van Spaendonck-Zwarts, A Yoshimura, E Legius. Legius syndrome in fourteen families.. Hum Mutat. 2011a;32:E1985-98", "E Denayer, MJ Descheemaeker, DR Stewart, K Keymolen, E Plasschaert, SL Ruppert, J Snow, AE Thurm, LA Joseph, JP Fryns, E Legius. Observations on intelligence and behavior in 15 patients with Legius syndrome.. Am J Med Genet C Semin Med Genet 2011b;157C:123-8", "T Dunzendorfer-Matt, EL Mercado, K Maly, F McCormick, K Scheffzek. The neurofibromin recruitment factor Spred1 binds to the GAP related domain without affecting Ras inactivation.. Proc Natl Acad Sci U S A. 2016;113:7497-502", "DG Evans, N Bowers, E Burkitt-Wright, E Miles, S Garg, V Scott-Kitching, M Penman-Splitt, A Dobbie, E Howard, J Ealing, G Vassalo, AJ Wallace, W Newman, SM Huson. Comprehensive RNA analysis of the NF1 gene in classically affected NF1 affected individuals meeting NIH criteria has high sensitivity and mutation negative testing is reassuring in isolated cases with pigmentary features only.. EBioMedicine. 2016;7:212-20", "T Giugliano, C Santoro, A Torella, F Del Vecchio Blanco, A Grandone, ME Onore, MAB Melone, G Straccia, D Melis, V Piccolo, G Limongelli, S Buono, S Perrotta, V Nigro, G Piluso. Clinical and genetic findings in children with neurofibromatosis type 1, Legius syndrome, and other related neurocutaneous disorders.. Genes (Basel) 2019;10:580", "DH Gutmann, A Aylsworth, JC Carey, B Korf, J Marks, RE Pyeritz, A Rubenstein, D Viskochil. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2.. JAMA 1997;278:51-7", "Y Hirata, H Brems, M Suzuki, M Kanamori, M Okada, R Morita, I Llano-Rivas, T Ose, L Messiaen, E Legius, A Yoshimura. Interaction between a domain of the negative regulator of the Ras-ERK pathway, SPRED1 protein, and the GTPase-activating protein-related domain of neurofibromin is implicated in Legius syndrome and neurofibromatosis type 1.. J Biol Chem. 2016;291:3124-34", "RK Jobling, I Lara-Corrales, MC Hsiao, A Shugar, S Hedges, L Messiaen, P Kannu. Mosaicism for a SPRED1 deletion revealed in a patient with clinically suspected mosaic neurofibromatosis.. Br J Dermatol. 2017;176:1077-8", "M Koczkowska, T Callens, A Gomes, A Sharp, Y Chen, AD Hicks, AS Aylsworth, AA Azizi, DG Basel, G Bellus, LM Bird, MA Blazo, LW Burke, A Cannon, F Collins, C DeFilippo, E Denayer, MC Digilio, SK Dills, L Dosa, RS Greenwood, C Griffis, P Gupta, RK Hachen, C Hernández-Chico, S Janssens, KJ Jones, JT Jordan, P Kannu, BR Korf, AM Lewis, RH Listernick, F Lonardo, MJ Mahoney, MM Ojeda, MT McDonald, C McDougall, N Mendelsohn, DT Miller, M Mori, R Oostenbrink, S Perreault, ME Pierpont, C Piscopo, DA Pond, LM Randolph, KA Rauen, S Rednam, SL Rutledge, V Saletti, GB Schaefer, EK Schorry, DA Scott, A Shugar, E Siqveland, LJ Starr, A Syed, PL Trapane, NJ Ullrich, EG Wakefield, LE Walsh, MF Wangler, E Zackai, KBM Claes, K Wimmer, R van Minkelen, A De Luca, Y Martin, E Legius, LM Messiaen. Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation.. Genet Med 2019;21:867-76", "S Laycock-van Spyk, HP Jim, L Thomas, G Spurlock, L Fares, S Palmer-Smith, U Kini, A Saggar, M Patton, V Mautner, DT Pilz, M Upadhyaya. Identification of five novel SPRED1 germline mutations in Legius syndrome.. Clin Genet 2011;80:93-6", "L Messiaen, S Yao, H Brems, T Callens, A Sathienkijkanchai, E Denayer, E Spencer, P Arn, D Babovic-Vuksanovic, C Bay, G Bobele, BH Cohen, L Escobar, D Eunpu, T Grebe, R Greenstein, R Hachen, M Irons, D Kronn, E Lemire, K Leppig, C Lim, M McDonald, V Narayanan, A Pearn, R Pederson, B Powell, L Shapiro, D Skidmore, D Tegay, H Thiese, E Zackai, R Vijzelaar, K Taniguchi, R Ayada, F Okamoto, A Yoshimura, A Parret, B Korf, E Legius. Clinical and mutational spectrum of neurofibromatosis type 1-like syndrome.. JAMA 2009;302:2111-8", "TM Muram-Zborovski, DA Stevenson, DH Viskochil, DC Dries, AR Wilson, Rong Mao. SPRED 1 mutations in a neurofibromatosis clinic.. J Child Neurol. 2010;25:1203-9", "F Newell, Y Kong, JS Wilmott, PA Johansson, PM Ferguson, C Cui, Z Li, SH Kazakoff, H Burke, TJ Dodds, AM Patch, K Nones, V Tembe, P Shang, L van der Weyden, K Wong, O Holmes, S Lo, C Leonard, S Wood, Q Xu, RV Rawson, P Mukhopadhyay, R Dummer, MP Levesque, G Jönsson, X Wang, I Yeh, H Wu, N Joseph, BC Bastian, GV Long, AJ Spillane, KF Shannon, JF Thompson, RPM Saw, DJ Adams, L Si, JV Pearson, NK Hayward, N Waddell, GJ Mann, J Guo, RA Scolyer. Whole-genome landscape of mucosal melanoma reveals diverse drivers and therapeutic targets.. Nat Commun. 2019;10:3163", "National Institutes of Health Consensus Development Conference Statement: neurofibromatosis. Bethesda, Md, USA, July 13-15, 1987.. Neurofibromatosis. 1988;1:172-8", "AM Nyström, S Ekvall, B Strömberg, G Holmström, AC Theuresson, G Annerén, ML Bondeson. A severe form of Noonan syndrome and autosomal dominant café-au-lait spots – evidence for different genetic origins.. Acta Paediatr 2009;98:693-8", "E Pasmant, P Ballerini, H Lapillonne, C Perot, D Vidaud, G Leverger, J Landman-Parker. SPRED1 disorder and predisposition to leukemia in children.. Blood 2009;114:1131", "E Pasmant, B Gilbert-Dussardier, A Petit, B de Laval, A Luscan, A Gruber, H Lapillonne, C Deswarte, P Goussard, I Laurendeau, B Uzan, F Pflumio, F Brizard, P Vabres, I Naguibvena, S Fasola, F Millot, F Porteu, D Vidaud, J Landman-Parker, P. Ballerini. SPRED1, a RAS MAPK pathway inhibitor that causes Legius syndrome, is a tumor suppressor downregulated in paediatric acute myeloblastic leukaemia.. Oncogene. 2015a;34:631-8", "E Pasmant, B Parfait, A Luscan, P Goussard, A Briand-Suleau, I Laurendeau, C Fouveaut, C Leroy, A Montadert, P Wolkenstein, M Vidaud, D. Vidaud. Neurofibromatosis type 1 molecular diagnosis: what can NGS do for you when you have a large gene with loss of function mutations?. Eur J Hum Genet. 2015b;23:596-601", "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", "K Rojnueangnit, J Xie, A Gomes, A Sharp, T Callens, Y Chen, Y Liu, M Cochran, MA Abbott, J Atkin, D Babovic-Vuksanovic, CP Barnett, M Crenshaw, DW Bartholomew, L Basel, G Bellus, S Ben-Shachar, MG Bialer, D Bick, B Blumberg, F Cortes, KL David, A Destree, A Duat-Rodriguez, D Earl, L Escobar, M Eswara, B Ezquieta, IM Frayling, M Frydman, K Gardner, KW Gripp, C Hernández-Chico, K Heyrman, J Ibrahim, S Janssens, BA Keena, I Llano-Rivas, K Leppig, M McDonald, VK Misra, J Mulbury, V Narayanan, N Orenstein, P Galvin-Parton, H Pedro, EK Pivnick, CM Powell, L Randolph, S Raskin, J Rosell, K Rubin, M Seashore, CP Schaaf, A Scheuerle, M Schultz, E Schorry, R Schnur, E Siqveland, A Tkachuk, J Tonsgard, M Upadhyaya, IC Verma, S Wallace, C Williams, E Zackai, J Zonana, C Lazaro, K Claes, B Korf, Y Martin, E Legius, L Messiaen. High incidence of Noonan syndrome features including short stature and pulmonic stenosis in patients carrying NF1 missense mutations affecting p.Arg1809: genotype-phenotype correlation.. Hum Mutat. 2015;36:1052-63", "N Sakai, T Maeda, H Kawakami, M Uchiyama, K Harada, R Tsuboi, Y. Mitsuhashi. Family with Legius syndrome (neurofibromatosis type 1-like syndrome).. J Dermatol. 2015;42:703-5", "M Sekelska, L Briatkova, T Olcak, A Bolcekova, D Ilencikova, L Kadasi, A. Zatkova. The first Slovak Legius syndrome patient carrying the SPRED1 gene mutation.. Gen Physiol Biophys. 2017;36:205-10", "E Spencer, J Davis, F Mikhail, C Fu, R Vijzelaar, EH Zackai, H Feret, MS Meyn, A Shugar, G Bellus, K Kocsis, S Kivirikko, M Pöyhönen, L Messiaen. Identification of SPRED1 deletions using RT-PCR, multiplex ligation-dependent probe amplification and quantitative PCR.. Am J Med Genet A. 2011;155A:1352-9", "G Spurlock, E Bennett, N Chuzhanova, N Thomas, HP Jim, L Side, S Davies, E Haan, B Kerr, SM Huson, M Upadhyaya. SPRED1 mutations (Legius syndrome): another clinically useful genotype for dissecting the NF1 phenotype.. J Med Genet 2009;46:431-7", "D Stevenson, D Viskochil. Pigmentary findings in neurofibromatosis type 1-like syndrome (Legius syndrome): potential diagnostic dilemmas.. JAMA 2009;302:2150-1", "IB Stowe, EL Mercado, TR Stowe, EL Bell, JA Oses-Prieto, H Hernández, AL Burlingame, F McCormick. A shared molecular mechanism underlies the human rasopathies Legius syndrome and Neurofibormatosis-1.. Genes Dev 2012;26:1421-6", "WE Tidyman, KA Rauen. The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation.. Curr Opin Genet Dev 2009;19:230-6", "T Wakioka, A Sasaki, R Kato, T Shouda, A Matsumoto, K Miyoshi, M Tsuneoka, S Komiya, R Baron, A Yoshimura. Spred is a Sprouty-related suppressor of Ras signaling.. Nature 2001;412:647-51", "L Witkowski, MW Dillon, E Murphy. S Lebo M, Mason-Suares H. Expanding the Noonan spectrum/RASopathy NGS panel: Benefits of adding NF1 and SPRED1.. Mol Genet Genomic Med. 2020;8", "I Yeh, E Jorgenson, L Shen, M Xu, JP North, AH Shain, D Reuss, H Wu, WA Robinson, A Olshen, A von Deimling, PY Kwok, BC Bastian, MM Asgari. Targeted genomic profiling of acral melanoma.. J Natl Cancer Inst. 2019;111:1068-77" ]	14/10/2010	6/8/2020	12/5/2011	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
leigh-nucl-ov	leigh-nucl-ov	[ "3-hydroxyisobutyryl-CoA hydrolase, mitochondrial", "4-hydroxyphenylpyruvate dioxygenase-like protein", "5-taurinomethyluridine-[tRNA] synthase subunit GTPB3, mitochondrial", "5-taurinomethyluridine-[tRNA] synthase subunit MTO1, mitochondrial", "All trans-polyprenyl-diphosphate synthase PDSS2", "Alpha-ketoglutarate dehydrogenase component 4", "Arginine-hydroxylase NDUFAF5, mitochondrial", "Asparaginyl-tRNA synthetase", "ATP synthase F(0) complex subunit k, mitochondrial", "ATP synthase peripheral stalk subunit OSCP, mitochondrial", "Biotinidase", "Cytochrome b-c1 complex subunit 8", "Cytochrome c oxidase assembly factor 6 homolog", "Cytochrome c oxidase subunit 4 isoform 1, mitochondrial", "Cytochrome c oxidase subunit 8A, mitochondrial", "Cytochrome c oxidase subunit NDUFA4", "Dihydrolipoyl dehydrogenase, mitochondrial", "Dihydrolipoyllysine-residue acetyltransferase component of pyruvate dehydrogenase complex, mitochondrial", "DnaJ homolog subfamily C member 30, mitochondrial", "Dynamin-1-like protein", "Elongation factor G, mitochondrial", "Enoyl-[acyl-carrier-protein] reductase, mitochondrial", "Enoyl-CoA hydratase, mitochondrial", "FAD-dependent oxidoreductase domain-containing protein 1", "FAST kinase domain-containing protein 2, mitochondrial", "F-box/LRR-repeat protein 4", "Heme A synthase COX15", "Isoleucine--tRNA ligase, mitochondrial", "L-2-hydroxyglutarate dehydrogenase, mitochondrial", "Large ribosomal subunit protein mL39", "Large ribosomal subunit protein uL3m", "Leucine-rich PPR motif-containing protein, mitochondrial", "Lipoyl amidotransferase LIPT1, mitochondrial", "Lipoyl synthase, mitochondrial", "Lon protease homolog, mitochondrial", "Methionyl-tRNA formyltransferase, mitochondrial", "Mitochondrial chaperone BCS1", "Mitochondrial disaggregase", "Mitochondrial fission factor", "Mitochondrial inner membrane protein Mpv17", "Mitochondrial pyruvate carrier 1", "Mitochondrial thiamine pyrophosphate carrier", "Mitochondrial translation release factor in rescue", "Mitofusin-2", "NADH dehydrogenase (ubiquinone) complex I, assembly factor 6", "NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 2", "NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 1", "NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10, mitochondrial", "NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 12", "NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 2", "NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9, mitochondrial", "NADH dehydrogenase [ubiquinone] flavoprotein 1, mitochondrial", "NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, mitochondrial", "NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial", "NADH dehydrogenase [ubiquinone] iron-sulfur protein 4, mitochondrial", "NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial", "NADH dehydrogenase [ubiquinone] iron-sulfur protein 8, mitochondrial", "NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial", "NADPH-dependent 3-demethoxyubiquinone 3-hydroxylase, mitochondrial", "Nondiscriminating glutamyl-tRNA synthetase EARS2, mitochondrial", "Persulfide dioxygenase ETHE1, mitochondrial", "Phenylalanine--tRNA ligase, mitochondrial", "Protein PET100 homolog, mitochondrial", "Protein SCO2 homolog, mitochondrial", "Protoheme IX farnesyltransferase, mitochondrial", "Pyruvate dehydrogenase E1 component subunit beta, mitochondrial", "Pyruvate dehydrogenase protein X component, mitochondrial", "Ribosome-releasing factor 2, mitochondrial", "Serine protease HTRA2, mitochondrial", "Small ribosomal subunit protein mS34", "Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial", "Surfeit locus protein 1", "Tetratricopeptide repeat protein 19, mitochondrial", "Thiamine pyrophosphokinase 1", "Thiamine transporter 2", "Translational activator of cytochrome c oxidase 1", "Ubiquinone biosynthesis protein COQ4 homolog, mitochondrial", "Ubiquinone biosynthesis protein COQ9, mitochondrial", "ATP5MK", "ATP5PO", "BCS1L", "BTD", "CLPB", "COA6", "COQ4", "COQ7", "COQ9", "COX10", "COX15", "COX4I1", "COX8A", "COXFA4", "DLAT", "DLD", "DNAJC30", "DNM1L", "EARS2", "ECHS1", "ETHE1", "FARS2", "FASTKD2", "FBXL4", "FOXRED1", "GFM1", "GFM2", "GTPBP3", "HIBCH", "HPDL", "HTRA2", "IARS2", "KGD4", "L2HGDH", "LIAS", "LIPT1", "LONP1", "LRPPRC", "MECR", "MFF", "MFN2", "MPC1", "MPV17", "MRPL3", "MRPL39", "MRPS34", "MTFMT", "MTO1", "MTRFR", "NARS2", "NDUFA1", "NDUFA10", "NDUFA12", "NDUFA2", "NDUFA9", "NDUFAF2", "NDUFAF5", "NDUFAF6", "NDUFS1", "NDUFS2", "NDUFS3", "NDUFS4", "NDUFS7", "NDUFS8", "NDUFV1", "PDHB", "PDHX", "PDSS2", "PET100", "SCO2", "SDHA", "SLC19A3", "SLC25A19", "SURF1", "TACO1", "TPK1", "TTC19", "UQCRQ", "Nuclear Gene-Encoded Leigh Syndrome Spectrum", "Overview" ]	Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview	Shamima Rahman, David R Thorburn, Megan Ball	Summary The purpose of this overview is to: Briefly describe the Review the Review the Provide an Review Inform	## Clinical Characteristics of Nuclear Gene-Encoded Leigh Syndrome Spectrum Nuclear gene-encoded Leigh syndrome spectrum (LSS) is a continuum of progressive neurodegenerative disorders caused by abnormalities of mitochondrial energy generation. Onset of nuclear gene-encoded LSS is typically in infancy or early childhood with sudden neurodevelopmental regression. This decompensation is often associated with elevated lactate concentration in the blood and/or cerebrospinal fluid (CSF) following an intercurrent illness or metabolic challenge (e.g., surgery, anesthesia, prolonged fasting). Although the clinical manifestations of LSS can vary, there is significant overlap between the clinical features (see Initial clinical features may be nonspecific and may vary with the age of onset. Approximately 75% of individuals present in the first 24 months of life, with some manifesting features in utero. Prenatally, intrauterine growth restriction, cardiomegaly, microcephaly, and oligohydramnios have been reported. Early-onset LSS (age <2 years) may present with nonspecific features such as poor weight gain, feeding difficulties, persistent vomiting, hypotonia, and developmental delay. Later-onset LSS (age >2 years) may present in childhood, adolescence, or even adulthood with predominant muscle weakness, movement disorders (ataxia and/or dystonia), peripheral neuropathy, and neurobehavioral/psychiatric manifestations. Other neurologic manifestations include developmental delay/regression, hypotonia, spasticity, seizures, movement disorders (including chorea), cerebellar ataxia, and peripheral neuropathy. Brain stem lesions may cause respiratory issues (apnea, central hypo- or hyperventilation, or irregular respiration), bulbar problems (e.g., abnormal swallowing and speech), and abnormalities of thermoregulation. Sensorineural hearing loss is present in approximately 15% of individuals. Ophthalmologic manifestations may include ophthalmoplegia, ptosis, optic atrophy, and retinopathy. Extraneurologic manifestations can include hypertrophic cardiomyopathy, gastrointestinal dysmotility, hepatopathy, renal tubulopathy, anemia, and hypertrichosis. It should be noted that several disorders, e.g., Poor prognosis has been associated with early-onset disease and brain stem involvement (e.g., apneas) [ Conflicting reports regarding the prognosis of specific genetic causes of LSS can make it difficult to provide adequate counseling for families. Survival into adulthood has been reported for individuals with some disorders, including Nuclear-Encoded Leigh Syndrome Spectrum: Frequency of Select Clinical Features Estimated percentages are based on several cohorts of individuals with nuclear gene-encoded LSS and mtDNA-encoded LSS (~1,000 individuals); however, each clinical feature was not reported for every individual [ The term "Leigh syndrome spectrum" comprises both Leigh syndrome and Leigh-like syndrome. "Leigh-like syndrome" has been used historically when clinical and other features strongly suggest Leigh syndrome but do not fulfil the stringent diagnostic criteria for Leigh syndrome because of atypical or normal neuroimaging, lack of evidence of abnormal energy metabolism, atypical neuropathology (variation in the distribution or character of lesions or with the presence of additional unusual features such as extensive cortical destruction), and/or incomplete evaluation. The authors recommend that the term "Leigh-like" no longer be used, as it is now incorporated within the umbrella term LSS. • Prenatally, intrauterine growth restriction, cardiomegaly, microcephaly, and oligohydramnios have been reported. • Early-onset LSS (age <2 years) may present with nonspecific features such as poor weight gain, feeding difficulties, persistent vomiting, hypotonia, and developmental delay. • Later-onset LSS (age >2 years) may present in childhood, adolescence, or even adulthood with predominant muscle weakness, movement disorders (ataxia and/or dystonia), peripheral neuropathy, and neurobehavioral/psychiatric manifestations. ## Nomenclature The term "Leigh syndrome spectrum" comprises both Leigh syndrome and Leigh-like syndrome. "Leigh-like syndrome" has been used historically when clinical and other features strongly suggest Leigh syndrome but do not fulfil the stringent diagnostic criteria for Leigh syndrome because of atypical or normal neuroimaging, lack of evidence of abnormal energy metabolism, atypical neuropathology (variation in the distribution or character of lesions or with the presence of additional unusual features such as extensive cortical destruction), and/or incomplete evaluation. The authors recommend that the term "Leigh-like" no longer be used, as it is now incorporated within the umbrella term LSS. ## Causes of Nuclear Gene-Encoded Leigh Syndrome Spectrum The pathogenic variants in more than 120 nuclear genes associated with autosomal recessive, autosomal dominant, and X-linked nuclear gene-encoded Leigh syndrome spectrum (LSS) are summarized below [ Clinical criteria for nuclear gene-encoded LSS are adapted from Table 2 McCormick et al 2023] ( Developmental regression Developmental delay Neurobehavioral/psychiatric features Elevated concentration of lactate in blood and/or cerebrospinal fluid (CSF) Elevated glycine concentrations (if the responsible gene is required for biosynthesis of lipoic acid) Magnetic resonance spectroscopy (MRS) lactate peak (in the absence of acute seizures) Respiratory chain enzyme activity deficiency (<30% enzyme activity) in affected tissues (muscle, liver, fibroblasts) Pyruvate dehydrogenase complex deficiency (in fibroblasts, >2 standard deviations below mean) Mitochondrial fission/fusion defect (detected by electron microscopy of muscle or immunofluorescence studies of cultured skin fibroblasts) Diminished respiratory activity measured by microscale oxygraphy (e.g., Oroboros or Seahorse assays) The advent of widespread use of MRI made it possible to establish a diagnosis of LSS by neuroimaging, and thus postmortem examination is now rarely performed outside of a research context. Autosomal recessive nuclear gene-encoded LSS ( Pathogenic (or likely pathogenic) variants in genes encoding proteins needed for: Oxidative phosphorylation (OXPHOS) enzyme activity and assembly; Mitochondrial DNA (mtDNA) maintenance (see Cofactor biosynthesis (lipoic acid and coenzyme Q Mitochondrial membrane lipid remodeling, quality control, and dynamics; Pyruvate dehydrogenase (see Organic acidemias with accumulation of metabolites leading to secondary OXPHOS dysfunction. Autosomal Recessive Leigh Syndrome Spectrum with Targeted Therapy: Associated Genes AR = autosomal recessive; CC = corpus callosum; fb = cultured skin fibroblasts; HCM = hypertrophic cardiomyopathy; IUGR = intrauterine growth restriction; LSS = Leigh syndrome spectrum; m = muscle biopsy; MRS = magnetic resonance spectroscopy; MT = mitochondrial; PDH = pyruvate dehydrogenase; RCE = respiratory chain enzyme; SNHL = sensorineural hearing loss Other than those of classic Leigh syndrome Autosomal Recessive Leigh Syndrome Spectrum: Other Associated Genes α-KGDH = alpha-ketoglutarate dehydrogenase; BCAA = branched-chain amino acid; BCKDH = branched-chain ketoacid dehydrogenase; BN-PAGE = blue native polyacrylamide gel electrophoresis; CC = corpus callosum; CT = computed tomography; EEG = electroencephalogram; EM = electron microscopy; fb = cultured skin fibroblasts; FILA = fatal infantile lactic acidosis; GI = gastrointestinal; HCM = hypertrophic cardiomyopathy; IUGR = intrauterine growth restriction; LS = Leigh syndrome; LSS = Leigh syndrome spectrum; m = muscle biopsy; MEGD(H)EL syndrome = 3- Other than those of classic Leigh syndrome Autosomal dominant Isolated SNHL without Leigh syndrome in some individuals; Alpers syndrome in others Autosomal dominant Causes of autosomal dominant nuclear gene-encoded LSS are summarized in Autosomal Dominant Leigh Syndrome Spectrum: Associated Genes fb = cultured skin fibroblasts; HCM = hypertrophic cardiomyopathy; fb = fibroblasts; LSS = Leigh syndrome spectrum; m = muscle biopsy; mt = mitochondrial; mtDNA = mitochondrial DNA; RCE = respiratory chain enzyme Other than those of classic Leigh syndrome Autosomal recessive LSS has also been reported in association with biallelic pathogenic variants in this gene (see Causes of X-linked nuclear gene-encoded LSS are summarized in X-Linked Leigh Syndrome Spectrum with Targeted Therapy: Associated Genes CC = corpus callosum; CSF = cerebrospinal fluid; fb = cultured skin fibroblasts; LSS = Leigh syndrome spectrum; PDH = pyruvate dehydrogenase Other than those of classic Leigh syndrome X-Linked Leigh Syndrome Spectrum: Other Genes DD = developmental delay; LSS = Leigh syndrome spectrum; m = muscle biopsy; RCE = respiratory chain enzyme Other than those of classic Leigh syndrome Pathologic Mechanism of Genes in Nuclear-Encoded LSS mtDNA = mitochondrial DNA • Developmental regression • Developmental delay • Neurobehavioral/psychiatric features • Elevated concentration of lactate in blood and/or cerebrospinal fluid (CSF) • Elevated glycine concentrations (if the responsible gene is required for biosynthesis of lipoic acid) • Magnetic resonance spectroscopy (MRS) lactate peak (in the absence of acute seizures) • Respiratory chain enzyme activity deficiency (<30% enzyme activity) in affected tissues (muscle, liver, fibroblasts) • Pyruvate dehydrogenase complex deficiency (in fibroblasts, >2 standard deviations below mean) • Mitochondrial fission/fusion defect (detected by electron microscopy of muscle or immunofluorescence studies of cultured skin fibroblasts) • Diminished respiratory activity measured by microscale oxygraphy (e.g., Oroboros or Seahorse assays) • Pathogenic (or likely pathogenic) variants in genes encoding proteins needed for: • Oxidative phosphorylation (OXPHOS) enzyme activity and assembly; • Mitochondrial DNA (mtDNA) maintenance (see • Cofactor biosynthesis (lipoic acid and coenzyme Q • Mitochondrial membrane lipid remodeling, quality control, and dynamics; • Pyruvate dehydrogenase (see • Oxidative phosphorylation (OXPHOS) enzyme activity and assembly; • Mitochondrial DNA (mtDNA) maintenance (see • Cofactor biosynthesis (lipoic acid and coenzyme Q • Mitochondrial membrane lipid remodeling, quality control, and dynamics; • Pyruvate dehydrogenase (see • Organic acidemias with accumulation of metabolites leading to secondary OXPHOS dysfunction. • Oxidative phosphorylation (OXPHOS) enzyme activity and assembly; • Mitochondrial DNA (mtDNA) maintenance (see • Cofactor biosynthesis (lipoic acid and coenzyme Q • Mitochondrial membrane lipid remodeling, quality control, and dynamics; • Pyruvate dehydrogenase (see ## Clinical Criteria Clinical criteria for nuclear gene-encoded LSS are adapted from Table 2 McCormick et al 2023] ( Developmental regression Developmental delay Neurobehavioral/psychiatric features Elevated concentration of lactate in blood and/or cerebrospinal fluid (CSF) Elevated glycine concentrations (if the responsible gene is required for biosynthesis of lipoic acid) Magnetic resonance spectroscopy (MRS) lactate peak (in the absence of acute seizures) Respiratory chain enzyme activity deficiency (<30% enzyme activity) in affected tissues (muscle, liver, fibroblasts) Pyruvate dehydrogenase complex deficiency (in fibroblasts, >2 standard deviations below mean) Mitochondrial fission/fusion defect (detected by electron microscopy of muscle or immunofluorescence studies of cultured skin fibroblasts) Diminished respiratory activity measured by microscale oxygraphy (e.g., Oroboros or Seahorse assays) The advent of widespread use of MRI made it possible to establish a diagnosis of LSS by neuroimaging, and thus postmortem examination is now rarely performed outside of a research context. • Developmental regression • Developmental delay • Neurobehavioral/psychiatric features • Elevated concentration of lactate in blood and/or cerebrospinal fluid (CSF) • Elevated glycine concentrations (if the responsible gene is required for biosynthesis of lipoic acid) • Magnetic resonance spectroscopy (MRS) lactate peak (in the absence of acute seizures) • Respiratory chain enzyme activity deficiency (<30% enzyme activity) in affected tissues (muscle, liver, fibroblasts) • Pyruvate dehydrogenase complex deficiency (in fibroblasts, >2 standard deviations below mean) • Mitochondrial fission/fusion defect (detected by electron microscopy of muscle or immunofluorescence studies of cultured skin fibroblasts) • Diminished respiratory activity measured by microscale oxygraphy (e.g., Oroboros or Seahorse assays) ## Autosomal Recessive Leigh Syndrome Spectrum Autosomal recessive nuclear gene-encoded LSS ( Pathogenic (or likely pathogenic) variants in genes encoding proteins needed for: Oxidative phosphorylation (OXPHOS) enzyme activity and assembly; Mitochondrial DNA (mtDNA) maintenance (see Cofactor biosynthesis (lipoic acid and coenzyme Q Mitochondrial membrane lipid remodeling, quality control, and dynamics; Pyruvate dehydrogenase (see Organic acidemias with accumulation of metabolites leading to secondary OXPHOS dysfunction. Autosomal Recessive Leigh Syndrome Spectrum with Targeted Therapy: Associated Genes AR = autosomal recessive; CC = corpus callosum; fb = cultured skin fibroblasts; HCM = hypertrophic cardiomyopathy; IUGR = intrauterine growth restriction; LSS = Leigh syndrome spectrum; m = muscle biopsy; MRS = magnetic resonance spectroscopy; MT = mitochondrial; PDH = pyruvate dehydrogenase; RCE = respiratory chain enzyme; SNHL = sensorineural hearing loss Other than those of classic Leigh syndrome Autosomal Recessive Leigh Syndrome Spectrum: Other Associated Genes α-KGDH = alpha-ketoglutarate dehydrogenase; BCAA = branched-chain amino acid; BCKDH = branched-chain ketoacid dehydrogenase; BN-PAGE = blue native polyacrylamide gel electrophoresis; CC = corpus callosum; CT = computed tomography; EEG = electroencephalogram; EM = electron microscopy; fb = cultured skin fibroblasts; FILA = fatal infantile lactic acidosis; GI = gastrointestinal; HCM = hypertrophic cardiomyopathy; IUGR = intrauterine growth restriction; LS = Leigh syndrome; LSS = Leigh syndrome spectrum; m = muscle biopsy; MEGD(H)EL syndrome = 3- Other than those of classic Leigh syndrome Autosomal dominant Isolated SNHL without Leigh syndrome in some individuals; Alpers syndrome in others Autosomal dominant • Pathogenic (or likely pathogenic) variants in genes encoding proteins needed for: • Oxidative phosphorylation (OXPHOS) enzyme activity and assembly; • Mitochondrial DNA (mtDNA) maintenance (see • Cofactor biosynthesis (lipoic acid and coenzyme Q • Mitochondrial membrane lipid remodeling, quality control, and dynamics; • Pyruvate dehydrogenase (see • Oxidative phosphorylation (OXPHOS) enzyme activity and assembly; • Mitochondrial DNA (mtDNA) maintenance (see • Cofactor biosynthesis (lipoic acid and coenzyme Q • Mitochondrial membrane lipid remodeling, quality control, and dynamics; • Pyruvate dehydrogenase (see • Organic acidemias with accumulation of metabolites leading to secondary OXPHOS dysfunction. • Oxidative phosphorylation (OXPHOS) enzyme activity and assembly; • Mitochondrial DNA (mtDNA) maintenance (see • Cofactor biosynthesis (lipoic acid and coenzyme Q • Mitochondrial membrane lipid remodeling, quality control, and dynamics; • Pyruvate dehydrogenase (see ## Autosomal Dominant Leigh Syndrome Spectrum Causes of autosomal dominant nuclear gene-encoded LSS are summarized in Autosomal Dominant Leigh Syndrome Spectrum: Associated Genes fb = cultured skin fibroblasts; HCM = hypertrophic cardiomyopathy; fb = fibroblasts; LSS = Leigh syndrome spectrum; m = muscle biopsy; mt = mitochondrial; mtDNA = mitochondrial DNA; RCE = respiratory chain enzyme Other than those of classic Leigh syndrome Autosomal recessive LSS has also been reported in association with biallelic pathogenic variants in this gene (see ## X-Linked Leigh Syndrome Spectrum Causes of X-linked nuclear gene-encoded LSS are summarized in X-Linked Leigh Syndrome Spectrum with Targeted Therapy: Associated Genes CC = corpus callosum; CSF = cerebrospinal fluid; fb = cultured skin fibroblasts; LSS = Leigh syndrome spectrum; PDH = pyruvate dehydrogenase Other than those of classic Leigh syndrome X-Linked Leigh Syndrome Spectrum: Other Genes DD = developmental delay; LSS = Leigh syndrome spectrum; m = muscle biopsy; RCE = respiratory chain enzyme Other than those of classic Leigh syndrome ## Pathologic Mechanism of Genes in Nuclear-Encoded Leigh Syndrome Spectrum Pathologic Mechanism of Genes in Nuclear-Encoded LSS mtDNA = mitochondrial DNA ## Differential Diagnosis of Nuclear Gene-Encoded Leigh Syndrome Spectrum The differential diagnosis of genetic causes of nuclear gene-encoded Leigh syndrome spectrum (LSS) include mitochondrial DNA-associated Leigh syndrome (see Other non-mitochondrial monogenic disorders that cause or resemble LSS are listed in Non-Mitochondrial Monogenic Disorders That Cause or Resemble Leigh Syndrome Spectrum AD = autosomal dominant; AR = autosomal recessive; CDG = congenital disorder of glycosylation; MOI = mode of inheritance Acquired non-genetic conditions in the differential diagnosis of LSS include viral encephalopathy, hypoxic-ischemic encephalopathy, Wernicke encephalopathy secondary to thiamine deficiency, and acute necrotizing encephalopathy (which may be triggered by viral infection). ## Evaluation Strategies to Identify the Genetic Cause of Nuclear Gene-Encoded Leigh Syndrome Spectrum in a Proband Establishing a specific genetic cause of nuclear gene-encoded LSS: Can aid in discussions of prognosis (which are beyond the scope of this Usually involves a medical history, physical examination, imaging studies such as brain MRI, biochemical testing, family history, and genomic/genetic testing. While some clinical features are associated with some specific nuclear-encoded LSS genes (see Some examples of specific clinical features that may increase suspicion for a particular gene include hypertrichosis (suggestive of NDUFAF2 deficiency is associated with brain stem lesions seen within the mamillothalamic tracts, substantia nigra, medial lemniscus, medial longitudinal fasciculus, and spinothalamic tracts on T Brain malformations are typically seen in males with a hemizygous Elevated blood and/or cerebrospinal fluid (CSF) lactate concentrations may strongly support the diagnosis of nuclear-encoded LSS. Note: A normal blood and/or CSF lactate concentration does not exclude nuclear-encoded LSS. A normal to low lactate-to-pyruvate ratio may indicate a disorder associated with pyruvate dehydrogenase complex deficiency. Plasma amino acids may show: Increased alanine concentration, reflecting persistent hyperlactatemia; Elevated glycine concentrations that may indicate a defect in lipoic acid biosynthesis (except LIPT1 deficiency). Acylcarnitine profile may be abnormal, with characteristic patterns associated with the following disorders: Elevated hydroxy-C4-carnitine may be associated with HIBCH deficiency; Elevated C3-carnitine may be associated with SUCLG1 and SUCLA2 deficiencies. Abnormalities in urine organic acids may be nonspecific and may show lactic aciduria, increased Krebs cycle intermediates, and increased dicarboxylic acids. However, some gene defects are associated with a specific urine metabolite profile, including the following: SERAC1, CLPB, and HTRA2 deficiencies are associated with 3-methylglutaconic aciduria. SUCLG1 and SUCLA2 deficiencies are associated with methylmalonic aciduria. ETHE1 deficiency is associated with ethylmalonic aciduria. ECHS1 and HIBCH deficiencies are associated with marked elevation of urine 2-methyl-2,3-dihydroxybutyrate and S-(2-carboxypropyl) cysteine. See Activity of enzymes, such as pyruvate dehydrogenase (PDH), are typically measured in cultured skin fibroblasts (fb), and respiratory chain enzymes are typically measured in a skeletal muscle biopsy (m); see Respiratory chain enzymology can identify deficient enzyme activity (<30% of control mean values) of one or more of the respiratory chain enzyme complexes. Complex I and Complex IV deficiencies are the most common enzyme abnormalities observed in individuals with nuclear-encoded LSS. Although identifying deficiency of an enzyme can help prioritize molecular genetic testing, this approach still leaves a large number of genes to be tested (e.g., respiratory chain complex I-deficient LSS has been shown to be caused by pathogenic variants in at least 28 nuclear genes and six mtDNA genes). Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click Genome sequencing is preferred (if available), as it allows analysis of the mitochondrial and nuclear genome, and typically has the highest diagnostic rate. About 30% of children with suspected LSS have mtDNA-encoded LSS (see When testing children, family trio genome sequencing should be considered to assist in the identification of either biallelic pathogenic variants that cause rare autosomal recessive disorders or For an introduction to comprehensive genomic testing click • Can aid in discussions of prognosis (which are beyond the scope of this • Usually involves a medical history, physical examination, imaging studies such as brain MRI, biochemical testing, family history, and genomic/genetic testing. • NDUFAF2 deficiency is associated with brain stem lesions seen within the mamillothalamic tracts, substantia nigra, medial lemniscus, medial longitudinal fasciculus, and spinothalamic tracts on T • Brain malformations are typically seen in males with a hemizygous • Note: A normal blood and/or CSF lactate concentration does not exclude nuclear-encoded LSS. • A normal to low lactate-to-pyruvate ratio may indicate a disorder associated with pyruvate dehydrogenase complex deficiency. • Increased alanine concentration, reflecting persistent hyperlactatemia; • Elevated glycine concentrations that may indicate a defect in lipoic acid biosynthesis (except LIPT1 deficiency). • Elevated hydroxy-C4-carnitine may be associated with HIBCH deficiency; • Elevated C3-carnitine may be associated with SUCLG1 and SUCLA2 deficiencies. • SERAC1, CLPB, and HTRA2 deficiencies are associated with 3-methylglutaconic aciduria. • SUCLG1 and SUCLA2 deficiencies are associated with methylmalonic aciduria. • ETHE1 deficiency is associated with ethylmalonic aciduria. • ECHS1 and HIBCH deficiencies are associated with marked elevation of urine 2-methyl-2,3-dihydroxybutyrate and S-(2-carboxypropyl) cysteine. • Activity of enzymes, such as pyruvate dehydrogenase (PDH), are typically measured in cultured skin fibroblasts (fb), and respiratory chain enzymes are typically measured in a skeletal muscle biopsy (m); see • Respiratory chain enzymology can identify deficient enzyme activity (<30% of control mean values) of one or more of the respiratory chain enzyme complexes. Complex I and Complex IV deficiencies are the most common enzyme abnormalities observed in individuals with nuclear-encoded LSS. • Although identifying deficiency of an enzyme can help prioritize molecular genetic testing, this approach still leaves a large number of genes to be tested (e.g., respiratory chain complex I-deficient LSS has been shown to be caused by pathogenic variants in at least 28 nuclear genes and six mtDNA genes). • Genome sequencing is preferred (if available), as it allows analysis of the mitochondrial and nuclear genome, and typically has the highest diagnostic rate. About 30% of children with suspected LSS have mtDNA-encoded LSS (see • When testing children, family trio genome sequencing should be considered to assist in the identification of either biallelic pathogenic variants that cause rare autosomal recessive disorders or ## Biochemical and Genomic/Genetic Testing Elevated blood and/or cerebrospinal fluid (CSF) lactate concentrations may strongly support the diagnosis of nuclear-encoded LSS. Note: A normal blood and/or CSF lactate concentration does not exclude nuclear-encoded LSS. A normal to low lactate-to-pyruvate ratio may indicate a disorder associated with pyruvate dehydrogenase complex deficiency. Plasma amino acids may show: Increased alanine concentration, reflecting persistent hyperlactatemia; Elevated glycine concentrations that may indicate a defect in lipoic acid biosynthesis (except LIPT1 deficiency). Acylcarnitine profile may be abnormal, with characteristic patterns associated with the following disorders: Elevated hydroxy-C4-carnitine may be associated with HIBCH deficiency; Elevated C3-carnitine may be associated with SUCLG1 and SUCLA2 deficiencies. Abnormalities in urine organic acids may be nonspecific and may show lactic aciduria, increased Krebs cycle intermediates, and increased dicarboxylic acids. However, some gene defects are associated with a specific urine metabolite profile, including the following: SERAC1, CLPB, and HTRA2 deficiencies are associated with 3-methylglutaconic aciduria. SUCLG1 and SUCLA2 deficiencies are associated with methylmalonic aciduria. ETHE1 deficiency is associated with ethylmalonic aciduria. ECHS1 and HIBCH deficiencies are associated with marked elevation of urine 2-methyl-2,3-dihydroxybutyrate and S-(2-carboxypropyl) cysteine. See Activity of enzymes, such as pyruvate dehydrogenase (PDH), are typically measured in cultured skin fibroblasts (fb), and respiratory chain enzymes are typically measured in a skeletal muscle biopsy (m); see Respiratory chain enzymology can identify deficient enzyme activity (<30% of control mean values) of one or more of the respiratory chain enzyme complexes. Complex I and Complex IV deficiencies are the most common enzyme abnormalities observed in individuals with nuclear-encoded LSS. Although identifying deficiency of an enzyme can help prioritize molecular genetic testing, this approach still leaves a large number of genes to be tested (e.g., respiratory chain complex I-deficient LSS has been shown to be caused by pathogenic variants in at least 28 nuclear genes and six mtDNA genes). Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click Genome sequencing is preferred (if available), as it allows analysis of the mitochondrial and nuclear genome, and typically has the highest diagnostic rate. About 30% of children with suspected LSS have mtDNA-encoded LSS (see When testing children, family trio genome sequencing should be considered to assist in the identification of either biallelic pathogenic variants that cause rare autosomal recessive disorders or For an introduction to comprehensive genomic testing click • Note: A normal blood and/or CSF lactate concentration does not exclude nuclear-encoded LSS. • A normal to low lactate-to-pyruvate ratio may indicate a disorder associated with pyruvate dehydrogenase complex deficiency. • Increased alanine concentration, reflecting persistent hyperlactatemia; • Elevated glycine concentrations that may indicate a defect in lipoic acid biosynthesis (except LIPT1 deficiency). • Elevated hydroxy-C4-carnitine may be associated with HIBCH deficiency; • Elevated C3-carnitine may be associated with SUCLG1 and SUCLA2 deficiencies. • SERAC1, CLPB, and HTRA2 deficiencies are associated with 3-methylglutaconic aciduria. • SUCLG1 and SUCLA2 deficiencies are associated with methylmalonic aciduria. • ETHE1 deficiency is associated with ethylmalonic aciduria. • ECHS1 and HIBCH deficiencies are associated with marked elevation of urine 2-methyl-2,3-dihydroxybutyrate and S-(2-carboxypropyl) cysteine. • Activity of enzymes, such as pyruvate dehydrogenase (PDH), are typically measured in cultured skin fibroblasts (fb), and respiratory chain enzymes are typically measured in a skeletal muscle biopsy (m); see • Respiratory chain enzymology can identify deficient enzyme activity (<30% of control mean values) of one or more of the respiratory chain enzyme complexes. Complex I and Complex IV deficiencies are the most common enzyme abnormalities observed in individuals with nuclear-encoded LSS. • Although identifying deficiency of an enzyme can help prioritize molecular genetic testing, this approach still leaves a large number of genes to be tested (e.g., respiratory chain complex I-deficient LSS has been shown to be caused by pathogenic variants in at least 28 nuclear genes and six mtDNA genes). • Genome sequencing is preferred (if available), as it allows analysis of the mitochondrial and nuclear genome, and typically has the highest diagnostic rate. About 30% of children with suspected LSS have mtDNA-encoded LSS (see • When testing children, family trio genome sequencing should be considered to assist in the identification of either biallelic pathogenic variants that cause rare autosomal recessive disorders or ## Biochemical Testing Elevated blood and/or cerebrospinal fluid (CSF) lactate concentrations may strongly support the diagnosis of nuclear-encoded LSS. Note: A normal blood and/or CSF lactate concentration does not exclude nuclear-encoded LSS. A normal to low lactate-to-pyruvate ratio may indicate a disorder associated with pyruvate dehydrogenase complex deficiency. Plasma amino acids may show: Increased alanine concentration, reflecting persistent hyperlactatemia; Elevated glycine concentrations that may indicate a defect in lipoic acid biosynthesis (except LIPT1 deficiency). Acylcarnitine profile may be abnormal, with characteristic patterns associated with the following disorders: Elevated hydroxy-C4-carnitine may be associated with HIBCH deficiency; Elevated C3-carnitine may be associated with SUCLG1 and SUCLA2 deficiencies. Abnormalities in urine organic acids may be nonspecific and may show lactic aciduria, increased Krebs cycle intermediates, and increased dicarboxylic acids. However, some gene defects are associated with a specific urine metabolite profile, including the following: SERAC1, CLPB, and HTRA2 deficiencies are associated with 3-methylglutaconic aciduria. SUCLG1 and SUCLA2 deficiencies are associated with methylmalonic aciduria. ETHE1 deficiency is associated with ethylmalonic aciduria. ECHS1 and HIBCH deficiencies are associated with marked elevation of urine 2-methyl-2,3-dihydroxybutyrate and S-(2-carboxypropyl) cysteine. See Activity of enzymes, such as pyruvate dehydrogenase (PDH), are typically measured in cultured skin fibroblasts (fb), and respiratory chain enzymes are typically measured in a skeletal muscle biopsy (m); see Respiratory chain enzymology can identify deficient enzyme activity (<30% of control mean values) of one or more of the respiratory chain enzyme complexes. Complex I and Complex IV deficiencies are the most common enzyme abnormalities observed in individuals with nuclear-encoded LSS. Although identifying deficiency of an enzyme can help prioritize molecular genetic testing, this approach still leaves a large number of genes to be tested (e.g., respiratory chain complex I-deficient LSS has been shown to be caused by pathogenic variants in at least 28 nuclear genes and six mtDNA genes). • Note: A normal blood and/or CSF lactate concentration does not exclude nuclear-encoded LSS. • A normal to low lactate-to-pyruvate ratio may indicate a disorder associated with pyruvate dehydrogenase complex deficiency. • Increased alanine concentration, reflecting persistent hyperlactatemia; • Elevated glycine concentrations that may indicate a defect in lipoic acid biosynthesis (except LIPT1 deficiency). • Elevated hydroxy-C4-carnitine may be associated with HIBCH deficiency; • Elevated C3-carnitine may be associated with SUCLG1 and SUCLA2 deficiencies. • SERAC1, CLPB, and HTRA2 deficiencies are associated with 3-methylglutaconic aciduria. • SUCLG1 and SUCLA2 deficiencies are associated with methylmalonic aciduria. • ETHE1 deficiency is associated with ethylmalonic aciduria. • ECHS1 and HIBCH deficiencies are associated with marked elevation of urine 2-methyl-2,3-dihydroxybutyrate and S-(2-carboxypropyl) cysteine. • Activity of enzymes, such as pyruvate dehydrogenase (PDH), are typically measured in cultured skin fibroblasts (fb), and respiratory chain enzymes are typically measured in a skeletal muscle biopsy (m); see • Respiratory chain enzymology can identify deficient enzyme activity (<30% of control mean values) of one or more of the respiratory chain enzyme complexes. Complex I and Complex IV deficiencies are the most common enzyme abnormalities observed in individuals with nuclear-encoded LSS. • Although identifying deficiency of an enzyme can help prioritize molecular genetic testing, this approach still leaves a large number of genes to be tested (e.g., respiratory chain complex I-deficient LSS has been shown to be caused by pathogenic variants in at least 28 nuclear genes and six mtDNA genes). ## Molecular Genetic Testing Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click Genome sequencing is preferred (if available), as it allows analysis of the mitochondrial and nuclear genome, and typically has the highest diagnostic rate. About 30% of children with suspected LSS have mtDNA-encoded LSS (see When testing children, family trio genome sequencing should be considered to assist in the identification of either biallelic pathogenic variants that cause rare autosomal recessive disorders or For an introduction to comprehensive genomic testing click • Genome sequencing is preferred (if available), as it allows analysis of the mitochondrial and nuclear genome, and typically has the highest diagnostic rate. About 30% of children with suspected LSS have mtDNA-encoded LSS (see • When testing children, family trio genome sequencing should be considered to assist in the identification of either biallelic pathogenic variants that cause rare autosomal recessive disorders or ## For an introduction to multigene panels click ## Genome sequencing is preferred (if available), as it allows analysis of the mitochondrial and nuclear genome, and typically has the highest diagnostic rate. About 30% of children with suspected LSS have mtDNA-encoded LSS (see When testing children, family trio genome sequencing should be considered to assist in the identification of either biallelic pathogenic variants that cause rare autosomal recessive disorders or For an introduction to comprehensive genomic testing click • Genome sequencing is preferred (if available), as it allows analysis of the mitochondrial and nuclear genome, and typically has the highest diagnostic rate. About 30% of children with suspected LSS have mtDNA-encoded LSS (see • When testing children, family trio genome sequencing should be considered to assist in the identification of either biallelic pathogenic variants that cause rare autosomal recessive disorders or ## Management of Nuclear Gene-Encoded Leigh Syndrome Targeted therapies are available for some specific nuclear gene-encoded Leigh syndrome spectrum (LSS) disorders, listed in Leigh Syndrome Spectrum Disorders with Targeted Therapies All persons w/profound biotinidase deficiency (<10% mean normal serum enzyme activity) & those w/partial biotinidase deficiency (10%-30% of mean normal serum enzyme activity) should be treated w/oral biotin in the free form as opposed to the protein-bound form. Persons w/biotinidase deficiency who are diagnosed before they have developed manifestations (e.g., by newborn screening) & who are treated w/biotin have normal development. Treatment should be instituted as early as possible because it can limit disease progression & reverse some manifestations; however, established severe neurologic &/or kidney damage cannot be reversed. Response is highly variable, & depends on both the specific genetic defect & disease severity, but also other unknown factors. Thiamine treatment is lifelong. Thiamine dose must be ↑ during febrile illness, surgery, or acute decompensation (by 25%). Variable response to thiamine among affected persons, w/response reported in approximately 50% of individuals [ More effective with early diagnosis 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 Nuclear Gene-Encoded Leigh Syndrome Spectrum: Treatment of Manifestations Sodium bicarbonate or sodium citrate for significant acidosis Consider THAM if hypernatremia occurs. Sodium valproate should be avoided because of its inhibitory effects on the mitochondrial respiratory chain. Education of parents/caregivers Should be used w/caution given potential side effects of exacerbating muscle weakness. Should not be used in head & neck because of risk of adverse events (e.g., impaired swallow). Referral to pulmonologist as needed Ventilatory support for persons w/LSS & respiratory compromise Caloric & nutritional supplementation as needed (incl micronutrients) Feeding therapy as needed; gastrostomy tube placement may improve nutritional intake for those w/persistent feeding issues, choking, or aspiration risk due to dysphagia Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia While ketogenic diet may be indicated for persons w/PDH deficiency or drug-resistant epilepsy, there is no evidence for efficacy of ketogenic diet in other forms of LSS. Hearing aids or cochlear implants for SNHL Referral to speech-language therapist Referral to hearing support services Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ASM = anti-seizure medication; LSS = Leigh syndrome spectrum; OT = occupational therapy; PDH = pyruvate dehydrogenase; PT = physical therapy; SNHL = sensorineural hearing loss; THAM = tris-hydroxymethyl aminomethane Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Affected individuals should be followed at regular intervals (typically every 6-12 months) to monitor progression of known manifestations and the appearance of new manifestations. Neurologic, ophthalmologic, audiologic, and cardiologic evaluations are recommended (see Nuclear Gene-Encoded Leigh Syndrome Spectrum: Recommended Surveillance Measurement of growth parameters Eval of nutritional status (incl micronutrients) & safety of oral intake Blood pressure Electrocardiogram Echocardiogram Urinalysis, urine albumin-to-creatinine ratio, urine amino acids Serum electrolytes, BUN, creatinine Fasting glucose Consider hemoglobin A1c or OGTT if clinical features consistent w/diabetes mellitus. Consider early morning cortisol & ACTH stimulation test if concerns about adrenal insufficiency. ACTH = adrenocorticotropic hormone; BUN = blood urea nitrogen; OGTT = oral glucose tolerance test; OT = occupational therapy; PT = physical therapy A Delphi review has examined drug safety in mitochondrial disorders [ Sodium valproate should be avoided if possible, because of its inhibitory effect on respiratory chain enzymes. Absolute contraindication in all individuals with Anesthesia can potentially aggravate respiratory manifestations and precipitate respiratory failure; thus, careful consideration should be given to its use and to monitoring the individual prior to, during, and after its use [ Prolonged propofol use during maintenance anesthesia may increase the risk of lactic acidosis. Catabolism should be prevented by minimizing preoperative fasting and considering intravenous glucose perioperatively during prolonged anesthesia (unless the individual is on a ketogenic diet). Neuromuscular blocking drugs should be avoided in individuals with muscle disease, or if necessary, used under strict monitoring. Avoid lactate-containing agents (e.g., Ringer's lactate) in those at risk of lactic acidosis [ • All persons w/profound biotinidase deficiency (<10% mean normal serum enzyme activity) & those w/partial biotinidase deficiency (10%-30% of mean normal serum enzyme activity) should be treated w/oral biotin in the free form as opposed to the protein-bound form. • Persons w/biotinidase deficiency who are diagnosed before they have developed manifestations (e.g., by newborn screening) & who are treated w/biotin have normal development. • Treatment should be instituted as early as possible because it can limit disease progression & reverse some manifestations; however, established severe neurologic &/or kidney damage cannot be reversed. • Response is highly variable, & depends on both the specific genetic defect & disease severity, but also other unknown factors. • Thiamine treatment is lifelong. • Thiamine dose must be ↑ during febrile illness, surgery, or acute decompensation (by 25%). • Variable response to thiamine among affected persons, w/response reported in approximately 50% of individuals [ • More effective with early diagnosis • Sodium bicarbonate or sodium citrate for significant acidosis • Consider THAM if hypernatremia occurs. • Sodium valproate should be avoided because of its inhibitory effects on the mitochondrial respiratory chain. • Education of parents/caregivers • Should be used w/caution given potential side effects of exacerbating muscle weakness. • Should not be used in head & neck because of risk of adverse events (e.g., impaired swallow). • Referral to pulmonologist as needed • Ventilatory support for persons w/LSS & respiratory compromise • Caloric & nutritional supplementation as needed (incl micronutrients) • Feeding therapy as needed; gastrostomy tube placement may improve nutritional intake for those w/persistent feeding issues, choking, or aspiration risk due to dysphagia • Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia • While ketogenic diet may be indicated for persons w/PDH deficiency or drug-resistant epilepsy, there is no evidence for efficacy of ketogenic diet in other forms of LSS. • Hearing aids or cochlear implants for SNHL • Referral to speech-language therapist • Referral to hearing support services • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Measurement of growth parameters • Eval of nutritional status (incl micronutrients) & safety of oral intake • Blood pressure • Electrocardiogram • Echocardiogram • Urinalysis, urine albumin-to-creatinine ratio, urine amino acids • Serum electrolytes, BUN, creatinine • Fasting glucose • Consider hemoglobin A1c or OGTT if clinical features consistent w/diabetes mellitus. • Consider early morning cortisol & ACTH stimulation test if concerns about adrenal insufficiency. • Sodium valproate should be avoided if possible, because of its inhibitory effect on respiratory chain enzymes. Absolute contraindication in all individuals with • Anesthesia can potentially aggravate respiratory manifestations and precipitate respiratory failure; thus, careful consideration should be given to its use and to monitoring the individual prior to, during, and after its use [ • Prolonged propofol use during maintenance anesthesia may increase the risk of lactic acidosis. • Catabolism should be prevented by minimizing preoperative fasting and considering intravenous glucose perioperatively during prolonged anesthesia (unless the individual is on a ketogenic diet). • Neuromuscular blocking drugs should be avoided in individuals with muscle disease, or if necessary, used under strict monitoring. • Avoid lactate-containing agents (e.g., Ringer's lactate) in those at risk of lactic acidosis [ ## Treatment of Manifestations Targeted therapies are available for some specific nuclear gene-encoded Leigh syndrome spectrum (LSS) disorders, listed in Leigh Syndrome Spectrum Disorders with Targeted Therapies All persons w/profound biotinidase deficiency (<10% mean normal serum enzyme activity) & those w/partial biotinidase deficiency (10%-30% of mean normal serum enzyme activity) should be treated w/oral biotin in the free form as opposed to the protein-bound form. Persons w/biotinidase deficiency who are diagnosed before they have developed manifestations (e.g., by newborn screening) & who are treated w/biotin have normal development. Treatment should be instituted as early as possible because it can limit disease progression & reverse some manifestations; however, established severe neurologic &/or kidney damage cannot be reversed. Response is highly variable, & depends on both the specific genetic defect & disease severity, but also other unknown factors. Thiamine treatment is lifelong. Thiamine dose must be ↑ during febrile illness, surgery, or acute decompensation (by 25%). Variable response to thiamine among affected persons, w/response reported in approximately 50% of individuals [ More effective with early diagnosis 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 Nuclear Gene-Encoded Leigh Syndrome Spectrum: Treatment of Manifestations Sodium bicarbonate or sodium citrate for significant acidosis Consider THAM if hypernatremia occurs. Sodium valproate should be avoided because of its inhibitory effects on the mitochondrial respiratory chain. Education of parents/caregivers Should be used w/caution given potential side effects of exacerbating muscle weakness. Should not be used in head & neck because of risk of adverse events (e.g., impaired swallow). Referral to pulmonologist as needed Ventilatory support for persons w/LSS & respiratory compromise Caloric & nutritional supplementation as needed (incl micronutrients) Feeding therapy as needed; gastrostomy tube placement may improve nutritional intake for those w/persistent feeding issues, choking, or aspiration risk due to dysphagia Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia While ketogenic diet may be indicated for persons w/PDH deficiency or drug-resistant epilepsy, there is no evidence for efficacy of ketogenic diet in other forms of LSS. Hearing aids or cochlear implants for SNHL Referral to speech-language therapist Referral to hearing support services Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ASM = anti-seizure medication; LSS = Leigh syndrome spectrum; OT = occupational therapy; PDH = pyruvate dehydrogenase; PT = physical therapy; SNHL = sensorineural hearing loss; THAM = tris-hydroxymethyl aminomethane Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see • All persons w/profound biotinidase deficiency (<10% mean normal serum enzyme activity) & those w/partial biotinidase deficiency (10%-30% of mean normal serum enzyme activity) should be treated w/oral biotin in the free form as opposed to the protein-bound form. • Persons w/biotinidase deficiency who are diagnosed before they have developed manifestations (e.g., by newborn screening) & who are treated w/biotin have normal development. • Treatment should be instituted as early as possible because it can limit disease progression & reverse some manifestations; however, established severe neurologic &/or kidney damage cannot be reversed. • Response is highly variable, & depends on both the specific genetic defect & disease severity, but also other unknown factors. • Thiamine treatment is lifelong. • Thiamine dose must be ↑ during febrile illness, surgery, or acute decompensation (by 25%). • Variable response to thiamine among affected persons, w/response reported in approximately 50% of individuals [ • More effective with early diagnosis • Sodium bicarbonate or sodium citrate for significant acidosis • Consider THAM if hypernatremia occurs. • Sodium valproate should be avoided because of its inhibitory effects on the mitochondrial respiratory chain. • Education of parents/caregivers • Should be used w/caution given potential side effects of exacerbating muscle weakness. • Should not be used in head & neck because of risk of adverse events (e.g., impaired swallow). • Referral to pulmonologist as needed • Ventilatory support for persons w/LSS & respiratory compromise • Caloric & nutritional supplementation as needed (incl micronutrients) • Feeding therapy as needed; gastrostomy tube placement may improve nutritional intake for those w/persistent feeding issues, choking, or aspiration risk due to dysphagia • Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia • While ketogenic diet may be indicated for persons w/PDH deficiency or drug-resistant epilepsy, there is no evidence for efficacy of ketogenic diet in other forms of LSS. • Hearing aids or cochlear implants for SNHL • Referral to speech-language therapist • Referral to hearing support services • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ## Targeted Therapies Targeted therapies are available for some specific nuclear gene-encoded Leigh syndrome spectrum (LSS) disorders, listed in Leigh Syndrome Spectrum Disorders with Targeted Therapies All persons w/profound biotinidase deficiency (<10% mean normal serum enzyme activity) & those w/partial biotinidase deficiency (10%-30% of mean normal serum enzyme activity) should be treated w/oral biotin in the free form as opposed to the protein-bound form. Persons w/biotinidase deficiency who are diagnosed before they have developed manifestations (e.g., by newborn screening) & who are treated w/biotin have normal development. Treatment should be instituted as early as possible because it can limit disease progression & reverse some manifestations; however, established severe neurologic &/or kidney damage cannot be reversed. Response is highly variable, & depends on both the specific genetic defect & disease severity, but also other unknown factors. Thiamine treatment is lifelong. Thiamine dose must be ↑ during febrile illness, surgery, or acute decompensation (by 25%). Variable response to thiamine among affected persons, w/response reported in approximately 50% of individuals [ More effective with early diagnosis • All persons w/profound biotinidase deficiency (<10% mean normal serum enzyme activity) & those w/partial biotinidase deficiency (10%-30% of mean normal serum enzyme activity) should be treated w/oral biotin in the free form as opposed to the protein-bound form. • Persons w/biotinidase deficiency who are diagnosed before they have developed manifestations (e.g., by newborn screening) & who are treated w/biotin have normal development. • Treatment should be instituted as early as possible because it can limit disease progression & reverse some manifestations; however, established severe neurologic &/or kidney damage cannot be reversed. • Response is highly variable, & depends on both the specific genetic defect & disease severity, but also other unknown factors. • Thiamine treatment is lifelong. • Thiamine dose must be ↑ during febrile illness, surgery, or acute decompensation (by 25%). • Variable response to thiamine among affected persons, w/response reported in approximately 50% of individuals [ • More effective with early diagnosis ## Supportive Treatment 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 Nuclear Gene-Encoded Leigh Syndrome Spectrum: Treatment of Manifestations Sodium bicarbonate or sodium citrate for significant acidosis Consider THAM if hypernatremia occurs. Sodium valproate should be avoided because of its inhibitory effects on the mitochondrial respiratory chain. Education of parents/caregivers Should be used w/caution given potential side effects of exacerbating muscle weakness. Should not be used in head & neck because of risk of adverse events (e.g., impaired swallow). Referral to pulmonologist as needed Ventilatory support for persons w/LSS & respiratory compromise Caloric & nutritional supplementation as needed (incl micronutrients) Feeding therapy as needed; gastrostomy tube placement may improve nutritional intake for those w/persistent feeding issues, choking, or aspiration risk due to dysphagia Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia While ketogenic diet may be indicated for persons w/PDH deficiency or drug-resistant epilepsy, there is no evidence for efficacy of ketogenic diet in other forms of LSS. Hearing aids or cochlear implants for SNHL Referral to speech-language therapist Referral to hearing support services Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ASM = anti-seizure medication; LSS = Leigh syndrome spectrum; OT = occupational therapy; PDH = pyruvate dehydrogenase; PT = physical therapy; SNHL = sensorineural hearing loss; THAM = tris-hydroxymethyl aminomethane Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see • Sodium bicarbonate or sodium citrate for significant acidosis • Consider THAM if hypernatremia occurs. • Sodium valproate should be avoided because of its inhibitory effects on the mitochondrial respiratory chain. • Education of parents/caregivers • Should be used w/caution given potential side effects of exacerbating muscle weakness. • Should not be used in head & neck because of risk of adverse events (e.g., impaired swallow). • Referral to pulmonologist as needed • Ventilatory support for persons w/LSS & respiratory compromise • Caloric & nutritional supplementation as needed (incl micronutrients) • Feeding therapy as needed; gastrostomy tube placement may improve nutritional intake for those w/persistent feeding issues, choking, or aspiration risk due to dysphagia • Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia • While ketogenic diet may be indicated for persons w/PDH deficiency or drug-resistant epilepsy, there is no evidence for efficacy of ketogenic diet in other forms of LSS. • Hearing aids or cochlear implants for SNHL • Referral to speech-language therapist • Referral to hearing support services • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ## Surveillance Affected individuals should be followed at regular intervals (typically every 6-12 months) to monitor progression of known manifestations and the appearance of new manifestations. Neurologic, ophthalmologic, audiologic, and cardiologic evaluations are recommended (see Nuclear Gene-Encoded Leigh Syndrome Spectrum: Recommended Surveillance Measurement of growth parameters Eval of nutritional status (incl micronutrients) & safety of oral intake Blood pressure Electrocardiogram Echocardiogram Urinalysis, urine albumin-to-creatinine ratio, urine amino acids Serum electrolytes, BUN, creatinine Fasting glucose Consider hemoglobin A1c or OGTT if clinical features consistent w/diabetes mellitus. Consider early morning cortisol & ACTH stimulation test if concerns about adrenal insufficiency. ACTH = adrenocorticotropic hormone; BUN = blood urea nitrogen; OGTT = oral glucose tolerance test; OT = occupational therapy; PT = physical therapy • Measurement of growth parameters • Eval of nutritional status (incl micronutrients) & safety of oral intake • Blood pressure • Electrocardiogram • Echocardiogram • Urinalysis, urine albumin-to-creatinine ratio, urine amino acids • Serum electrolytes, BUN, creatinine • Fasting glucose • Consider hemoglobin A1c or OGTT if clinical features consistent w/diabetes mellitus. • Consider early morning cortisol & ACTH stimulation test if concerns about adrenal insufficiency. ## Agents/Circumstances to Avoid A Delphi review has examined drug safety in mitochondrial disorders [ Sodium valproate should be avoided if possible, because of its inhibitory effect on respiratory chain enzymes. Absolute contraindication in all individuals with Anesthesia can potentially aggravate respiratory manifestations and precipitate respiratory failure; thus, careful consideration should be given to its use and to monitoring the individual prior to, during, and after its use [ Prolonged propofol use during maintenance anesthesia may increase the risk of lactic acidosis. Catabolism should be prevented by minimizing preoperative fasting and considering intravenous glucose perioperatively during prolonged anesthesia (unless the individual is on a ketogenic diet). Neuromuscular blocking drugs should be avoided in individuals with muscle disease, or if necessary, used under strict monitoring. Avoid lactate-containing agents (e.g., Ringer's lactate) in those at risk of lactic acidosis [ • Sodium valproate should be avoided if possible, because of its inhibitory effect on respiratory chain enzymes. Absolute contraindication in all individuals with • Anesthesia can potentially aggravate respiratory manifestations and precipitate respiratory failure; thus, careful consideration should be given to its use and to monitoring the individual prior to, during, and after its use [ • Prolonged propofol use during maintenance anesthesia may increase the risk of lactic acidosis. • Catabolism should be prevented by minimizing preoperative fasting and considering intravenous glucose perioperatively during prolonged anesthesia (unless the individual is on a ketogenic diet). • Neuromuscular blocking drugs should be avoided in individuals with muscle disease, or if necessary, used under strict monitoring. • Avoid lactate-containing agents (e.g., Ringer's lactate) in those at risk of lactic acidosis [ ## Genetic Counseling Nuclear gene-encoded Leigh syndrome spectrum (LSS) can be inherited in an autosomal recessive, X-linked, or autosomal dominant manner. Of the more than 115 nuclear gene-encoded LSS-related genes identified to date, pathogenic variants in all but six genes are associated with LSS caused by a heterozygous or hemizygous pathogenic variant in Two genes, 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. The parents of an affected child are presumed to be heterozygous for an LSS-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 an LSS-related pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an LSS-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. The father of an affected male will not have X-linked LSS nor will he be hemizygous for an In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the familial pathogenic variant cannot be detected in her leukocyte DNA, she most likely has gonadal mosaicism. If a male is the only affected family member (i.e., a simplex case): The mother may be heterozygous for the X-linked LSS-related pathogenic variant or have somatic/gonadal mosaicism; or The affected male may have a Molecular genetic testing of the mother is recommended to evaluate her genetic status and inform recurrence risk assessment. Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. A female proband may have X-linked LSS as the result of a Detailed evaluation of the parents and review of the extended family history may help to distinguish probands with a The risk to sibs of a male proband of inheriting an X-linked LSS-related pathogenic variant depends on the genetic status of the mother: if the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. The risk to sibs of a female proband of inheriting a pathogenic variant depends on the genetic status of the mother and the father: if the mother of the proband has an X-linked LSS-related pathogenic variant, the chance of transmitting it in each pregnancy is 50%; if the father of the proband has a pathogenic variant, he will transmit it to all his daughters and none of his sons. The risk that a sib who inherits an X-linked LSS-related pathogenic variant will have manifestations of the disorder cannot be fully predicted. The risk of manifestations is influenced by the sex of the sib and – in the case of Males who inherit an X-linked LSS-related pathogenic variant will be affected; females who inherit a pathogenic variant will be heterozygotes and their clinical manifestations may range from asymptomatic to as severely affected as hemizygous males. As a result of the difference in If the proband represents a simplex case and the pathogenic variant cannot be detected in the leukocyte DNA of the mother (or, if the proband is female and the pathogenic variant cannot be detected in the leukocyte DNA of the mother or the father), the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of parental gonadal mosaicism. Males with X-linked LSS have not been known to reproduce. Each child of a female with X-linked LSS has a 50% chance of inheriting the pathogenic variant. All probands reported to date with Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. If a parent of the proband has the autosomal dominant LSS-related pathogenic variant, the risk to the sibs of inheriting the variant is 50%. If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [ Once the LSS-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • Of the more than 115 nuclear gene-encoded LSS-related genes identified to date, pathogenic variants in all but six genes are associated with • LSS caused by a heterozygous or hemizygous pathogenic variant in • Two genes, • The parents of an affected child are presumed to be heterozygous for an LSS-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 an LSS-related pathogenic variant and to allow reliable recurrence risk assessment. • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an LSS-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The father of an affected male will not have X-linked LSS nor will he be hemizygous for an • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the familial pathogenic variant cannot be detected in her leukocyte DNA, she most likely has gonadal mosaicism. • If a male is the only affected family member (i.e., a simplex case): • The mother may be heterozygous for the X-linked LSS-related pathogenic variant or have somatic/gonadal mosaicism; or • The affected male may have a • The mother may be heterozygous for the X-linked LSS-related pathogenic variant or have somatic/gonadal mosaicism; or • The affected male may have a • Molecular genetic testing of the mother is recommended to evaluate her genetic status and inform recurrence risk assessment. Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The mother may be heterozygous for the X-linked LSS-related pathogenic variant or have somatic/gonadal mosaicism; or • The affected male may have a • A female proband may have X-linked LSS as the result of a • Detailed evaluation of the parents and review of the extended family history may help to distinguish probands with a • The risk to sibs of a male proband of inheriting an X-linked LSS-related pathogenic variant depends on the genetic status of the mother: if the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. • The risk to sibs of a female proband of inheriting a pathogenic variant depends on the genetic status of the mother and the father: if the mother of the proband has an X-linked LSS-related pathogenic variant, the chance of transmitting it in each pregnancy is 50%; if the father of the proband has a pathogenic variant, he will transmit it to all his daughters and none of his sons. • The risk that a sib who inherits an X-linked LSS-related pathogenic variant will have manifestations of the disorder cannot be fully predicted. The risk of manifestations is influenced by the sex of the sib and – in the case of • Males who inherit an X-linked LSS-related pathogenic variant will be affected; females who inherit a pathogenic variant will be heterozygotes and their clinical manifestations may range from asymptomatic to as severely affected as hemizygous males. • As a result of the difference in • Males who inherit an X-linked LSS-related pathogenic variant will be affected; females who inherit a pathogenic variant will be heterozygotes and their clinical manifestations may range from asymptomatic to as severely affected as hemizygous males. • As a result of the difference in • If the proband represents a simplex case and the pathogenic variant cannot be detected in the leukocyte DNA of the mother (or, if the proband is female and the pathogenic variant cannot be detected in the leukocyte DNA of the mother or the father), the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of parental gonadal mosaicism. • Males who inherit an X-linked LSS-related pathogenic variant will be affected; females who inherit a pathogenic variant will be heterozygotes and their clinical manifestations may range from asymptomatic to as severely affected as hemizygous males. • As a result of the difference in • Males with X-linked LSS have not been known to reproduce. • Each child of a female with X-linked LSS has a 50% chance of inheriting the pathogenic variant. • All probands reported to date with • Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • If a parent of the proband has the autosomal dominant LSS-related pathogenic variant, the risk to the sibs of inheriting the variant is 50%. • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [ ## Mode of Inheritance Nuclear gene-encoded Leigh syndrome spectrum (LSS) can be inherited in an autosomal recessive, X-linked, or autosomal dominant manner. Of the more than 115 nuclear gene-encoded LSS-related genes identified to date, pathogenic variants in all but six genes are associated with LSS caused by a heterozygous or hemizygous pathogenic variant in Two genes, 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. • Of the more than 115 nuclear gene-encoded LSS-related genes identified to date, pathogenic variants in all but six genes are associated with • LSS caused by a heterozygous or hemizygous pathogenic variant in • Two genes, ## Autosomal Recessive Inheritance – Risk to Family Members The parents of an affected child are presumed to be heterozygous for an LSS-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 an LSS-related pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an LSS-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The parents of an affected child are presumed to be heterozygous for an LSS-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 an LSS-related pathogenic variant and to allow reliable recurrence risk assessment. • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an LSS-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## X-Linked Inheritance – Risk to Family Members The father of an affected male will not have X-linked LSS nor will he be hemizygous for an In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the familial pathogenic variant cannot be detected in her leukocyte DNA, she most likely has gonadal mosaicism. If a male is the only affected family member (i.e., a simplex case): The mother may be heterozygous for the X-linked LSS-related pathogenic variant or have somatic/gonadal mosaicism; or The affected male may have a Molecular genetic testing of the mother is recommended to evaluate her genetic status and inform recurrence risk assessment. Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. A female proband may have X-linked LSS as the result of a Detailed evaluation of the parents and review of the extended family history may help to distinguish probands with a The risk to sibs of a male proband of inheriting an X-linked LSS-related pathogenic variant depends on the genetic status of the mother: if the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. The risk to sibs of a female proband of inheriting a pathogenic variant depends on the genetic status of the mother and the father: if the mother of the proband has an X-linked LSS-related pathogenic variant, the chance of transmitting it in each pregnancy is 50%; if the father of the proband has a pathogenic variant, he will transmit it to all his daughters and none of his sons. The risk that a sib who inherits an X-linked LSS-related pathogenic variant will have manifestations of the disorder cannot be fully predicted. The risk of manifestations is influenced by the sex of the sib and – in the case of Males who inherit an X-linked LSS-related pathogenic variant will be affected; females who inherit a pathogenic variant will be heterozygotes and their clinical manifestations may range from asymptomatic to as severely affected as hemizygous males. As a result of the difference in If the proband represents a simplex case and the pathogenic variant cannot be detected in the leukocyte DNA of the mother (or, if the proband is female and the pathogenic variant cannot be detected in the leukocyte DNA of the mother or the father), the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of parental gonadal mosaicism. Males with X-linked LSS have not been known to reproduce. Each child of a female with X-linked LSS has a 50% chance of inheriting the pathogenic variant. • The father of an affected male will not have X-linked LSS nor will he be hemizygous for an • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the familial pathogenic variant cannot be detected in her leukocyte DNA, she most likely has gonadal mosaicism. • If a male is the only affected family member (i.e., a simplex case): • The mother may be heterozygous for the X-linked LSS-related pathogenic variant or have somatic/gonadal mosaicism; or • The affected male may have a • The mother may be heterozygous for the X-linked LSS-related pathogenic variant or have somatic/gonadal mosaicism; or • The affected male may have a • Molecular genetic testing of the mother is recommended to evaluate her genetic status and inform recurrence risk assessment. Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The mother may be heterozygous for the X-linked LSS-related pathogenic variant or have somatic/gonadal mosaicism; or • The affected male may have a • A female proband may have X-linked LSS as the result of a • Detailed evaluation of the parents and review of the extended family history may help to distinguish probands with a • The risk to sibs of a male proband of inheriting an X-linked LSS-related pathogenic variant depends on the genetic status of the mother: if the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. • The risk to sibs of a female proband of inheriting a pathogenic variant depends on the genetic status of the mother and the father: if the mother of the proband has an X-linked LSS-related pathogenic variant, the chance of transmitting it in each pregnancy is 50%; if the father of the proband has a pathogenic variant, he will transmit it to all his daughters and none of his sons. • The risk that a sib who inherits an X-linked LSS-related pathogenic variant will have manifestations of the disorder cannot be fully predicted. The risk of manifestations is influenced by the sex of the sib and – in the case of • Males who inherit an X-linked LSS-related pathogenic variant will be affected; females who inherit a pathogenic variant will be heterozygotes and their clinical manifestations may range from asymptomatic to as severely affected as hemizygous males. • As a result of the difference in • Males who inherit an X-linked LSS-related pathogenic variant will be affected; females who inherit a pathogenic variant will be heterozygotes and their clinical manifestations may range from asymptomatic to as severely affected as hemizygous males. • As a result of the difference in • If the proband represents a simplex case and the pathogenic variant cannot be detected in the leukocyte DNA of the mother (or, if the proband is female and the pathogenic variant cannot be detected in the leukocyte DNA of the mother or the father), the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of parental gonadal mosaicism. • Males who inherit an X-linked LSS-related pathogenic variant will be affected; females who inherit a pathogenic variant will be heterozygotes and their clinical manifestations may range from asymptomatic to as severely affected as hemizygous males. • As a result of the difference in • Males with X-linked LSS have not been known to reproduce. • Each child of a female with X-linked LSS has a 50% chance of inheriting the pathogenic variant. ## Autosomal Dominant Inheritance – Risk to Family Members All probands reported to date with Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. If a parent of the proband has the autosomal dominant LSS-related pathogenic variant, the risk to the sibs of inheriting the variant is 50%. If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [ • All probands reported to date with • Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • If a parent of the proband has the autosomal dominant LSS-related pathogenic variant, the risk to the sibs of inheriting the variant is 50%. • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [ ## Related Genetic Counseling Issues ## Prenatal Testing and Preimplantation Genetic Testing Once the LSS-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources France Germany Australia Canada Italy United Kingdom United Kingdom • • • • France • • • Germany • • • • • Australia • • • • • Canada • • • • Italy • • • • • • United Kingdom • • • United Kingdom • • • ## Chapter Notes Professor Rahman's research interests include identification of novel nuclear genes causing mitochondrial disease using a combination of approaches including homozygosity mapping and exome and genome next-generation sequencing. Her group has identified a number of nuclear genes causing childhood-onset mitochondrial disorders, including genes involved in mitochondrial DNA maintenance and expression, complex I and complex IV function, and biosynthesis of coenzyme Q Professor Thorburn's research focuses on improving diagnosis, prevention, and treatment of mitochondrial energy generation disorders. This has included translating knowledge of mitochondrial DNA genetics into reproductive options for families, defining diagnostic criteria and epidemiology, and discovery of new "disease" genes through genomic, multi-omic, and targeted functional testing. His group also uses pluripotent and other cellular models to understand pathogenic mechanisms and trial new treatment approaches. The authors would like to acknowledge the support of clinicians, researchers, and patient advocacy groups for nuclear gene-encoded LSS. They would also like to acknowledge all the patients and families who have generously given their time and shared their experiences to advance the understanding of nuclear gene-encoded LSS. 1 May 2025 (bp) Comprehensive update posted live 16 July 2020 (bp) Comprehensive update posted live 1 October 2015 (me) Review posted live 17 February 2015 (sr) Original submission • 1 May 2025 (bp) Comprehensive update posted live • 16 July 2020 (bp) Comprehensive update posted live • 1 October 2015 (me) Review posted live • 17 February 2015 (sr) Original submission ## Author Notes Professor Rahman's research interests include identification of novel nuclear genes causing mitochondrial disease using a combination of approaches including homozygosity mapping and exome and genome next-generation sequencing. Her group has identified a number of nuclear genes causing childhood-onset mitochondrial disorders, including genes involved in mitochondrial DNA maintenance and expression, complex I and complex IV function, and biosynthesis of coenzyme Q Professor Thorburn's research focuses on improving diagnosis, prevention, and treatment of mitochondrial energy generation disorders. This has included translating knowledge of mitochondrial DNA genetics into reproductive options for families, defining diagnostic criteria and epidemiology, and discovery of new "disease" genes through genomic, multi-omic, and targeted functional testing. His group also uses pluripotent and other cellular models to understand pathogenic mechanisms and trial new treatment approaches. ## Acknowledgments The authors would like to acknowledge the support of clinicians, researchers, and patient advocacy groups for nuclear gene-encoded LSS. They would also like to acknowledge all the patients and families who have generously given their time and shared their experiences to advance the understanding of nuclear gene-encoded LSS. ## Revision History 1 May 2025 (bp) Comprehensive update posted live 16 July 2020 (bp) Comprehensive update posted live 1 October 2015 (me) Review posted live 17 February 2015 (sr) Original submission • 1 May 2025 (bp) Comprehensive update posted live • 16 July 2020 (bp) Comprehensive update posted live • 1 October 2015 (me) Review posted live • 17 February 2015 (sr) Original submission ## Key Sections in This ## References ## Literature Cited	[]	1/10/2015	1/5/2025		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
lenz	lenz	[ "BCL-6 corepressor", "N-alpha-acetyltransferase 10", "BCOR", "NAA10", "Lenz Microphthalmia Syndrome" ]	Lenz Microphthalmia Syndrome – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY	David Ng	Summary Lenz microphthalmia syndrome (LMS) is characterized by unilateral or bilateral microphthalmia and/or clinical anophthalmia with malformations of the ears, teeth, fingers, skeleton, and/or genitourinary system. Microphthalmia is often accompanied by microcornea and glaucoma. Coloboma is present in approximately 60% of microphthalmic eyes with severity ranging from isolated iris coloboma to coloboma of the ciliary body, choroid, and optic disk. Ears may be low set, anteverted, posteriorly rotated, simple, cup shaped, or abnormally modeled. Hearing loss has been observed. Dental findings include irregularly shaped, missing, or widely spaced teeth. Duplicated thumbs, syndactyly, clinodactyly, camptodactyly, and microcephaly are common, as are narrow/sloping shoulders, underdeveloped clavicles, kyphoscoliosis, exaggerated lumbar lordosis, long cylindric thorax, and webbed neck. Genitourinary anomalies include hypospadias, cryptorchidism, renal hypoplasia/aplasia, and hydroureter. Approximately 60% of affected males have mild-to-severe intellectual disability or developmental delay. The diagnosis of Lenz microphthalmia syndrome is based on clinical findings. Mild simple microphthalmia can be identified by measuring the axial length of the globe with A-scan ultrasonography. Lenz microphthalmia syndrome is inherited in an X-linked manner. The risk to sibs depends on the carrier status of the mother. If the mother is a carrier, the chance of transmitting the pathogenic variant is 50% in each pregnancy: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers. The majority of males with Lenz microphthalmia syndrome do not reproduce. Carrier testing for at-risk female relatives and prenatal testing for pregnancies at increased risk are possible for families in which the pathogenic variant has been identified in an affected family member. Prenatal ultrasound examination at 18 weeks' gestation can be offered for pregnancies at increased risk to evaluate fetal renal development.	## Diagnosis Lenz microphthalmia syndrome (LMS) should be suspected in males with a combination of the following clinical findings: Hypospadias, cryptorchidism, renal aplasia/hypoplasia, hydroureter (77% of individuals) Simple, anteverted, abnormally modeled ears (63%) Abnormal shape of incisors, irregularly spaced teeth (48%) Duplicated thumbs, syndactyly, clinodactyly, camptodactyly (44%) Microcephaly (37%) Narrow/sloping shoulders, underdeveloped clavicles, kyphoscoliosis, exaggerated lumbar lordosis, long cylindrical thorax, webbed neck (26%) Cleft lip/palate (7%) The diagnosis of LMS is established in a proband with identification of a pathogenic variant in one of two known genes, For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Lenz Microphthalmia Syndrome See Pathogenic variants included in a panel may vary by laboratory. A pathogenic missense variant, c.254C>T, resulting in a change of amino acid at position 85 from proline to leucine (p.Pro85Leu) in 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 c.471+2T>A, a splice variant that may lead to aberrant splicing of exons 7 and 8 of 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 inlcude quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. An Irish family with microphthalmia/anophthalmia, ankyloblepharon and intellectual disability (MCOPS4) was previously mapped to Xq27-q28 [ • Hypospadias, cryptorchidism, renal aplasia/hypoplasia, hydroureter (77% of individuals) • Simple, anteverted, abnormally modeled ears (63%) • Abnormal shape of incisors, irregularly spaced teeth (48%) • Duplicated thumbs, syndactyly, clinodactyly, camptodactyly (44%) • Microcephaly (37%) • Narrow/sloping shoulders, underdeveloped clavicles, kyphoscoliosis, exaggerated lumbar lordosis, long cylindrical thorax, webbed neck (26%) • Cleft lip/palate (7%) • Hypospadias, cryptorchidism, renal aplasia/hypoplasia, hydroureter (77% of individuals) • Simple, anteverted, abnormally modeled ears (63%) • Abnormal shape of incisors, irregularly spaced teeth (48%) • Duplicated thumbs, syndactyly, clinodactyly, camptodactyly (44%) • Microcephaly (37%) • Narrow/sloping shoulders, underdeveloped clavicles, kyphoscoliosis, exaggerated lumbar lordosis, long cylindrical thorax, webbed neck (26%) • Cleft lip/palate (7%) • Hypospadias, cryptorchidism, renal aplasia/hypoplasia, hydroureter (77% of individuals) • Simple, anteverted, abnormally modeled ears (63%) • Abnormal shape of incisors, irregularly spaced teeth (48%) • Duplicated thumbs, syndactyly, clinodactyly, camptodactyly (44%) • Microcephaly (37%) • Narrow/sloping shoulders, underdeveloped clavicles, kyphoscoliosis, exaggerated lumbar lordosis, long cylindrical thorax, webbed neck (26%) • Cleft lip/palate (7%) ## Suggestive Findings Lenz microphthalmia syndrome (LMS) should be suspected in males with a combination of the following clinical findings: Hypospadias, cryptorchidism, renal aplasia/hypoplasia, hydroureter (77% of individuals) Simple, anteverted, abnormally modeled ears (63%) Abnormal shape of incisors, irregularly spaced teeth (48%) Duplicated thumbs, syndactyly, clinodactyly, camptodactyly (44%) Microcephaly (37%) Narrow/sloping shoulders, underdeveloped clavicles, kyphoscoliosis, exaggerated lumbar lordosis, long cylindrical thorax, webbed neck (26%) Cleft lip/palate (7%) • Hypospadias, cryptorchidism, renal aplasia/hypoplasia, hydroureter (77% of individuals) • Simple, anteverted, abnormally modeled ears (63%) • Abnormal shape of incisors, irregularly spaced teeth (48%) • Duplicated thumbs, syndactyly, clinodactyly, camptodactyly (44%) • Microcephaly (37%) • Narrow/sloping shoulders, underdeveloped clavicles, kyphoscoliosis, exaggerated lumbar lordosis, long cylindrical thorax, webbed neck (26%) • Cleft lip/palate (7%) • Hypospadias, cryptorchidism, renal aplasia/hypoplasia, hydroureter (77% of individuals) • Simple, anteverted, abnormally modeled ears (63%) • Abnormal shape of incisors, irregularly spaced teeth (48%) • Duplicated thumbs, syndactyly, clinodactyly, camptodactyly (44%) • Microcephaly (37%) • Narrow/sloping shoulders, underdeveloped clavicles, kyphoscoliosis, exaggerated lumbar lordosis, long cylindrical thorax, webbed neck (26%) • Cleft lip/palate (7%) • Hypospadias, cryptorchidism, renal aplasia/hypoplasia, hydroureter (77% of individuals) • Simple, anteverted, abnormally modeled ears (63%) • Abnormal shape of incisors, irregularly spaced teeth (48%) • Duplicated thumbs, syndactyly, clinodactyly, camptodactyly (44%) • Microcephaly (37%) • Narrow/sloping shoulders, underdeveloped clavicles, kyphoscoliosis, exaggerated lumbar lordosis, long cylindrical thorax, webbed neck (26%) • Cleft lip/palate (7%) ## Establishing the Diagnosis The diagnosis of LMS is established in a proband with identification of a pathogenic variant in one of two known genes, For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Lenz Microphthalmia Syndrome See Pathogenic variants included in a panel may vary by laboratory. A pathogenic missense variant, c.254C>T, resulting in a change of amino acid at position 85 from proline to leucine (p.Pro85Leu) in 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 c.471+2T>A, a splice variant that may lead to aberrant splicing of exons 7 and 8 of 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 inlcude quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. An Irish family with microphthalmia/anophthalmia, ankyloblepharon and intellectual disability (MCOPS4) was previously mapped to Xq27-q28 [ ## Clinical Characteristics The phenotype of Lenz microphthalmia syndrome, microphthalmia with developmental delay and skeletal and urogenital anomalies associated with Lenz microphthalmia syndrome has a wide spectrum of ocular and extraocular abnormalities. Since mild microphthalmia may not be obvious on clinical examination, individuals with LMS with retained vision may not be identified until the first ophthalmologic examination when high hyperopia (+7 to +11 diopters) secondary to a foreshortened posterior segment of the globe is diagnosed. Cataracts may be present. Nystagmus may be present secondary to impaired vision. Absence or diminished size of the globe may cause secondary underdevelopment of the bony orbits, shortened palpebral fissures, and fusion of the eyelid margins (ankyloblepharon). Ears may be low set, anteverted, posteriorly rotated, simple, cup shaped, or abnormally modeled. Preauricular tags may be present. Hearing loss has been observed. Cleft lip/palate or high arched palate is present in approximately 12/30 of individuals [ Dental development may be delayed. Nonspecific dental findings include irregularly shaped, missing, or widely spaced teeth. Motor development may be delayed. Seizures, behavioral disturbance, and self-mutilation may manifest in males with severe intellectual disability. Sleep-wake cycles can be disturbed because of lack of normal diurnal variation. Cranial MRI often reveals absent or hypoplastic optic nerves and optic chiasm. In addition, hypoplasia of the corpus callosum and cingulate gyrus has been noted. The latter is often clinically silent. No genotype-phenotype correlations are known. Males reported with LMS and a An insufficient number of cases of Lenz microphthalmia exist to comment on penetrance. Lenz microphthalmia syndrome (LMS) has been referred to as Lenz dysplasia, Lenz dysmorphogenetic syndrome, and microphthalmia with associated anomalies. The two loci were formerly designated MAA and MAA2 (or ANOP2). The locus designations MAA (now associated with syndromic microphthalmia 1 [MCOPS1, MCOPS2 has since been redesignated oculofaciocardiodental syndrome (OFCD) due to the higher prevalence of Although the consensus inheritance pattern is X-linked recessive, the term Lenz microphthalmia is used by clinicians for simplex cases (i.e., single occurrence in a family) with a Lenz-like phenotype. Prevalence in ethnic groups is unknown. Most reported cases are of European descent. ## Clinical Description The phenotype of Lenz microphthalmia syndrome, microphthalmia with developmental delay and skeletal and urogenital anomalies associated with Lenz microphthalmia syndrome has a wide spectrum of ocular and extraocular abnormalities. Since mild microphthalmia may not be obvious on clinical examination, individuals with LMS with retained vision may not be identified until the first ophthalmologic examination when high hyperopia (+7 to +11 diopters) secondary to a foreshortened posterior segment of the globe is diagnosed. Cataracts may be present. Nystagmus may be present secondary to impaired vision. Absence or diminished size of the globe may cause secondary underdevelopment of the bony orbits, shortened palpebral fissures, and fusion of the eyelid margins (ankyloblepharon). Ears may be low set, anteverted, posteriorly rotated, simple, cup shaped, or abnormally modeled. Preauricular tags may be present. Hearing loss has been observed. Cleft lip/palate or high arched palate is present in approximately 12/30 of individuals [ Dental development may be delayed. Nonspecific dental findings include irregularly shaped, missing, or widely spaced teeth. Motor development may be delayed. Seizures, behavioral disturbance, and self-mutilation may manifest in males with severe intellectual disability. Sleep-wake cycles can be disturbed because of lack of normal diurnal variation. Cranial MRI often reveals absent or hypoplastic optic nerves and optic chiasm. In addition, hypoplasia of the corpus callosum and cingulate gyrus has been noted. The latter is often clinically silent. ## Genotype-Phenotype Correlations No genotype-phenotype correlations are known. Males reported with LMS and a ## Penetrance An insufficient number of cases of Lenz microphthalmia exist to comment on penetrance. ## Nomenclature Lenz microphthalmia syndrome (LMS) has been referred to as Lenz dysplasia, Lenz dysmorphogenetic syndrome, and microphthalmia with associated anomalies. The two loci were formerly designated MAA and MAA2 (or ANOP2). The locus designations MAA (now associated with syndromic microphthalmia 1 [MCOPS1, MCOPS2 has since been redesignated oculofaciocardiodental syndrome (OFCD) due to the higher prevalence of Although the consensus inheritance pattern is X-linked recessive, the term Lenz microphthalmia is used by clinicians for simplex cases (i.e., single occurrence in a family) with a Lenz-like phenotype. ## Prevalence Prevalence in ethnic groups is unknown. Most reported cases are of European descent. ## Genetically Related (Allelic) Disorders OFCD syndrome is inherited in an X-linked pattern with male lethality. Females with OFCD syndrome may have congenital cataracts as the sole ocular manifestation or unilateral/bilateral microphthalmia with congenital cataracts. Microphthalmia is less severe in OFCD syndrome than in LMS. Extraocular features include long narrow face, broad nasal tip with separated nasal cartilage, cleft palate, submucous cleft palate, cardiac anomalies (ventricular septal defect, atrial septal defect, floppy mitral valve) and dental anomalies (retained deciduous teeth, canine radiculomegaly, root dilacerations, oligodontia). Females with OFCD syndrome have normal intelligence, in contrast to males with LMS, who often have developmental delay/intellectual disability, microcephaly, and structural CNS abnormalities. The majority of individuals with OFCD syndrome analyzed thus far have detectable Individuals with OFCD syndrome have pathogenic variants that are predicted to prematurely truncate the BCOR protein. In hemizygous males, truncating variants are hypothesized to lead to a complete loss of Based on the known cases of OFCD syndrome scanned for Three females with features of OFCD syndrome but with notable absence of dental radiculomegaly did not have identifiable ## Differential Diagnosis A Hispanic family with isolated X-linked colobomatous microphthalmia has been reported [ ## Management To establish the extent of disease and needs in an individual diagnosed with Lenz microphthalmia syndrome (LMS), the following evaluations are recommended: Physical examination for the presence of anomalies associated with the disorder Cranial MRI to estimate the size of the globes for prognosis regarding potential visual function and to detect concurrent CNS malformations such as hypoplastic corpus callosum and cingulate gyrus Visual evoked response testing and ophthalmologic examination to help determine visual acuity and/or the potential for vision Consideration of echocardiogram if physical exam detects findings suggestive of a congenital cardiac malformation. (A single case report from Japan described an infant with a molecularly confirmed LMS (BCOR p.Pro85Leu) dying of an unspecified cardiac defect at age six months [ Renal ultrasound examination to evaluate for renal aplasia, hypoplasia, and hydroureter Consideration of hearing evaluation during infancy if: Head and neck examination reveals malformations of the auricle or ear canal, presence of skin tags or dimples around the ear, presence of cleft lip or palate, asymmetric facies, and microcephaly The parents have concerns that the child cannot hear (e.g., infant does not startle to loud noises, awaken to sound). The type of examination should be adjusted for the individual's cognitive level to allow for cooperation and maximize the chance of an informative test (see Consideration of sleep evaluation if parents report excessive daytime somnolence, altered sleep-wake cycles, difficulty awakening the child or getting the child to fall asleep, apnea, loud snoring, and/or difficulty breathing while asleep Clinical genetics consultation Individuals with anophthalmos or extreme microphthalmos benefit from regular evaluations by an ocularist for placement of serial enlarging orbital expanders to prevent deformation of facial structures and to encourage normal development of eye lashes and lid margins. Early intervention with physical therapy and occupational therapy helps to address disturbances of the sleep-wake cycle caused by lack of light perception and problems of delayed gross motor development often observed in children with visual impairment. Early intervention with special education maximizes cognitive development. Referral to services for the visually impaired is recommended. Treatment for hearing loss and sleep disorders is dependent on the specific defect and similar to the general population. Referral to a sleep disorder specialist may be necessary depending on the individual's history and presentation to determine the appropriate tests. Dental examinations and cleaning should be instituted to monitor dental hygiene, especially when the affected individual has cognitive developmental delay. Missing and irregularly shaped teeth and wide spacing of teeth are common. Treatment is the same as for the general population in restoring masticatory function. No special preventative care is recommended. Follow-up care is personalized based on the physical impairments found in the individual. The following are appropriate: Annual ophthalmologic examination for those with residual vision given the predisposition to glaucoma and high hyperopia from foreshortening of the globe Monitoring of renal function (BUN, creatinine, and urine analysis) in those with known renal/ureteral anomalies Developmental assessments performed with each well-child visit as recommended by the American Academy of Pediatrics. More frequent and specialized assessments are tailored to each child if development is not on track. Lifelong case management to help affected individuals gain access to social services and assistive devices for the blind In those with residual vision, dilating drops and medications that may dilate the pupils (i.e., antihistamines, decongestants, tricyclic antidepressants) should be used in consultation with an ophthalmologist because of the narrow anterior chamber and risk for angle closure glaucoma. See Search • Physical examination for the presence of anomalies associated with the disorder • Cranial MRI to estimate the size of the globes for prognosis regarding potential visual function and to detect concurrent CNS malformations such as hypoplastic corpus callosum and cingulate gyrus • Visual evoked response testing and ophthalmologic examination to help determine visual acuity and/or the potential for vision • Consideration of echocardiogram if physical exam detects findings suggestive of a congenital cardiac malformation. (A single case report from Japan described an infant with a molecularly confirmed LMS (BCOR p.Pro85Leu) dying of an unspecified cardiac defect at age six months [ • Renal ultrasound examination to evaluate for renal aplasia, hypoplasia, and hydroureter • Consideration of hearing evaluation during infancy if: • Head and neck examination reveals malformations of the auricle or ear canal, presence of skin tags or dimples around the ear, presence of cleft lip or palate, asymmetric facies, and microcephaly • The parents have concerns that the child cannot hear (e.g., infant does not startle to loud noises, awaken to sound). The type of examination should be adjusted for the individual's cognitive level to allow for cooperation and maximize the chance of an informative test (see • Head and neck examination reveals malformations of the auricle or ear canal, presence of skin tags or dimples around the ear, presence of cleft lip or palate, asymmetric facies, and microcephaly • The parents have concerns that the child cannot hear (e.g., infant does not startle to loud noises, awaken to sound). The type of examination should be adjusted for the individual's cognitive level to allow for cooperation and maximize the chance of an informative test (see • Consideration of sleep evaluation if parents report excessive daytime somnolence, altered sleep-wake cycles, difficulty awakening the child or getting the child to fall asleep, apnea, loud snoring, and/or difficulty breathing while asleep • Clinical genetics consultation • Head and neck examination reveals malformations of the auricle or ear canal, presence of skin tags or dimples around the ear, presence of cleft lip or palate, asymmetric facies, and microcephaly • The parents have concerns that the child cannot hear (e.g., infant does not startle to loud noises, awaken to sound). The type of examination should be adjusted for the individual's cognitive level to allow for cooperation and maximize the chance of an informative test (see • Annual ophthalmologic examination for those with residual vision given the predisposition to glaucoma and high hyperopia from foreshortening of the globe • Monitoring of renal function (BUN, creatinine, and urine analysis) in those with known renal/ureteral anomalies • Developmental assessments performed with each well-child visit as recommended by the American Academy of Pediatrics. More frequent and specialized assessments are tailored to each child if development is not on track. • Lifelong case management to help affected individuals gain access to social services and assistive devices for the blind ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Lenz microphthalmia syndrome (LMS), the following evaluations are recommended: Physical examination for the presence of anomalies associated with the disorder Cranial MRI to estimate the size of the globes for prognosis regarding potential visual function and to detect concurrent CNS malformations such as hypoplastic corpus callosum and cingulate gyrus Visual evoked response testing and ophthalmologic examination to help determine visual acuity and/or the potential for vision Consideration of echocardiogram if physical exam detects findings suggestive of a congenital cardiac malformation. (A single case report from Japan described an infant with a molecularly confirmed LMS (BCOR p.Pro85Leu) dying of an unspecified cardiac defect at age six months [ Renal ultrasound examination to evaluate for renal aplasia, hypoplasia, and hydroureter Consideration of hearing evaluation during infancy if: Head and neck examination reveals malformations of the auricle or ear canal, presence of skin tags or dimples around the ear, presence of cleft lip or palate, asymmetric facies, and microcephaly The parents have concerns that the child cannot hear (e.g., infant does not startle to loud noises, awaken to sound). The type of examination should be adjusted for the individual's cognitive level to allow for cooperation and maximize the chance of an informative test (see Consideration of sleep evaluation if parents report excessive daytime somnolence, altered sleep-wake cycles, difficulty awakening the child or getting the child to fall asleep, apnea, loud snoring, and/or difficulty breathing while asleep Clinical genetics consultation • Physical examination for the presence of anomalies associated with the disorder • Cranial MRI to estimate the size of the globes for prognosis regarding potential visual function and to detect concurrent CNS malformations such as hypoplastic corpus callosum and cingulate gyrus • Visual evoked response testing and ophthalmologic examination to help determine visual acuity and/or the potential for vision • Consideration of echocardiogram if physical exam detects findings suggestive of a congenital cardiac malformation. (A single case report from Japan described an infant with a molecularly confirmed LMS (BCOR p.Pro85Leu) dying of an unspecified cardiac defect at age six months [ • Renal ultrasound examination to evaluate for renal aplasia, hypoplasia, and hydroureter • Consideration of hearing evaluation during infancy if: • Head and neck examination reveals malformations of the auricle or ear canal, presence of skin tags or dimples around the ear, presence of cleft lip or palate, asymmetric facies, and microcephaly • The parents have concerns that the child cannot hear (e.g., infant does not startle to loud noises, awaken to sound). The type of examination should be adjusted for the individual's cognitive level to allow for cooperation and maximize the chance of an informative test (see • Head and neck examination reveals malformations of the auricle or ear canal, presence of skin tags or dimples around the ear, presence of cleft lip or palate, asymmetric facies, and microcephaly • The parents have concerns that the child cannot hear (e.g., infant does not startle to loud noises, awaken to sound). The type of examination should be adjusted for the individual's cognitive level to allow for cooperation and maximize the chance of an informative test (see • Consideration of sleep evaluation if parents report excessive daytime somnolence, altered sleep-wake cycles, difficulty awakening the child or getting the child to fall asleep, apnea, loud snoring, and/or difficulty breathing while asleep • Clinical genetics consultation • Head and neck examination reveals malformations of the auricle or ear canal, presence of skin tags or dimples around the ear, presence of cleft lip or palate, asymmetric facies, and microcephaly • The parents have concerns that the child cannot hear (e.g., infant does not startle to loud noises, awaken to sound). The type of examination should be adjusted for the individual's cognitive level to allow for cooperation and maximize the chance of an informative test (see ## Treatment of Manifestations Individuals with anophthalmos or extreme microphthalmos benefit from regular evaluations by an ocularist for placement of serial enlarging orbital expanders to prevent deformation of facial structures and to encourage normal development of eye lashes and lid margins. Early intervention with physical therapy and occupational therapy helps to address disturbances of the sleep-wake cycle caused by lack of light perception and problems of delayed gross motor development often observed in children with visual impairment. Early intervention with special education maximizes cognitive development. Referral to services for the visually impaired is recommended. Treatment for hearing loss and sleep disorders is dependent on the specific defect and similar to the general population. Referral to a sleep disorder specialist may be necessary depending on the individual's history and presentation to determine the appropriate tests. Dental examinations and cleaning should be instituted to monitor dental hygiene, especially when the affected individual has cognitive developmental delay. Missing and irregularly shaped teeth and wide spacing of teeth are common. Treatment is the same as for the general population in restoring masticatory function. ## Prevention of Secondary Complications No special preventative care is recommended. Follow-up care is personalized based on the physical impairments found in the individual. ## Surveillance The following are appropriate: Annual ophthalmologic examination for those with residual vision given the predisposition to glaucoma and high hyperopia from foreshortening of the globe Monitoring of renal function (BUN, creatinine, and urine analysis) in those with known renal/ureteral anomalies Developmental assessments performed with each well-child visit as recommended by the American Academy of Pediatrics. More frequent and specialized assessments are tailored to each child if development is not on track. Lifelong case management to help affected individuals gain access to social services and assistive devices for the blind • Annual ophthalmologic examination for those with residual vision given the predisposition to glaucoma and high hyperopia from foreshortening of the globe • Monitoring of renal function (BUN, creatinine, and urine analysis) in those with known renal/ureteral anomalies • Developmental assessments performed with each well-child visit as recommended by the American Academy of Pediatrics. More frequent and specialized assessments are tailored to each child if development is not on track. • Lifelong case management to help affected individuals gain access to social services and assistive devices for the blind ## Agents/Circumstances to Avoid In those with residual vision, dilating drops and medications that may dilate the pupils (i.e., antihistamines, decongestants, tricyclic antidepressants) should be used in consultation with an ophthalmologist because of the narrow anterior chamber and risk for angle closure glaucoma. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Lenz microphthalmia syndrome is inherited in an X-linked manner. The father of an affected male will neither have the disease nor be a carrier of a In a family with more than one affected male, the mother of an affected male is an obligate carrier. If only one male in the family is affected, the mother may be a carrier or the affected male may have a To date there are no reports of germline mosaicism in a mother. 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 pathogenic variant 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 germline mosaicism. Carrier testing for at-risk females requires prior identification of the Note: Carriers are heterozygous for this X-linked disorder and are generally asymptomatic (see The optimal time for discussion 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 father of an affected male will neither have the disease nor be a carrier of a • In a family with more than one affected male, the mother of an affected male is an obligate carrier. • If only one male in the family is affected, the mother may be a carrier or the affected male may have a • To date there are no reports of germline mosaicism in a mother. • 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 pathogenic variant 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 germline mosaicism. • The optimal time for discussion 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 Lenz microphthalmia syndrome is inherited in an X-linked manner. ## Risk to Family Members The father of an affected male will neither have the disease nor be a carrier of a In a family with more than one affected male, the mother of an affected male is an obligate carrier. If only one male in the family is affected, the mother may be a carrier or the affected male may have a To date there are no reports of germline mosaicism in a mother. 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 pathogenic variant 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 germline mosaicism. • The father of an affected male will neither have the disease nor be a carrier of a • In a family with more than one affected male, the mother of an affected male is an obligate carrier. • If only one male in the family is affected, the mother may be a carrier or the affected male may have a • To date there are no reports of germline mosaicism in a mother. • 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 pathogenic variant 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 germline mosaicism. ## Carrier Detection Carrier testing for at-risk females requires prior identification of the Note: Carriers are heterozygous for this X-linked disorder and are generally asymptomatic (see ## Related Genetic Counseling Issues The optimal time for discussion 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 discussion 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 ## Resources c/o Center for Developmental Medicine and Genetics 5501 Old York Road Genetics, Levy 2 West Philadelphia PA 19141 31 Center Drive MSC 2510 Bethesda MD 20892-2510 200 East Wells Street (at Jernigan Place) Baltimore MD 21230 • • • • c/o Center for Developmental Medicine and Genetics • 5501 Old York Road • Genetics, Levy 2 West • Philadelphia PA 19141 • • • 31 Center Drive • MSC 2510 • Bethesda MD 20892-2510 • • • 200 East Wells Street • (at Jernigan Place) • Baltimore MD 21230 • ## Molecular Genetics Lenz Microphthalmia Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Lenz Microphthalmia Syndrome ( Variants listed in the table have been provided by the author. Variants listed in the table have been provided by the author. ## References ## Literature Cited ## Chapter Notes 7 November 2019 (ma) Chapter retired: extremely rare 2 October 2014 (me) Comprehensive update posted live 29 April 2010 (me) Comprehensive update posted live 27 July 2007 (cd) Revision: clinical testing for 6 September 2006 (cd) Revision: FISH, mutation scanning, linkage analysis, and X-chromosome inactivation studies no longer clinically available for 23 June 2006 (ca) Comprehensive update posted live 12 April 2005 (dn) Revision: 13 May 2004 (me) Comprehensive update posted live 5 February 2004 (dn) Revision: Molecular Genetics 4 June 2002 (me) Review posted live 8 February 2002 (dn) Original submission Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the • 7 November 2019 (ma) Chapter retired: extremely rare • 2 October 2014 (me) Comprehensive update posted live • 29 April 2010 (me) Comprehensive update posted live • 27 July 2007 (cd) Revision: clinical testing for • 6 September 2006 (cd) Revision: FISH, mutation scanning, linkage analysis, and X-chromosome inactivation studies no longer clinically available for • 23 June 2006 (ca) Comprehensive update posted live • 12 April 2005 (dn) Revision: • 13 May 2004 (me) Comprehensive update posted live • 5 February 2004 (dn) Revision: Molecular Genetics • 4 June 2002 (me) Review posted live • 8 February 2002 (dn) Original submission ## Revision History 7 November 2019 (ma) Chapter retired: extremely rare 2 October 2014 (me) Comprehensive update posted live 29 April 2010 (me) Comprehensive update posted live 27 July 2007 (cd) Revision: clinical testing for 6 September 2006 (cd) Revision: FISH, mutation scanning, linkage analysis, and X-chromosome inactivation studies no longer clinically available for 23 June 2006 (ca) Comprehensive update posted live 12 April 2005 (dn) Revision: 13 May 2004 (me) Comprehensive update posted live 5 February 2004 (dn) Revision: Molecular Genetics 4 June 2002 (me) Review posted live 8 February 2002 (dn) Original submission Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the • 7 November 2019 (ma) Chapter retired: extremely rare • 2 October 2014 (me) Comprehensive update posted live • 29 April 2010 (me) Comprehensive update posted live • 27 July 2007 (cd) Revision: clinical testing for • 6 September 2006 (cd) Revision: FISH, mutation scanning, linkage analysis, and X-chromosome inactivation studies no longer clinically available for • 23 June 2006 (ca) Comprehensive update posted live • 12 April 2005 (dn) Revision: • 13 May 2004 (me) Comprehensive update posted live • 5 February 2004 (dn) Revision: Molecular Genetics • 4 June 2002 (me) Review posted live • 8 February 2002 (dn) Original submission	[ "T. Arnesen. Protein N-terminal acetylation: NAT 2007-2008 Symposia.. BMC Proc. 2009;3:S1", "T Esmailpour, H Riazifar, L Liu, S Donkervoort, VH Huang, S Madaan, BM Shoucri, A Busch, J Wu, A Towbin, RB Chadwick, A Sequeira, MP Vawter, G Sun, JJ Johnston, LG Biesecker, R Kawaguchi, H Sun, V Kimonis, T Huang. A splice donor mutation in NAA10 results in the dysregulation of the retinoic acid signalling pathway and causes Lenz microphthalmia syndrome.. J Med Genet 2014;51:185-96", "S Forrester, MJ Kovach, NM Reynolds, R Urban, V Kimonis. Manifestations in four males with and an obligate carrier of the Lenz microphthalmia syndrome.. Am J Med Genet 2001;98:92-100", "CA Graham, RM Redmond, NC Nevin. X-linked clinical anophthalmos. Localization of the gene to Xq27-Xq28.. Ophthalmic Paediatr Genet 1991;12:43-8", "E Hilton, J Johnston, S Whalen, N Okamoto, Y Hatsukawa, J Nishio, H Kohara, Y Hirano, S Mizuno, C Torii, K Kosaki, S Manouvrier, O Boute, R Perveen, C Law, A Moore, D Fitzpatrick, J Lemke, F Fellmann, FG Debray, F Dastot-Le-Moal, M Gerard, J Martin, P Bitoun, M Goossens, A Verloes, A Schinzel, D Bartholdi, T Bardakjian, B Hay, K Jenny, K Johnston, M Lyons, JW Belmont, LG Biesecker, I Giurgea, G Black. BCOR analysis in patients with OFCD and Lenz microphthalmia syndromes, mental retardation with ocular anomalies, and cardiac laterality defects.. Eur J Hum Genet 2009;17:1325-35", "D Horn, M Chyrek, S Kleier, S Lüttgen, H Bolz, GK Hinkel, GC Korenke, A Riess, C Schell-Apacik, S Tinschert, D Wieczorek, G Gillessen-Kaesbach, K Kutsche. Novel mutations in BCOR in three patients with oculo-facio-cardio-dental syndrome, but none in Lenz microphthalmia syndrome.. Eur J Hum Genet. 2005;13:563-9", "DM Lehman, WE Sponsel, RF Stratton, J Mensah, JC Macdonald, TL Johnson-Pais, H Coon, XT Reveles, JD Cody, RJ Leach. Genetic mapping of a novel X-linked recessive colobomatous microphthalmia.. Am J Med Genet 2001;101:114-9", "D Ng, DW Hadley, CJ Tifft, LG Biesecker. Genetic heterogeneity of syndromic X-linked recessive microphthalmia-anophthalmia: is Lenz microphthalmia a single disorder?. Am J Med Genet 2002;110:308-14", "D Ng, N Thakker, CM Corcoran, D Donnai, R Perveen, A Schneider, DW Hadley, C Tifft, L Zhang, AO Wilkie, JJ van der Smagt, RJ Gorlin, SM Burgess, VJ Bardwell, GC Black, LG Biesecker. Oculofaciocardiodental and Lenz microphthalmia syndromes result from distinct classes of mutations in BCOR.. Nat Genet 2004;36:411-6", "S Oberoi, AE Winder, J Johnston, K Vargervik, AM Slavotinek. Case reports of oculofaciocardiodental syndrome with unusual dental findings.. Am J Med Genet A 2005;136:275-7", "AF Rope, K Wang, R Evjenth, J Xing, JJ Johnston, JJ Swensen, WE Johnson, B Moore, CD Huff, LM Bird, JC Carey, JM Opitz, CA Stevens, T Jiang, C Schank, HD Fain, R Robison, B Dalley, S Chin, ST South, TJ Pysher, LB Jorde, H Hakonarson, JR Lillehaug, LG Biesecker, M Yandell, T Arnesen, GJ Lyon. Using VAAST to identify an X-linked disorder resulting in lethality in male infants due to N-terminal acetyltransferase deficiency.. Am J Hum Genet. 2011;89:28-43", "AF Scott, DW Mohr, LM Kasch, JA Barton, R Pittiglio, R Ingersoll, B Craig, BA Marosy, KF Doheny, WC Bromley, TH Roderick, N Chassaing, P Calvas, SS Prabhu, EW Jabs. Identification of an HMGB3 frameshift mutation in a family with an X-linked colobomatous microphthalmia syndrome using whole-genome and X-exome sequencing.. JAMA Ophthalmol. 2014;132:1215-20", "KK Starheim, D Gromyko, R Velde, JE Varhaug, T Arnesen. Composition and biological significance of the human Nalpha-terminal acetyltransferases.. BMC Proc. 2009;3:S3", "N Suzumori, T Kaname, Y Muramatsu, K Yanagi, K Kumagai, S Mizuno, K Naritomi, S Saitoh, M Sugiura-Ogasawara. Prenatal diagnosis of X-linked recessive Lenz microphthalmia.. J Obstet Gynaecol Res 2013;39:1545-7" ]	4/6/2002	2/10/2014	29/7/2007	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
leopard	leopard	[ "LEOPARD Syndrome", "Multiple Lentigines Syndrome", "Multiple Lentigines Syndrome", "LEOPARD Syndrome", "Dual specificity mitogen-activated protein kinase kinase 1", "RAF proto-oncogene serine/threonine-protein kinase", "Serine/threonine-protein kinase B-raf", "Tyrosine-protein phosphatase non-receptor type 11", "BRAF", "MAP2K1", "PTPN11", "RAF1", "Noonan Syndrome with Multiple Lentigines" ]	Noonan Syndrome with Multiple Lentigines	Bruce D Gelb, Marco Tartaglia	Summary Noonan syndrome with multiple lentigines (NSML) is a condition in which the cardinal features consist of lentigines, hypertrophic cardiomyopathy, short stature, pectus deformity, and dysmorphic facial features including widely spaced eyes and ptosis. Multiple lentigines present as dispersed flat, black-brown macules, mostly on the face, neck, and upper part of the trunk with sparing of the mucosa. In general, lentigines do not appear until age four to five years but then increase to the thousands by puberty. Some individuals with NSML do not exhibit lentigines. Approximately 85% of affected individuals have heart defects, including hypertrophic cardiomyopathy (typically appearing during infancy and sometimes progressive) and pulmonary valve stenosis. Postnatal growth restriction resulting in short stature occurs in fewer than 50% of affected persons, although most affected individuals have a height that is less than the 25th centile for age. Sensorineural hearing deficits, present in approximately 20% of affected individuals, are poorly characterized. Intellectual disability, typically mild, is observed in approximately 30% of persons with NSML. The clinical diagnosis of Noonan syndrome with multiple lentigines can be established in a proband with multiple lentigines plus two other cardinal features (cardiac abnormalities; poor linear growth / short stature; pectus deformity; and dysmorphic facial features including widely spaced eyes and ptosis) OR, in the absence of lentigines, three of the other cardinal manifestations plus an affected first-degree relative. The molecular diagnosis can be established in a proband with suggestive findings and a heterozygous pathogenic variant in one of four genes ( NSML is inherited in an autosomal dominant manner. A proband with NSML may have the disorder as the result of a	## Diagnosis Suggested clinical diagnostic criteria for Noonan syndrome with multiple lentigines (NSML) have been published [ NSML Lentigines Cardiac abnormalities, particularly hypertrophic cardiomyopathy Poor linear growth / short stature Pectus deformity Dysmorphic facial features including widely spaced eyes and ptosis Additional features occurring frequently in NSML: Variable degree of cognitive deficits Sensorineural hearing loss Cryptorchidism Skeletal anomalies Café au lait macules Family history consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations) Note: Absence of a known family history does not preclude the diagnosis. The clinical diagnosis of NSML can be established in a proband based on clinical criteria [ Multiple lentigines plus two of the other In the absence of lentigines, three of the other cardinal features plus a first-degree relative with NSML [ 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 variant of uncertain significance in one of the genes listed in Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in When the phenotypic and family history findings suggest the diagnosis of NSML, molecular genetic testing approaches can include use of a For an introduction to multigene panels click When the diagnosis of NSML has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Noonan Syndrome with Multiple Lentigines 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. Sequence analysis of all coding exons detected pathogenic missense variants in two individuals with clinical features of NSML [ No exon or whole-gene deletion or duplication involving Sequence analysis of all coding exons detected pathogenic missense variants in one individual with clinical features of NSML [ Most pathogenic variants causing NSML are identified in exons 7, 12, and 13 [ Sequence analysis of coding exons 6, 13, and 16 detects all reported pathogenic missense variants [ It is likely that one or more additional, as-yet undefined genes, possibly related to RAS signal transduction, are associated with a small proportion of individuals with NSML in whom no pathogenic variant has been identified in • Lentigines • Cardiac abnormalities, particularly hypertrophic cardiomyopathy • Poor linear growth / short stature • Pectus deformity • Dysmorphic facial features including widely spaced eyes and ptosis • Variable degree of cognitive deficits • Sensorineural hearing loss • Cryptorchidism • Skeletal anomalies • Café au lait macules • Family history consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations) • Note: Absence of a known family history does not preclude the diagnosis. • Multiple lentigines plus two of the other • In the absence of lentigines, three of the other cardinal features plus a first-degree relative with NSML [ ## Suggestive Findings NSML Lentigines Cardiac abnormalities, particularly hypertrophic cardiomyopathy Poor linear growth / short stature Pectus deformity Dysmorphic facial features including widely spaced eyes and ptosis Additional features occurring frequently in NSML: Variable degree of cognitive deficits Sensorineural hearing loss Cryptorchidism Skeletal anomalies Café au lait macules Family history consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations) Note: Absence of a known family history does not preclude the diagnosis. • Lentigines • Cardiac abnormalities, particularly hypertrophic cardiomyopathy • Poor linear growth / short stature • Pectus deformity • Dysmorphic facial features including widely spaced eyes and ptosis • Variable degree of cognitive deficits • Sensorineural hearing loss • Cryptorchidism • Skeletal anomalies • Café au lait macules • Family history consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations) • Note: Absence of a known family history does not preclude the diagnosis. ## Establishing the Diagnosis The clinical diagnosis of NSML can be established in a proband based on clinical criteria [ Multiple lentigines plus two of the other In the absence of lentigines, three of the other cardinal features plus a first-degree relative with NSML [ 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 variant of uncertain significance in one of the genes listed in Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in When the phenotypic and family history findings suggest the diagnosis of NSML, molecular genetic testing approaches can include use of a For an introduction to multigene panels click When the diagnosis of NSML has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Noonan Syndrome with Multiple Lentigines 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. Sequence analysis of all coding exons detected pathogenic missense variants in two individuals with clinical features of NSML [ No exon or whole-gene deletion or duplication involving Sequence analysis of all coding exons detected pathogenic missense variants in one individual with clinical features of NSML [ Most pathogenic variants causing NSML are identified in exons 7, 12, and 13 [ Sequence analysis of coding exons 6, 13, and 16 detects all reported pathogenic missense variants [ It is likely that one or more additional, as-yet undefined genes, possibly related to RAS signal transduction, are associated with a small proportion of individuals with NSML in whom no pathogenic variant has been identified in • Multiple lentigines plus two of the other • In the absence of lentigines, three of the other cardinal features plus a first-degree relative with NSML [ ## Option 1 When the phenotypic and family history findings suggest the diagnosis of NSML, molecular genetic testing approaches can include use of a For an introduction to multigene panels click ## Option 2 When the diagnosis of NSML has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Noonan Syndrome with Multiple Lentigines 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. Sequence analysis of all coding exons detected pathogenic missense variants in two individuals with clinical features of NSML [ No exon or whole-gene deletion or duplication involving Sequence analysis of all coding exons detected pathogenic missense variants in one individual with clinical features of NSML [ Most pathogenic variants causing NSML are identified in exons 7, 12, and 13 [ Sequence analysis of coding exons 6, 13, and 16 detects all reported pathogenic missense variants [ It is likely that one or more additional, as-yet undefined genes, possibly related to RAS signal transduction, are associated with a small proportion of individuals with NSML in whom no pathogenic variant has been identified in ## Clinical Characteristics To date, more than 150 individuals with Noonan syndrome with multiple lentigines (NSML) have been reported. Noonan Syndrome with Multiple Lentigines: Frequency of Select Features NSML = Noonan syndrome with multiple lentigines Café au lait macules are also observed in up to 70%-80% of affected individuals [ Skin hyperelasticity has also been described. Neurofibromas have been described but are rare. Hypertrophic cardiomyopathy is detected in up to 70% of individuals with heart defects (compared to 25% in NS). It most commonly appears during infancy and can be progressive. Pulmonary valve stenosis is noted in approximately 25% of affected individuals. Abnormalities of the aortic and mitral valves are also observed in a minority of persons with NSML. EKG abnormalities, aside from those typically associated with hypertrophic cardiomyopathy, include conduction defects (23%). One reported individual with NSML, who had a pathogenic variant in A second affected individual, who had a pathogenic variant in Three individuals had leukemia; all 3 had a germline pathogenic variant in One individual had neuroblastoma and one had cerebellar meduloblastoma; both had a germline pathogenic c.1402C>T (p.Thr468Met) One individual with a clinical diagnosis of NSML had a unilateral corneal choristoma. No genotype-phenotype correlations for NSML was referred to as cardiomyopathic lentiginosis in the older medical literature. It was also formerly referred to by the acronym LEOPARD syndrome; this designation is no longer considered appropriate. The population prevalence of NSML is not known. • Café au lait macules are also observed in up to 70%-80% of affected individuals [ • Skin hyperelasticity has also been described. • Neurofibromas have been described but are rare. • Hypertrophic cardiomyopathy is detected in up to 70% of individuals with heart defects (compared to 25% in NS). It most commonly appears during infancy and can be progressive. • Pulmonary valve stenosis is noted in approximately 25% of affected individuals. Abnormalities of the aortic and mitral valves are also observed in a minority of persons with NSML. • EKG abnormalities, aside from those typically associated with hypertrophic cardiomyopathy, include conduction defects (23%). • One reported individual with NSML, who had a pathogenic variant in • A second affected individual, who had a pathogenic variant in • One reported individual with NSML, who had a pathogenic variant in • A second affected individual, who had a pathogenic variant in • Three individuals had leukemia; all 3 had a germline pathogenic variant in • One individual had neuroblastoma and one had cerebellar meduloblastoma; both had a germline pathogenic c.1402C>T (p.Thr468Met) • One individual with a clinical diagnosis of NSML had a unilateral corneal choristoma. • Three individuals had leukemia; all 3 had a germline pathogenic variant in • One individual had neuroblastoma and one had cerebellar meduloblastoma; both had a germline pathogenic c.1402C>T (p.Thr468Met) • One individual with a clinical diagnosis of NSML had a unilateral corneal choristoma. • One reported individual with NSML, who had a pathogenic variant in • A second affected individual, who had a pathogenic variant in • Three individuals had leukemia; all 3 had a germline pathogenic variant in • One individual had neuroblastoma and one had cerebellar meduloblastoma; both had a germline pathogenic c.1402C>T (p.Thr468Met) • One individual with a clinical diagnosis of NSML had a unilateral corneal choristoma. ## Clinical Description To date, more than 150 individuals with Noonan syndrome with multiple lentigines (NSML) have been reported. Noonan Syndrome with Multiple Lentigines: Frequency of Select Features NSML = Noonan syndrome with multiple lentigines Café au lait macules are also observed in up to 70%-80% of affected individuals [ Skin hyperelasticity has also been described. Neurofibromas have been described but are rare. Hypertrophic cardiomyopathy is detected in up to 70% of individuals with heart defects (compared to 25% in NS). It most commonly appears during infancy and can be progressive. Pulmonary valve stenosis is noted in approximately 25% of affected individuals. Abnormalities of the aortic and mitral valves are also observed in a minority of persons with NSML. EKG abnormalities, aside from those typically associated with hypertrophic cardiomyopathy, include conduction defects (23%). One reported individual with NSML, who had a pathogenic variant in A second affected individual, who had a pathogenic variant in Three individuals had leukemia; all 3 had a germline pathogenic variant in One individual had neuroblastoma and one had cerebellar meduloblastoma; both had a germline pathogenic c.1402C>T (p.Thr468Met) One individual with a clinical diagnosis of NSML had a unilateral corneal choristoma. • Café au lait macules are also observed in up to 70%-80% of affected individuals [ • Skin hyperelasticity has also been described. • Neurofibromas have been described but are rare. • Hypertrophic cardiomyopathy is detected in up to 70% of individuals with heart defects (compared to 25% in NS). It most commonly appears during infancy and can be progressive. • Pulmonary valve stenosis is noted in approximately 25% of affected individuals. Abnormalities of the aortic and mitral valves are also observed in a minority of persons with NSML. • EKG abnormalities, aside from those typically associated with hypertrophic cardiomyopathy, include conduction defects (23%). • One reported individual with NSML, who had a pathogenic variant in • A second affected individual, who had a pathogenic variant in • One reported individual with NSML, who had a pathogenic variant in • A second affected individual, who had a pathogenic variant in • Three individuals had leukemia; all 3 had a germline pathogenic variant in • One individual had neuroblastoma and one had cerebellar meduloblastoma; both had a germline pathogenic c.1402C>T (p.Thr468Met) • One individual with a clinical diagnosis of NSML had a unilateral corneal choristoma. • Three individuals had leukemia; all 3 had a germline pathogenic variant in • One individual had neuroblastoma and one had cerebellar meduloblastoma; both had a germline pathogenic c.1402C>T (p.Thr468Met) • One individual with a clinical diagnosis of NSML had a unilateral corneal choristoma. • One reported individual with NSML, who had a pathogenic variant in • A second affected individual, who had a pathogenic variant in • Three individuals had leukemia; all 3 had a germline pathogenic variant in • One individual had neuroblastoma and one had cerebellar meduloblastoma; both had a germline pathogenic c.1402C>T (p.Thr468Met) • One individual with a clinical diagnosis of NSML had a unilateral corneal choristoma. ## Genotype-Phenotype Correlations No genotype-phenotype correlations for ## Nomenclature NSML was referred to as cardiomyopathic lentiginosis in the older medical literature. It was also formerly referred to by the acronym LEOPARD syndrome; this designation is no longer considered appropriate. ## Prevalence The population prevalence of NSML is not known. ## Genetically Related (Allelic) Disorders The phenotypic overlap that occurs in individuals with germline pathogenic variants in genes causing Noonan syndrome with multiple lentigines (NSML), Noonan syndrome (NS), and cardiofaciocutaneous syndrome (CFCS) (see Allelic Disorders in the Differential Diagnosis of Noonan Syndrome with Multiple Lentigines CFCS & NSML have similar cardiac findings; however, in CFCS, ID is usually more severe, w/higher likelihood of structural CNS anomalies & seizures; more skin pathology; & more severe & long-lasting GI problems. In CFCS, facial appearance tends to be coarser; dolichocephaly & absent eyebrows are more common; & blue eyes are less common than in NS. The proportion of CFCS attributed to pathogenic variants in NS is typically assoc w/short stature, congenital heart defect, broad or webbed neck, pectus deformities, variable DD, cryptorchidism, & characteristic facies. NS shows significant overlap w/NSML, but affected persons are unlikely to be deaf or to have profusion of pigmented lesions, lentigines, & café au lait patches. The proportion of NS attributed to pathogenic variants in CNS = central nervous system; DD = developmental delay; GI = gastrointestinal; ID = intellectual disability; NSML = Noonan syndrome with multiple lentigines • CFCS & NSML have similar cardiac findings; however, in CFCS, ID is usually more severe, w/higher likelihood of structural CNS anomalies & seizures; more skin pathology; & more severe & long-lasting GI problems. In CFCS, facial appearance tends to be coarser; dolichocephaly & absent eyebrows are more common; & blue eyes are less common than in NS. • The proportion of CFCS attributed to pathogenic variants in • NS is typically assoc w/short stature, congenital heart defect, broad or webbed neck, pectus deformities, variable DD, cryptorchidism, & characteristic facies. NS shows significant overlap w/NSML, but affected persons are unlikely to be deaf or to have profusion of pigmented lesions, lentigines, & café au lait patches. • The proportion of NS attributed to pathogenic variants in ## Differential Diagnosis Noonan syndrome with multiple lentigines (NSML) should be distinguished from Turner syndrome, Williams syndrome, and monogenic disorders with developmental delay, short stature, congenital heart defects, and distinctive facies (see Monogenic Disorders of Interest in the Differential Diagnosis of Noonan Syndrome with Multiple Lentigines AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; GI = gastrointestinal; ID = intellectual disability; JMML = juvenile myelomonocytic leukemia; MOI = mode of inheritance; NSML = Noonan syndrome with multiple lentigines; XL = X-linked NS is most often inherited in an autosomal dominant manner. NS caused by pathogenic variants in Because of the significant phenotypic overlap with classic NS, most RASopathy diagnostic gene panels include testing for the common ## Management No clinical practice guidelines for Noonan syndrome with multiple lentigines (NSML) have been published. To establish the extent of disease and needs in an individual diagnosed with NSML, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Noonan Syndrome with Multiple Lentigines To incl motor, adaptive, cognitive, & speech/language eval Eval for early intervention / special education Community or Social work involvement for parental support; Home nursing referral. MOI = mode of inheritance; NSML = Noonan syndrome with multiple lentigines Complete assessment of auditory acuity using age-appropriate tests (e.g., ABR testing, auditory steady-state response [ASSR] testing, pure-tone audiometry). Medical geneticist, certified genetic counselor, certified advanced genetic nurse Treatment of Manifestations in Individuals with Noonan Syndrome with Multiple Lentigines Growth hormone therapy may be contraindicated in persons w/HCM. Prior to instituting growth hormone therapy, cardiac eval for HCM is recommended; continued surveillance for development of HCM while on growth hormone therapy is reasonable. 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. HCM = hypertrophic cardiomyopathy; NSML = Noonan syndrome with multiple lentigines 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. Not everyone with NSML will have developmental delay. The following recommendations apply to those in whom neurodevelopmental delays have been noted. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Recommended Surveillance for Individuals with Noonan Syndrome with Multiple Lentigines For individuals with hypertrophic cardiomyopathy: Treatment with growth hormone must be undertaken with great caution – if at all – to avoid exacerbating a cardiac condition; Certain physical activities may be curtailed in order to reduce the risk of sudden cardiac death. It is appropriate to evaluate relatives at risk in order to identify as early as possible those with hypertrophic cardiomyopathy who would benefit from initiation of treatment and preventive measures. If the If the pathogenic variant in the family is not known, a thorough physical examination with particular attention to the features of NSML may clarify the disease status of at-risk relatives. If NSML is suspected, a cardiology evaluation with echocardiogram is recommended. See For affected women, cardiac status should be monitored during pregnancy. Those with hypertrophic cardiomyopathy or valve dysfunction may be at risk for the development or exacerbation of heart failure during pregnancy, especially during the second and third trimesters. Some affected pregnant women may be on medications for their cardiovascular issues. See Search • To incl motor, adaptive, cognitive, & speech/language eval • Eval for early intervention / special education • Community or • Social work involvement for parental support; • Home nursing referral. • Growth hormone therapy may be contraindicated in persons w/HCM. • Prior to instituting growth hormone therapy, cardiac eval for HCM is recommended; continued surveillance for development of HCM while on growth hormone therapy is reasonable. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or Special Olympics. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Treatment with growth hormone must be undertaken with great caution – if at all – to avoid exacerbating a cardiac condition; • Certain physical activities may be curtailed in order to reduce the risk of sudden cardiac death. • If the • If the pathogenic variant in the family is not known, a thorough physical examination with particular attention to the features of NSML may clarify the disease status of at-risk relatives. If NSML is suspected, a cardiology evaluation with echocardiogram is recommended. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with NSML, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Noonan Syndrome with Multiple Lentigines To incl motor, adaptive, cognitive, & speech/language eval Eval for early intervention / special education Community or Social work involvement for parental support; Home nursing referral. MOI = mode of inheritance; NSML = Noonan syndrome with multiple lentigines Complete assessment of auditory acuity using age-appropriate tests (e.g., ABR testing, auditory steady-state response [ASSR] testing, pure-tone audiometry). Medical geneticist, certified genetic counselor, certified advanced genetic nurse • To incl motor, adaptive, cognitive, & speech/language eval • Eval for early intervention / special education • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Treatment of Manifestations in Individuals with Noonan Syndrome with Multiple Lentigines Growth hormone therapy may be contraindicated in persons w/HCM. Prior to instituting growth hormone therapy, cardiac eval for HCM is recommended; continued surveillance for development of HCM while on growth hormone therapy is reasonable. 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. HCM = hypertrophic cardiomyopathy; NSML = Noonan syndrome with multiple lentigines 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. Not everyone with NSML will have developmental delay. The following recommendations apply to those in whom neurodevelopmental delays have been noted. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • Growth hormone therapy may be contraindicated in persons w/HCM. • Prior to instituting growth hormone therapy, cardiac eval for HCM is recommended; continued surveillance for development of HCM while on growth hormone therapy is reasonable. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or Special Olympics. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## 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. Not everyone with NSML will have developmental delay. The following recommendations apply to those in whom neurodevelopmental delays have been noted. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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 ## Surveillance Recommended Surveillance for Individuals with Noonan Syndrome with Multiple Lentigines ## Agents/Circumstances to Avoid For individuals with hypertrophic cardiomyopathy: Treatment with growth hormone must be undertaken with great caution – if at all – to avoid exacerbating a cardiac condition; Certain physical activities may be curtailed in order to reduce the risk of sudden cardiac death. • Treatment with growth hormone must be undertaken with great caution – if at all – to avoid exacerbating a cardiac condition; • Certain physical activities may be curtailed in order to reduce the risk of sudden cardiac death. ## Evaluation of Relatives at Risk It is appropriate to evaluate relatives at risk in order to identify as early as possible those with hypertrophic cardiomyopathy who would benefit from initiation of treatment and preventive measures. If the If the pathogenic variant in the family is not known, a thorough physical examination with particular attention to the features of NSML may clarify the disease status of at-risk relatives. If NSML is suspected, a cardiology evaluation with echocardiogram is recommended. See • If the • If the pathogenic variant in the family is not known, a thorough physical examination with particular attention to the features of NSML may clarify the disease status of at-risk relatives. If NSML is suspected, a cardiology evaluation with echocardiogram is recommended. ## Pregnancy Management For affected women, cardiac status should be monitored during pregnancy. Those with hypertrophic cardiomyopathy or valve dysfunction may be at risk for the development or exacerbation of heart failure during pregnancy, especially during the second and third trimesters. Some affected pregnant women may be on medications for their cardiovascular issues. See ## Therapies Under Investigation Search ## Genetic Counseling Noonan syndrome with multiple lentigines (NSML) is inherited in an autosomal dominant manner. Some individuals diagnosed with NSML have an affected parent. (Note: Because NSML is associated with variable expressivity and the manifestations of the disorder are frequently subtle, many affected adults are diagnosed only after the birth of a more obviously affected infant.) A proband with NSML may have the disorder as the result of a If the proband is the only family member known to be affected with NSML, recommended evaluations of both parents include: Molecular genetic testing if the NSML-causing pathogenic variant in the proband is known; A thorough physical examination with particular attention to the features of NSML if the NSML-causing pathogenic variant in the proband is not known. If NSML is suspected, a cardiology evaluation with echocardiogram is recommended. If the proband has an NSML-related pathogenic variant that is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present only in the germ cells. The family history of some individuals diagnosed with NSML may appear to be negative because of failure to recognize the disorder in affected family members. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband). If a parent 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 there can be significant intrafamilial variability, sibs may not have the same phenotypic findings as other affected family members. If the proband has a known NSML-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 (based on appropriate clinical evaluation) 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 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. Once the NSML-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 within families regarding the use 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 NSML have an affected parent. (Note: Because NSML is associated with variable expressivity and the manifestations of the disorder are frequently subtle, many affected adults are diagnosed only after the birth of a more obviously affected infant.) • A proband with NSML may have the disorder as the result of a • If the proband is the only family member known to be affected with NSML, recommended evaluations of both parents include: • Molecular genetic testing if the NSML-causing pathogenic variant in the proband is known; • A thorough physical examination with particular attention to the features of NSML if the NSML-causing pathogenic variant in the proband is not known. If NSML is suspected, a cardiology evaluation with echocardiogram is recommended. • Molecular genetic testing if the NSML-causing pathogenic variant in the proband is known; • A thorough physical examination with particular attention to the features of NSML if the NSML-causing pathogenic variant in the proband is not known. If NSML is suspected, a cardiology evaluation with echocardiogram is recommended. • If the proband has an NSML-related pathogenic variant that is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present only in the germ cells. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present only in the germ cells. • The family history of some individuals diagnosed with NSML may appear to be negative because of failure to recognize the disorder in affected family members. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband). • Molecular genetic testing if the NSML-causing pathogenic variant in the proband is known; • A thorough physical examination with particular attention to the features of NSML if the NSML-causing pathogenic variant in the proband is not known. If NSML is suspected, a cardiology evaluation with echocardiogram is recommended. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present only in the germ cells. • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. • Because there can be significant intrafamilial variability, sibs may not have the same phenotypic findings as other affected family members. • If the proband has a known NSML-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 (based on appropriate clinical evaluation) 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 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. ## Mode of Inheritance Noonan syndrome with multiple lentigines (NSML) is inherited in an autosomal dominant manner. ## Risk to Family Members Some individuals diagnosed with NSML have an affected parent. (Note: Because NSML is associated with variable expressivity and the manifestations of the disorder are frequently subtle, many affected adults are diagnosed only after the birth of a more obviously affected infant.) A proband with NSML may have the disorder as the result of a If the proband is the only family member known to be affected with NSML, recommended evaluations of both parents include: Molecular genetic testing if the NSML-causing pathogenic variant in the proband is known; A thorough physical examination with particular attention to the features of NSML if the NSML-causing pathogenic variant in the proband is not known. If NSML is suspected, a cardiology evaluation with echocardiogram is recommended. If the proband has an NSML-related pathogenic variant that is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present only in the germ cells. The family history of some individuals diagnosed with NSML may appear to be negative because of failure to recognize the disorder in affected family members. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband). If a parent 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 there can be significant intrafamilial variability, sibs may not have the same phenotypic findings as other affected family members. If the proband has a known NSML-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 (based on appropriate clinical evaluation) 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 theoretic possibility of parental germline mosaicism. • Some individuals diagnosed with NSML have an affected parent. (Note: Because NSML is associated with variable expressivity and the manifestations of the disorder are frequently subtle, many affected adults are diagnosed only after the birth of a more obviously affected infant.) • A proband with NSML may have the disorder as the result of a • If the proband is the only family member known to be affected with NSML, recommended evaluations of both parents include: • Molecular genetic testing if the NSML-causing pathogenic variant in the proband is known; • A thorough physical examination with particular attention to the features of NSML if the NSML-causing pathogenic variant in the proband is not known. If NSML is suspected, a cardiology evaluation with echocardiogram is recommended. • Molecular genetic testing if the NSML-causing pathogenic variant in the proband is known; • A thorough physical examination with particular attention to the features of NSML if the NSML-causing pathogenic variant in the proband is not known. If NSML is suspected, a cardiology evaluation with echocardiogram is recommended. • If the proband has an NSML-related pathogenic variant that is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present only in the germ cells. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present only in the germ cells. • The family history of some individuals diagnosed with NSML may appear to be negative because of failure to recognize the disorder in affected family members. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband). • Molecular genetic testing if the NSML-causing pathogenic variant in the proband is known; • A thorough physical examination with particular attention to the features of NSML if the NSML-causing pathogenic variant in the proband is not known. If NSML is suspected, a cardiology evaluation with echocardiogram is recommended. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present only in the germ cells. • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. • Because there can be significant intrafamilial variability, sibs may not have the same phenotypic findings as other affected family members. • If the proband has a known NSML-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 (based on appropriate clinical evaluation) 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 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. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 NSML-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 within families regarding the use 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 Noonan Syndrome with Multiple Lentigines: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Noonan Syndrome with Multiple Lentigines ( Noonan syndrome with multiple lentigines (NSML) is a RASopathy, a class of disorders for which genetic variation alters proteins belonging to the RAS/mitogen-activated protein kinase (MAPK) signal transduction pathway. The pathogenic variants in Noonan Syndrome with Multiple Lentigines: Mechanism of Disease Causation Genes from Noonan Syndrome with Multiple Lentigines: Notable Pathogenic Variants by Gene Genes from Sporadic tumors (including leukemia and solid tumors) occurring as single tumors in the absence of any other findings of NSML may harbor somatic nucleotide variants in The spectrum of leukemogenesis associated with • The spectrum of leukemogenesis associated with ## Molecular Pathogenesis Noonan syndrome with multiple lentigines (NSML) is a RASopathy, a class of disorders for which genetic variation alters proteins belonging to the RAS/mitogen-activated protein kinase (MAPK) signal transduction pathway. The pathogenic variants in Noonan Syndrome with Multiple Lentigines: Mechanism of Disease Causation Genes from Noonan Syndrome with Multiple Lentigines: Notable Pathogenic Variants by Gene Genes from ## Cancer and Benign Tumors Sporadic tumors (including leukemia and solid tumors) occurring as single tumors in the absence of any other findings of NSML may harbor somatic nucleotide variants in The spectrum of leukemogenesis associated with • The spectrum of leukemogenesis associated with ## Chapter Notes Mindich Institute for Child Health and Development and the Departments of Pediatrics and Genetics & Genomics, Icahn School of Medicine at Mount Sinai, New York, NYEmail: Dr Gelb is trained in pediatric cardiology. His research focuses on understanding the causes and pathogenesis of the RASopathies as well as developing treatments for them. He is a member of the Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù IRCCS, Rome, ItalyEmail: Dr Tartaglia is a molecular geneticist. His research focuses on the molecular bases of human disorders affecting development. He is particularly interested in Noonan syndrome and related disorders, working to identify the genes implicated in these diseases, elucidate the mechanisms underlying pathogenesis, and characterize clinically relevant information for more effective patient care. This work was supported in part by grants from the National Institutes of Health (HL135742) to BDG; Associazione Italiana Ricerca sul Cancro (AIRC, IG21614), European Joint Program on Rare Diseases (NSEuroNet); Lazio Innova (Progetti Gruppi di Ricerca 2020 - Asse I Ricerca e Innovazione); Italian Ministry of Health (Ricerca Corrente); and Italian Ministry of Research (FOE 2019/2020) to MT. 30 June 2022 (ma) Comprehensive update posted live 14 May 2015 (me) Comprehensive update posted live 16 November 2010 (me) Comprehensive update posted live 30 November 2007 (me) Review posted live 13 November 2007 (bdg) Original submission • 30 June 2022 (ma) Comprehensive update posted live • 14 May 2015 (me) Comprehensive update posted live • 16 November 2010 (me) Comprehensive update posted live • 30 November 2007 (me) Review posted live • 13 November 2007 (bdg) Original submission ## Author Notes Mindich Institute for Child Health and Development and the Departments of Pediatrics and Genetics & Genomics, Icahn School of Medicine at Mount Sinai, New York, NYEmail: Dr Gelb is trained in pediatric cardiology. His research focuses on understanding the causes and pathogenesis of the RASopathies as well as developing treatments for them. He is a member of the Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù IRCCS, Rome, ItalyEmail: Dr Tartaglia is a molecular geneticist. His research focuses on the molecular bases of human disorders affecting development. He is particularly interested in Noonan syndrome and related disorders, working to identify the genes implicated in these diseases, elucidate the mechanisms underlying pathogenesis, and characterize clinically relevant information for more effective patient care. ## Acknowledgments This work was supported in part by grants from the National Institutes of Health (HL135742) to BDG; Associazione Italiana Ricerca sul Cancro (AIRC, IG21614), European Joint Program on Rare Diseases (NSEuroNet); Lazio Innova (Progetti Gruppi di Ricerca 2020 - Asse I Ricerca e Innovazione); Italian Ministry of Health (Ricerca Corrente); and Italian Ministry of Research (FOE 2019/2020) to MT. ## Revision History 30 June 2022 (ma) Comprehensive update posted live 14 May 2015 (me) Comprehensive update posted live 16 November 2010 (me) Comprehensive update posted live 30 November 2007 (me) Review posted live 13 November 2007 (bdg) Original submission • 30 June 2022 (ma) Comprehensive update posted live • 14 May 2015 (me) Comprehensive update posted live • 16 November 2010 (me) Comprehensive update posted live • 30 November 2007 (me) Review posted live • 13 November 2007 (bdg) Original submission ## References ## Literature Cited	[ "P Alfieri, L Cesarini, G Zampino, F Pantaleoni, A Selicorni, A Salerni, I Vasta, M Cerutti, A Dickmann, F Colitto, S Staccioli, C Leoni, D Ricci, C Brogna, M Tartaglia, E. Mercuri. Visual function in Noonan and LEOPARD syndrome.. Neuropediatrics. 2008;39:335-40", "M Bentires-Alj, JG Paez, FS David, H Keilhack, B Halmos, K Naoki, JM Maris, A Richardson, A Bardelli, DJ Sugarbaker, WG Richards, J Du, L Girard, JD Minna, ML Loh, DE Fisher, VE Velculescu, B Vogelstein, M Meyerson, WR Sellers, BG Neel. Activating mutations of the noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia.. Cancer Res 2004;64:8816-20", "BD Coppin, IK Temple. Multiple lentigines syndrome (LEOPARD syndrome or progressive cardiomyopathic lentiginosis).. J Med Genet 1997;34:582-6", "MC Digilio, E Conti, A Sarkozy, R Mingarelli, T Dottorini, B Marino, A Pizzuti, B Dallapiccola. Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene.. Am J Hum Genet 2002;71:389-94", "MC Digilio, A Sarkozy, A de Zorzi, G Pacileo, G Limongelli, R Mingarelli, R Calabro, B Marino, B Dallapiccola. LEOPARD syndrome: clinical diagnosis in the first year of life.. Am J Med Genet A 2006;140:740-6", "T Edouard, JP Combier, A Nédélec, S Bel-Vialar, M Métrich, F Conte-Auriol, S Lyonnet, B Parfait, M Tauber, JP Salles, F Lezoualc'h, A Yart, P Raynal. Functional effects of PTPN11 (SHP2) mutations causing LEOPARD syndrome on epidermal growth factor-induced phosphoinositide 3-kinase/AKT/glycogen synthase kinase 3beta signaling.. Mol Cell Biol. 2010;30:2498-507", "BD Gelb, AE Roberts, M Tartaglia. Cardiomyopathies in Noonan syndrome and the other RASopathies.. Prog Pediatr Cardiol. 2015;39:13-19", "MI Kontaridis, KD Swanson, FS David, D Barford, BG Neel. PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects.. J Biol Chem 2006;281:6785-92", "M Koudova, E Seemanova, M Zenker. Novel BRAF mutation in a patient with LEOPARD syndrome and normal intelligence.. Eur J Med Genet 2009;52:337-40", "E Legius, C Schrander-Stumpel, E Schollen, C Pulles-Heintzberger, M Gewillig, JP Fryns. PTPN11 mutations in LEOPARD syndrome.. J Med Genet 2002;39:571-4", "G Limongelli, G Pacileo, B Marino, MC Digilio, A Sarkozy, P Elliott, P Versacci, P Calabro, A De Zorzi, G Di Salvo, P Syrris, M Patton, WJ McKenna, B Dallapiccola, R Calabro. Prevalence and clinical significance of cardiovascular abnormalities in patients with the LEOPARD syndrome.. Am J Cardiol 2007;100:736-41", "TM Marin, K Keith, B Davies, DA Conner, P Guha, D Kalaitzidis, X Wu, J Lauriol, B Wang, M Bauer, R Bronson, KG Franchini, BG Neel, MI Kontaridis. Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome-associated PTPN11 mutation.. J Clin Invest. 2011;121:1026-43", "S Martinelli, A De Luca, E Stellacci, C Rossi, S Checquolo, F Lepri, V Caputo, M Silvano, F Buscherini, F Consoli, G Ferrara, MC Digilio, ML Cavaliere, JM van Hagen, G Zampino, I van der Burgt, GB Ferrero, L Mazzanti, I Screpanti, HG Yntema, WM Nillesen, R Savarirayan, M Zenker, B Dallapiccola, BD Gelb, M Tartaglia. Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype.. Am J Hum Genet. 2010;87:250-7", "S Martinelli, E Stellacci, L Pannone, D D'Agostino, F Consoli, C Lissewski, M Silvano, G Cencelli, F Lepri, S Maitz, S Pauli, A Rauch, G Zampino, A Selicorni, S Melançon, MC Digilio, BD Gelb, A De Luca, B Dallapiccola, M Zenker, M Tartaglia. Molecular diversity and associated phenotypic spectrum of germline CBL mutations.. Hum Mutat. 2015;36:787-96", "BS McDonald, M Pigors, DP Kelsell, EA O'Toole, E Burkitt-Wright, B Kerr, K Batta. Noonan syndrome with multiple lentigines and associated craniosynostosis.. Clin Exp Dermatol. 2018;43:357-9", "J McFarlane, T Knight, A Sinha, T Cole, N Kiely, R Freeman. Exostoses, enchondromatosis and metachondromatosis; diagnosis and management.. Acta Orthop Belg. 2016;82:102-5", "M Motta, G Fasano, S Gredy, J Brinkmann, AA Bonnard, PO Simsek-Kiper, EY Gulec, L Essaddam, GE Utine, I Guarnetti Prandi, M Venditti, F Pantaleoni, FC Radio, A Ciolfi, S Petrini, F Consoli, C Vignal, D Hepbasli, M Ullrich, E de Boer, LELM Vissers, S Gritli, C Rossi, A De Luca, S Ben Becher, BD Gelb, B Dallapiccola, A Lauri, G Chillemi, K Schuh, H Cavé, M Zenker, M Tartaglia. SPRED2 loss-of-function causes a recessive Noonan syndrome-like phenotype.. Am J Hum Genet. 2021;108:2112-29", "M Motta, L Pannone, F Pantaleoni, G Bocchinfuso, FC Radio, S Cecchetti, A Ciolfi, M Di Rocco, MW Elting, EH Brilstra, S Boni, L Mazzanti, F Tamburrino, L Walsh, K Payne, A Fernández-Jaén, M Ganapathi, WK Chung, DK Grange, A Dave-Wala, SC Reshmi, DW Bartholomew, D Mouhlas, G Carpentieri, A Bruselles, S Pizzi, E Bellacchio, F Piceci-Sparascio, C Lißewski, J Brinkmann, RR Waclaw, Q Waisfisz, K van Gassen, IM Wentzensen, MM Morrow, S Álvarez, M Martínez-García, A De Luca, L Memo, G Zampino, C Rossi, M Seri, BD Gelb, M Zenker, B Dallapiccola, L Stella, CE Prada, S Martinelli, E Flex, M Tartaglia. Enhanced MAPK1 function causes a neurodevelopmental disorder within the RASopathy clinical spectrum.. Am J Hum Genet. 2020;107:499-513", "CM Niemeyer, MW Kang, DH Shin, I Furlan, M Erlacher, NJ Bunin, S Bunda, JZ Finklestein, KM Sakamoto, TA Gorr, P Mehta, I Schmid, G Kropshofer, S Corbacioglu, PJ Lang, C Klein, PG Schlegel, A Heinzmann, M Schneider, J Starý, MM van den Heuvel-Eibrink, H Hasle, F Locatelli, D Sakai, S Archambeault, L Chen, RC Russell, SS Sybingco, M Ohh, BS Braun, C Flotho, ML Loh. Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia.. Nat Genet. 2010;42:794-800", "E Nishi, S Mizuno, Y Nanjo, T Niihori, Y Fukushima, Y Matsubara, Y Aoki, T Kosho. A novel heterozygous MAP2K1 mutation in a patient with Noonan syndrome with multiple lentigines.. Am J Med Genet A 2015;167A:407-11", "B Pandit, A Sarkozy, LA Pennacchio, C Carta, K Oishi, S Martinelli, EA Pogna, W Schackwitz, A Ustaszewska, A Landstrom, JM Bos, SR Ommen, G Esposito, F Lepri, C Faul, P Mundel, JP Lopez Siguero, R Tenconi, A Selicorni, C Rossi, L Mazzanti, I Torrente, B Marino, MC Digilio, G Zampino, MJ Ackerman, B Dallapiccola, M Tartaglia, BD Gelb. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy.. Nat Genet 2007;39:1007-12", "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", "MA Razzaque, T Nishizawa, Y Komoike, H Yagi, M Furutani, R Amo, M Kamisago, K Momma, H Katayama, M Nakagawa, Y Fujiwara, M Matsushima, K Mizuno, M Tokuyama, H Hirota, J Muneuchi, T Higashinakagawa, R Matsuoka. Germline gain-of-function mutations in RAF1 cause Noonan syndrome.. Nat Genet. 2007;39:1013-7", "F Rodríguez, D Ponce, FJ Berward, B Lopetegui, F Cassorla, M Aracena. RAF1 variant in a patient with Noonan syndrome with multiple lentigines and craniosynostosis.. Am J Med Genet A. 2019;179:1598-602", "A Sarkozy, C Carta, S Moretti, G Zampino, MC Digilio, F Pantaleoni, AP Scioletti, G Esposito, V Cordeddu, F Lepri, V Petrangeli, ML Dentici, GM Mancini, A Selicorni, C Rossi, L Mazzanti, B Marino, GB Ferrero, MC Silengo, L Memo, F Stanzial, F Faravelli, L Stuppia, E Puxeddu, BD Gelb, B Dallapiccola, M Tartaglia. Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum.. Hum Mutat 2009;30:695-702", "A Sarkozy, MC Digilio, B Dallapiccola. Leopard syndrome.. Orphanet J Rare Dis 2008;3:13", "P Smpokou, DJ Zand, KN Rosenbaum, ML Summar. Malignancy in Noonan syndrome and related disorders.. Clin Genet. 2015;88:516-22", "M Tartaglia, BD Gelb. Disorders of dysregulated signal traffic through the RAS-MAPK pathway: phenotypic spectrum and molecular mechanisms.. Ann N Y Acad Sci. 2010;1214:99-121", "M Tartaglia, S Martinelli, G Cazzaniga, V Cordeddu, I Iavarone, M Spinelli, C Palmi, C Carta, A Pession, M Arico, G Masera, G Basso, M Sorcini, BD Gelb, A Biondi. Genetic evidence for lineage-related and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia.. Blood 2004b;104:307-13", "M Tartaglia, CM Niemeyer, A Fragale, X Song, J Buechner, A Jung, K Hahlen, H Hasle, JD Licht, BD Gelb. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia.. Nat Genet 2003b;34:148-50", "JJ Van den Heurck, KB Boven, CC Claes. Optic disc coloboma and contralateral optic disc pit maculopathy treated by vitrectomy in a patient with Noonan syndrome with multiple lentigines.. Retin Cases Brief Rep. 2021", "A Villani, MC Greer, JM Kalish, A Nakagawara, KL Nathanson, KW Pajtler, SM Pfister, MF Walsh, JD Wasserman, K Zelley, CP Kratz. Recommendations for cancer surveillance in individuals with RASopathies and other rare genetic conditions with increased cancer risk.. Clin Cancer Res. 2017;23:e83-e90", "DA Voron, HH Hatfield, RK Kalkhoff. Multiple lentigines syndrome. Case report and review of the literature.. Am J Med. 1976;60:447-56", "Y Watanabe, S Yano, T Niihori, Y Aoki, Y Matsubara, M Yoshino, T. Matsuishi. A familial case of LEOPARD syndrome associated with a high-functioning autism spectrum disorder.. Brain Dev. 2011;33:576-9", "DR Witt, BA Keena, JG Hall, JE Allanson. Growth curves for height in Noonan syndrome.. Clin Genet 1986;30:150-3", "G Zhu, J Xie, W Kong, J Xie, Y Li, L Du, Q Zheng, L Sun, M Guan, H Li, T Zhu, H He, Z Liu, X Xia, C Kan, Y Tao, HC Shen, D Li, S Wang, Y Yu, ZH Yu, ZY Zhang, C Liu, J Zhu. Phase separation of disease-associated SHP2 mutants underlies MAPK hyperactivation.. Cell. 2020;183:490-502.e18" ]	30/11/2007	30/6/2022		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
leukodys-ov	leukodys-ov	[ "1,4-alpha-glucan-branching enzyme", "Aldehyde dehydrogenase family 3 member A2", "Arylsulfatase A", "Aspartate--tRNA ligase, mitochondrial", "Aspartoacylase", "ATP-binding cassette sub-family D member 1", "Deoxynucleoside triphosphate triphosphohydrolase SAMHD1", "DNA-directed RNA polymerase III subunit RPC1", "DNA-directed RNA polymerase III subunit RPC2", "Double-stranded RNA-specific adenosine deaminase", "Formylglycine-generating enzyme", "Galactocerebrosidase", "Gap junction alpha-1 protein", "Gap junction gamma-2 protein", "Glial fibrillary acidic protein", "Hepatocyte cell adhesion molecule", "Hyccin", "L-2-hydroxyglutarate dehydrogenase, mitochondrial", "Lamin-B1", "Macrophage colony-stimulating factor 1 receptor", "Membrane protein MLC1", "Myelin proteolipid protein", "Non-specific lipid-transfer protein", "Peroxisomal acyl-coenzyme A oxidase 1", "Peroxisomal biogenesis factor 19", "Peroxisomal biogenesis factor 3", "Peroxisomal membrane protein PEX13", "Peroxisomal membrane protein PEX14", "Peroxisomal membrane protein PEX16", "Peroxisomal multifunctional enzyme type 2", "Peroxisomal targeting signal 1 receptor", "Peroxisome assembly factor 2", "Peroxisome assembly protein 12", "Peroxisome assembly protein 26", "Peroxisome biogenesis factor 1", "Peroxisome biogenesis factor 10", "Peroxisome biogenesis factor 2", "Probable glutamate--tRNA ligase, mitochondrial", "Prosaposin", "Ribonuclease H2 subunit A", "Ribonuclease H2 subunit B", "Ribonuclease H2 subunit C", "Ribonuclease T2", "Sialin", "Sterol 26-hydroxylase, mitochondrial", "Three prime repair exonuclease 1", "Tissue alpha-L-fucosidase", "Transcription factor SOX-10", "Translation initiation factor eIF-2B subunit alpha", "Translation initiation factor eIF-2B subunit beta", "Translation initiation factor eIF-2B subunit delta", "Translation initiation factor eIF-2B subunit epsilon", "Translation initiation factor eIF-2B subunit gamma", "Tubulin beta-4A chain", "ABCD1", "ACOX1", "ADAR", "ALDH3A2", "ARSA", "ASPA", "CSF1R", "CYP27A1", "DARS2", "EARS2", "EIF2B1", "EIF2B2", "EIF2B3", "EIF2B4", "EIF2B5", "FAM126A", "FUCA1", "GALC", "GBE1", "GFAP", "GJA1", "GJC2", "HEPACAM", "HSD17B4", "L2HGDH", "LMNB1", "MLC1", "PEX1", "PEX10", "PEX12", "PEX13", "PEX14", "PEX16", "PEX19", "PEX2", "PEX26", "PEX3", "PEX5", "PEX6", "PLP1", "POLR3A", "POLR3B", "PSAP", "RNASEH2A", "RNASEH2B", "RNASEH2C", "RNASET2", "SAMHD1", "SCP2", "SLC17A5", "SOX10", "SUMF1", "TREX1", "TUBB4A", "Leukodystrophy", "Overview" ]	Leukodystrophy Overview – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY	Adeline Vanderver, Davide Tonduti, Raphael Schiffmann, Johanna Schmidt, Marjo S van der Knaap	Summary Leukodystrophies are heritable myelin disorders affecting the white matter of the central nervous system with or without peripheral nervous system myelin involvement. Involvement of the white matter tracts almost universally leads to motor involvement that manifests as hypotonia in early childhood and progresses to spasticity over time. This may lead to variable motor impairment, from mild spastic diplegia to severe spastic quadriplegia that limits purposeful movement. In addition, motor dysfunction is likely to significantly impair vital functions including swallowing, chewing, and (in some cases) respiration. Other findings that vary by disorder include extrapyramidal movement disorders (e.g., dystonia and/or dyskinesias), ataxia, seizures, and delay in cognitive development or change in cognitive function over time. Establishing the specific leukodystrophy present in a given individual usually involves: Obtaining a medical history and detailed family history Performing a physical examination and neurologic examination Review of brain MRI findings: T T Performing specialized laboratory testing, often including molecular genetic testing (either stepwise single-gene testing or use of a multigene panel targeted to the leukodystrophies). Leukodystrophies with an identified genetic cause may be inherited in an autosomal dominant manner, an autosomal recessive manner, or an X-linked recessive manner. 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. Prenatal testing for pregnancies at increased risk is possible for some types of leukodystrophy if the pathogenic variant(s) in the family are known. Many leukodystrophies are still without an identified genetic cause; once a genetic cause is identified, other inheritance patterns may emerge.	## Definition of Leukodystrophy The term "leukodystrophy," as well as associated terms such as "dysmyelination," "demyelination," and "leukoencephalopathy," is applied to a broad group of disorders. In this Leukodystrophies share the following findings: Abnormalities of the glial cell or myelin sheath, such that neuropathology – when known – is characterized primarily by involvement of oligodendrocytes, astrocytes, and other non-neuronal cell types. Of note, in many leukodystrophies the underlying disease mechanism is unknown. MRI findings (see T T • Abnormalities of the glial cell or myelin sheath, such that neuropathology – when known – is characterized primarily by involvement of oligodendrocytes, astrocytes, and other non-neuronal cell types. Of note, in many leukodystrophies the underlying disease mechanism is unknown. • MRI findings (see • T • T • T • T • T • T ## Clinical Manifestations of Leukodystrophies A number of leukodystrophies that meet the definition used in this Involvement of the white matter tracts almost universally leads to motor involvement that manifests as hypotonia in early childhood and progresses to spasticity over time. This may lead to variable motor impairment, from mild spastic diplegia to severe spastic quadriplegia that limits purposeful movement. In addition, motor dysfunction is likely to significantly impair vital functions including swallowing, chewing, and (in some cases) respiration. Spasticity may result in orthopedic complications such as scoliosis and large joint luxation. Significant pyramidal dysfunction (i.e., spasticity) may sometimes mask or overshadow the presence of extrapyramidal movement disorders such as dystonia and/or dyskinesias. For example, in Ataxia is a predominant finding in some leukodystrophies and can be disabling; for example, Seizures are an often late manifestation of leukodystrophies, with the exception of rare leukodystrophies (e.g., Delay in cognitive development or change in cognitive function over time, while far less pronounced than motor dysfunction, can be common in the child or adult with leukodystrophy. Because progressive loss of cognitive function is slow in the majority of leukodystrophies, dementia is not an early feature. ## Prevalence of Leukodystrophies Epidemiologic data on the frequency of leukodystrophies overall are limited [ Better information on prevalence is available for leukodystrophies that are seen regularly in specialized clinics and in general child neurology practices; these include As disorders such as certain adult-onset-only leukodystrophies and hypomyelinating leukodystrophies become better defined, the heterogeneity of the inherited white matter disorders is increasingly recognized. It is important to note that in approximately 50% of individuals with a white matter disorder the specific etiology is unknown because of the heterogeneity and complexity of these disorders [ ## Differential Diagnosis of Leukodystrophies The infantile variants of disorders like In other disorders, such as Disorders such as acute disseminated encephalomyelitis, multiple sclerosis, and neuromyelitis optica typically differ from heritable white matter disorders by their abrupt onset and multiphasic presentations. Brain MRI abnormalities are also more likely to be multifocal and patchy [ Non-genetic vascular insults • The infantile variants of disorders like • In other disorders, such as • The infantile variants of disorders like • In other disorders, such as • The infantile variants of disorders like • In other disorders, such as • Disorders such as acute disseminated encephalomyelitis, multiple sclerosis, and neuromyelitis optica typically differ from heritable white matter disorders by their abrupt onset and multiphasic presentations. Brain MRI abnormalities are also more likely to be multifocal and patchy [ • Non-genetic vascular insults ## Evaluation Strategy for an Individual with a Leukodystrophy Once a leukodystrophy is considered in an individual, the following approach can be used to determine the specific leukodystrophy to aid in discussions of prognosis and genetic counseling. Establishing the specific leukodystrophy ( Note: Adherence to the diagnostic approach discussed in this section notwithstanding, a specific diagnosis cannot be established in a clinical (i.e., not research) setting in a significant number of individuals with a leukodystrophy [ A history of certain clinical features may be helpful in identifying a specific leukodystrophy; however, in the majority of cases, only nonspecific loss of function (primarily motor) occurs and medical history alone does not provide insight into a specific diagnosis. In the hypomyelinating leukodystrophies helpful diagnostic clues may, for example, be the following: Congenital cataract: Hypodontia and/or hypogonadotropic hypogonadism: Severe seizures: In the demyelinating leukodystrophies helpful diagnostic clues may, for example, be the following: Recurrent vomiting: Adrenal dysfunction: Early-onset autonomic dysfunction: Chronic cerebrospinal fluid lymphocytosis or (more often) recurrent "aseptic meningitis": Abrupt loss of function after a fever or fall: A detailed three-generation family history should be compiled, focusing on individuals with hypotonia, spasticity, dystonia, seizures, ataxia, and/or delay in cognitive development or change in cognitive function over time. Because most leukodystrophies are autosomal recessive, special attention to parental consanguinity and medical problems in sibs is warranted. Evaluation of relatives and/or review of their medical records may be needed. In most instances physical findings do not suggest a specific diagnosis; however, certain findings may direct the reader to further explore specific underlying etiologies: Macrocephaly; see Abnormal dentition: Palatal myoclonus in adults: Xanthomas: Abnormalities of skin pigmentation: Ichthyosis: Sjögren-Larsson syndrome Vascular retinal abnormalities: cerebroretinal microangiopathy w/calcifications & cysts (CRMCC) Cherry red spot on retinal examination: disorders such as Establish whether the pattern of brain MRI abnormalities is consistent with a hypomyelinating leukodystrophy or a demyelinating leukodystrophy ( Within the hypomyelinating and demyelinating leukodystrophies, determine if patterns of involvement suggest specific diagnoses. Improvement of myelination over time (e.g., as seen in Severe atrophy of cortical gray matter (variably seen in primary neuronal disorders as well as a limited number of classic leukodystrophies; see Persistent hypomyelination without atrophy of cortical gray matter (e.g., in Cerebellar atrophy (e.g., in Basal ganglia involvement (e.g., in HABC syndrome; see Identify the region in which white matter abnormalities predominate. Distinguish confluent from multifocal lesions ( Confluent white matter lesions are extensive white matter abnormalities in significant portions of the brain, often affecting specific regions or tracts, although not necessarily perfectly symmetrically. Multifocal white matter lesions are more discrete, often asymmetric and involving a limited area. Multifocal abnormalities have a specific differential diagnosis. Specific patterns on neuroimaging in confluent disorders include ( Diffuse cerebral involvement (e.g., as seen in Frontal involvement (e.g., in Parieto-occipital involvement (e.g. in Temporal involvement (e.g., in Subcortical involvement (e.g., in Periventricular involvement (e.g., in Brain stem involvement (e.g., in Cerebellar/cerebellar peduncle involvement (e.g., in Large, asymmetric lesions (e.g., in Look for the following associated features which, in addition to the pattern of findings on brain MRI, can assist in recognition of a specific leukodystrophy: White matter rarefaction and cysts ( Calcium deposits and hemosiderin deposits ( Contrast enhancement ( Leukoencephalopathy with macrocephaly( Cortical gray matter lesions ( Cerebellar abnormalities ( Thinning of the corpus callosum ( Non-calcifying basal ganglia lesions ( Brain stem involvement ( Spinal cord involvement ( If the findings on brain MRI are consistent with a specific leukodystrophy, consider biochemical or molecular genetic testing for that disorder ( For an introduction to multigene panels click Leukodystrophies Meeting Strict Diagnostic Criteria AD = autosomal dominant; AR = autosomal recessive; VLCFA = very long-chain fatty acid; XL = X-linked Disorders listed in alphabetic order; naming as per Genetic testing is available for many of these genes. This disorder now appears to be distinct from Coats plus caused by pathogenic variants in Includes Salla disease; infantile sialic acid storage disease, intermediate form Defects in Pathogenic variants in Also known as adult-onset leukodystrophy w/ neuroaxonal spheroids & pigmented glia; may include hereditary diffuse; pigmentary type of orthochromatic leukodystrophy w/pigmented glia (POLD) Includes neonatal adrenoleukodystrophy; infantile Refsum disease Includes hypomyelination, hypodontia, hypogonadotropic hypogonadism (4H syndrome); ataxia, delayed dentition, and hypomyelination (ADDH); tremor-ataxia with central hypomyelination (TACH); leukodystrophy with oligodontia (LO); and hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum (HCAHC). Includes D-bifunctional protein (DBP) deficiency; sterol carrier protein-2 (SCPx) deficiency; peroxisomal acyl-CoA-oxidase deficiency • Congenital cataract: • Hypodontia and/or hypogonadotropic hypogonadism: • Severe seizures: • Recurrent vomiting: • Adrenal dysfunction: • Early-onset autonomic dysfunction: • Chronic cerebrospinal fluid lymphocytosis or (more often) recurrent "aseptic meningitis": • Abrupt loss of function after a fever or fall: • Because most leukodystrophies are autosomal recessive, special attention to parental consanguinity and medical problems in sibs is warranted. • Evaluation of relatives and/or review of their medical records may be needed. • Macrocephaly; see • Abnormal dentition: • Palatal myoclonus in adults: • Xanthomas: • Abnormalities of skin pigmentation: • Ichthyosis: Sjögren-Larsson syndrome • Vascular retinal abnormalities: cerebroretinal microangiopathy w/calcifications & cysts (CRMCC) • Cherry red spot on retinal examination: disorders such as • Improvement of myelination over time (e.g., as seen in • Severe atrophy of cortical gray matter (variably seen in primary neuronal disorders as well as a limited number of classic leukodystrophies; see • Persistent hypomyelination without atrophy of cortical gray matter (e.g., in • Cerebellar atrophy (e.g., in • Basal ganglia involvement (e.g., in HABC syndrome; see • Identify the region in which white matter abnormalities predominate. • Distinguish confluent from multifocal lesions ( • Confluent white matter lesions are extensive white matter abnormalities in significant portions of the brain, often affecting specific regions or tracts, although not necessarily perfectly symmetrically. • Multifocal white matter lesions are more discrete, often asymmetric and involving a limited area. Multifocal abnormalities have a specific differential diagnosis. • Confluent white matter lesions are extensive white matter abnormalities in significant portions of the brain, often affecting specific regions or tracts, although not necessarily perfectly symmetrically. • Multifocal white matter lesions are more discrete, often asymmetric and involving a limited area. Multifocal abnormalities have a specific differential diagnosis. • Confluent white matter lesions are extensive white matter abnormalities in significant portions of the brain, often affecting specific regions or tracts, although not necessarily perfectly symmetrically. • Multifocal white matter lesions are more discrete, often asymmetric and involving a limited area. Multifocal abnormalities have a specific differential diagnosis. • Diffuse cerebral involvement (e.g., as seen in • Frontal involvement (e.g., in • Parieto-occipital involvement (e.g. in • Temporal involvement (e.g., in • Subcortical involvement (e.g., in • Periventricular involvement (e.g., in • Brain stem involvement (e.g., in • Cerebellar/cerebellar peduncle involvement (e.g., in • Large, asymmetric lesions (e.g., in • White matter rarefaction and cysts ( • Calcium deposits and hemosiderin deposits ( • Contrast enhancement ( • Leukoencephalopathy with macrocephaly( • Cortical gray matter lesions ( • Cerebellar abnormalities ( • Thinning of the corpus callosum ( • Non-calcifying basal ganglia lesions ( • Brain stem involvement ( • Spinal cord involvement ( ## Medical History A history of certain clinical features may be helpful in identifying a specific leukodystrophy; however, in the majority of cases, only nonspecific loss of function (primarily motor) occurs and medical history alone does not provide insight into a specific diagnosis. In the hypomyelinating leukodystrophies helpful diagnostic clues may, for example, be the following: Congenital cataract: Hypodontia and/or hypogonadotropic hypogonadism: Severe seizures: In the demyelinating leukodystrophies helpful diagnostic clues may, for example, be the following: Recurrent vomiting: Adrenal dysfunction: Early-onset autonomic dysfunction: Chronic cerebrospinal fluid lymphocytosis or (more often) recurrent "aseptic meningitis": Abrupt loss of function after a fever or fall: • Congenital cataract: • Hypodontia and/or hypogonadotropic hypogonadism: • Severe seizures: • Recurrent vomiting: • Adrenal dysfunction: • Early-onset autonomic dysfunction: • Chronic cerebrospinal fluid lymphocytosis or (more often) recurrent "aseptic meningitis": • Abrupt loss of function after a fever or fall: ## Family History A detailed three-generation family history should be compiled, focusing on individuals with hypotonia, spasticity, dystonia, seizures, ataxia, and/or delay in cognitive development or change in cognitive function over time. Because most leukodystrophies are autosomal recessive, special attention to parental consanguinity and medical problems in sibs is warranted. Evaluation of relatives and/or review of their medical records may be needed. • Because most leukodystrophies are autosomal recessive, special attention to parental consanguinity and medical problems in sibs is warranted. • Evaluation of relatives and/or review of their medical records may be needed. ## Physical Examination and Neurologic Examination In most instances physical findings do not suggest a specific diagnosis; however, certain findings may direct the reader to further explore specific underlying etiologies: Macrocephaly; see Abnormal dentition: Palatal myoclonus in adults: Xanthomas: Abnormalities of skin pigmentation: Ichthyosis: Sjögren-Larsson syndrome Vascular retinal abnormalities: cerebroretinal microangiopathy w/calcifications & cysts (CRMCC) Cherry red spot on retinal examination: disorders such as • Macrocephaly; see • Abnormal dentition: • Palatal myoclonus in adults: • Xanthomas: • Abnormalities of skin pigmentation: • Ichthyosis: Sjögren-Larsson syndrome • Vascular retinal abnormalities: cerebroretinal microangiopathy w/calcifications & cysts (CRMCC) • Cherry red spot on retinal examination: disorders such as ## Brain MRI Findings Establish whether the pattern of brain MRI abnormalities is consistent with a hypomyelinating leukodystrophy or a demyelinating leukodystrophy ( Within the hypomyelinating and demyelinating leukodystrophies, determine if patterns of involvement suggest specific diagnoses. Improvement of myelination over time (e.g., as seen in Severe atrophy of cortical gray matter (variably seen in primary neuronal disorders as well as a limited number of classic leukodystrophies; see Persistent hypomyelination without atrophy of cortical gray matter (e.g., in Cerebellar atrophy (e.g., in Basal ganglia involvement (e.g., in HABC syndrome; see Identify the region in which white matter abnormalities predominate. Distinguish confluent from multifocal lesions ( Confluent white matter lesions are extensive white matter abnormalities in significant portions of the brain, often affecting specific regions or tracts, although not necessarily perfectly symmetrically. Multifocal white matter lesions are more discrete, often asymmetric and involving a limited area. Multifocal abnormalities have a specific differential diagnosis. Specific patterns on neuroimaging in confluent disorders include ( Diffuse cerebral involvement (e.g., as seen in Frontal involvement (e.g., in Parieto-occipital involvement (e.g. in Temporal involvement (e.g., in Subcortical involvement (e.g., in Periventricular involvement (e.g., in Brain stem involvement (e.g., in Cerebellar/cerebellar peduncle involvement (e.g., in Large, asymmetric lesions (e.g., in Look for the following associated features which, in addition to the pattern of findings on brain MRI, can assist in recognition of a specific leukodystrophy: White matter rarefaction and cysts ( Calcium deposits and hemosiderin deposits ( Contrast enhancement ( Leukoencephalopathy with macrocephaly( Cortical gray matter lesions ( Cerebellar abnormalities ( Thinning of the corpus callosum ( Non-calcifying basal ganglia lesions ( Brain stem involvement ( Spinal cord involvement ( • Improvement of myelination over time (e.g., as seen in • Severe atrophy of cortical gray matter (variably seen in primary neuronal disorders as well as a limited number of classic leukodystrophies; see • Persistent hypomyelination without atrophy of cortical gray matter (e.g., in • Cerebellar atrophy (e.g., in • Basal ganglia involvement (e.g., in HABC syndrome; see • Identify the region in which white matter abnormalities predominate. • Distinguish confluent from multifocal lesions ( • Confluent white matter lesions are extensive white matter abnormalities in significant portions of the brain, often affecting specific regions or tracts, although not necessarily perfectly symmetrically. • Multifocal white matter lesions are more discrete, often asymmetric and involving a limited area. Multifocal abnormalities have a specific differential diagnosis. • Confluent white matter lesions are extensive white matter abnormalities in significant portions of the brain, often affecting specific regions or tracts, although not necessarily perfectly symmetrically. • Multifocal white matter lesions are more discrete, often asymmetric and involving a limited area. Multifocal abnormalities have a specific differential diagnosis. • Confluent white matter lesions are extensive white matter abnormalities in significant portions of the brain, often affecting specific regions or tracts, although not necessarily perfectly symmetrically. • Multifocal white matter lesions are more discrete, often asymmetric and involving a limited area. Multifocal abnormalities have a specific differential diagnosis. • Diffuse cerebral involvement (e.g., as seen in • Frontal involvement (e.g., in • Parieto-occipital involvement (e.g. in • Temporal involvement (e.g., in • Subcortical involvement (e.g., in • Periventricular involvement (e.g., in • Brain stem involvement (e.g., in • Cerebellar/cerebellar peduncle involvement (e.g., in • Large, asymmetric lesions (e.g., in • White matter rarefaction and cysts ( • Calcium deposits and hemosiderin deposits ( • Contrast enhancement ( • Leukoencephalopathy with macrocephaly( • Cortical gray matter lesions ( • Cerebellar abnormalities ( • Thinning of the corpus callosum ( • Non-calcifying basal ganglia lesions ( • Brain stem involvement ( • Spinal cord involvement ( ## Step 1 Establish whether the pattern of brain MRI abnormalities is consistent with a hypomyelinating leukodystrophy or a demyelinating leukodystrophy ( ## Step 2 Within the hypomyelinating and demyelinating leukodystrophies, determine if patterns of involvement suggest specific diagnoses. Improvement of myelination over time (e.g., as seen in Severe atrophy of cortical gray matter (variably seen in primary neuronal disorders as well as a limited number of classic leukodystrophies; see Persistent hypomyelination without atrophy of cortical gray matter (e.g., in Cerebellar atrophy (e.g., in Basal ganglia involvement (e.g., in HABC syndrome; see Identify the region in which white matter abnormalities predominate. Distinguish confluent from multifocal lesions ( Confluent white matter lesions are extensive white matter abnormalities in significant portions of the brain, often affecting specific regions or tracts, although not necessarily perfectly symmetrically. Multifocal white matter lesions are more discrete, often asymmetric and involving a limited area. Multifocal abnormalities have a specific differential diagnosis. Specific patterns on neuroimaging in confluent disorders include ( Diffuse cerebral involvement (e.g., as seen in Frontal involvement (e.g., in Parieto-occipital involvement (e.g. in Temporal involvement (e.g., in Subcortical involvement (e.g., in Periventricular involvement (e.g., in Brain stem involvement (e.g., in Cerebellar/cerebellar peduncle involvement (e.g., in Large, asymmetric lesions (e.g., in • Improvement of myelination over time (e.g., as seen in • Severe atrophy of cortical gray matter (variably seen in primary neuronal disorders as well as a limited number of classic leukodystrophies; see • Persistent hypomyelination without atrophy of cortical gray matter (e.g., in • Cerebellar atrophy (e.g., in • Basal ganglia involvement (e.g., in HABC syndrome; see • Identify the region in which white matter abnormalities predominate. • Distinguish confluent from multifocal lesions ( • Confluent white matter lesions are extensive white matter abnormalities in significant portions of the brain, often affecting specific regions or tracts, although not necessarily perfectly symmetrically. • Multifocal white matter lesions are more discrete, often asymmetric and involving a limited area. Multifocal abnormalities have a specific differential diagnosis. • Confluent white matter lesions are extensive white matter abnormalities in significant portions of the brain, often affecting specific regions or tracts, although not necessarily perfectly symmetrically. • Multifocal white matter lesions are more discrete, often asymmetric and involving a limited area. Multifocal abnormalities have a specific differential diagnosis. • Confluent white matter lesions are extensive white matter abnormalities in significant portions of the brain, often affecting specific regions or tracts, although not necessarily perfectly symmetrically. • Multifocal white matter lesions are more discrete, often asymmetric and involving a limited area. Multifocal abnormalities have a specific differential diagnosis. • Diffuse cerebral involvement (e.g., as seen in • Frontal involvement (e.g., in • Parieto-occipital involvement (e.g. in • Temporal involvement (e.g., in • Subcortical involvement (e.g., in • Periventricular involvement (e.g., in • Brain stem involvement (e.g., in • Cerebellar/cerebellar peduncle involvement (e.g., in • Large, asymmetric lesions (e.g., in ## Step 3 Look for the following associated features which, in addition to the pattern of findings on brain MRI, can assist in recognition of a specific leukodystrophy: White matter rarefaction and cysts ( Calcium deposits and hemosiderin deposits ( Contrast enhancement ( Leukoencephalopathy with macrocephaly( Cortical gray matter lesions ( Cerebellar abnormalities ( Thinning of the corpus callosum ( Non-calcifying basal ganglia lesions ( Brain stem involvement ( Spinal cord involvement ( • White matter rarefaction and cysts ( • Calcium deposits and hemosiderin deposits ( • Contrast enhancement ( • Leukoencephalopathy with macrocephaly( • Cortical gray matter lesions ( • Cerebellar abnormalities ( • Thinning of the corpus callosum ( • Non-calcifying basal ganglia lesions ( • Brain stem involvement ( • Spinal cord involvement ( ## Specialized Laboratory Testing (Including Molecular Genetic Testing) If the findings on brain MRI are consistent with a specific leukodystrophy, consider biochemical or molecular genetic testing for that disorder ( For an introduction to multigene panels click Leukodystrophies Meeting Strict Diagnostic Criteria AD = autosomal dominant; AR = autosomal recessive; VLCFA = very long-chain fatty acid; XL = X-linked Disorders listed in alphabetic order; naming as per Genetic testing is available for many of these genes. This disorder now appears to be distinct from Coats plus caused by pathogenic variants in Includes Salla disease; infantile sialic acid storage disease, intermediate form Defects in Pathogenic variants in Also known as adult-onset leukodystrophy w/ neuroaxonal spheroids & pigmented glia; may include hereditary diffuse; pigmentary type of orthochromatic leukodystrophy w/pigmented glia (POLD) Includes neonatal adrenoleukodystrophy; infantile Refsum disease Includes hypomyelination, hypodontia, hypogonadotropic hypogonadism (4H syndrome); ataxia, delayed dentition, and hypomyelination (ADDH); tremor-ataxia with central hypomyelination (TACH); leukodystrophy with oligodontia (LO); and hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum (HCAHC). Includes D-bifunctional protein (DBP) deficiency; sterol carrier protein-2 (SCPx) deficiency; peroxisomal acyl-CoA-oxidase deficiency ## Genetic Counseling Leukodystrophies with an identified genetic cause may be inherited in an autosomal dominant manner, an autosomal recessive manner, or an X-linked recessive manner; other inheritance patterns may be identified as more genetic causes of leukodystrophy are discovered. If a proband has a specific syndrome associated with a leukodystrophy, counseling for that condition is indicated. Most individuals diagnosed as having autosomal dominant leukodystrophy have an affected parent, although occasionally the family history is negative. Family history may appear to be negative because of early death of a parent, failure to recognize autosomal dominant leukodystrophy in family members, late onset in a parent, reduced penetrance of the mutated allele in an asymptomatic parent, or a The risk to sibs depends on the genetic status of the proband's parents. If one of the proband's parents has a mutated allele, the risk to the sibs of inheriting the mutated allele is 50%. The parents are obligate heterozygotes and therefore carry a single copy of a 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. Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3. The father of an affected male will not have the disease nor will he be a carrier of the pathogenic variant. Women who have an affected son and another affected male relative are obligate heterozygotes. These females may be affected, sometimes with only certain features of the disease, or with milder symptoms. 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 has germline mosaicism. Rarely, the unaffected father of an affected female may have germline mosaicism. A mother of an affected female who has a pathogenic variant may have favorably skewed X-chromosome inactivation that results in her being unaffected or mildly affected. An individual who is the only affected family member (i.e., a simplex case) may have a If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Male sibs who inherit the variant will be affected; female sibs who inherit the variant will be carriers and will usually not be affected. 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 low but greater than that of the general population because of the possibility of maternal germline mosaicism. Daughters of an affected male will be obligate carriers and may or may not be affected; none of his sons will be affected. Each child of an affected female has a 50% chance of inheriting the pathogenic variant. Because of possible skewing of X-chromosome inactivation, variable phenotypes in females are possible. 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 leukodystrophy are possible. • Most individuals diagnosed as having autosomal dominant leukodystrophy have an affected parent, although occasionally the family history is negative. • Family history may appear to be negative because of early death of a parent, failure to recognize autosomal dominant leukodystrophy in family members, late onset in a parent, reduced penetrance of the mutated allele in an asymptomatic parent, or a • The risk to sibs depends on the genetic status of the proband's parents. • If one of the proband's parents has a mutated allele, the risk to the sibs of inheriting the mutated allele is 50%. • The parents are obligate heterozygotes and therefore carry a single copy of a 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. • Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3. • The father of an affected male will not have the disease nor will he be a carrier of the pathogenic variant. • Women who have an affected son and another affected male relative are obligate heterozygotes. These females may be affected, sometimes with only certain features of the disease, or with milder symptoms. 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 has germline mosaicism. Rarely, the unaffected father of an affected female may have germline mosaicism. • A mother of an affected female who has a pathogenic variant may have favorably skewed X-chromosome inactivation that results in her being unaffected or mildly affected. • An individual who is the only affected family member (i.e., a simplex case) may have a • If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Male sibs who inherit the variant will be affected; female sibs who inherit the variant will be carriers and will usually not be affected. • 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 low but greater than that of the general population because of the possibility of maternal germline mosaicism. • Daughters of an affected male will be obligate carriers and may or may not be affected; none of his sons will be affected. • Each child of an affected female has a 50% chance of inheriting the pathogenic variant. • Because of possible skewing of X-chromosome inactivation, variable phenotypes in females are possible. ## Mode of Inheritance Leukodystrophies with an identified genetic cause may be inherited in an autosomal dominant manner, an autosomal recessive manner, or an X-linked recessive manner; other inheritance patterns may be identified as more genetic causes of leukodystrophy are discovered. If a proband has a specific syndrome associated with a leukodystrophy, counseling for that condition is indicated. ## Risk to Family Members Most individuals diagnosed as having autosomal dominant leukodystrophy have an affected parent, although occasionally the family history is negative. Family history may appear to be negative because of early death of a parent, failure to recognize autosomal dominant leukodystrophy in family members, late onset in a parent, reduced penetrance of the mutated allele in an asymptomatic parent, or a The risk to sibs depends on the genetic status of the proband's parents. If one of the proband's parents has a mutated allele, the risk to the sibs of inheriting the mutated allele is 50%. The parents are obligate heterozygotes and therefore carry a single copy of a 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. Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3. The father of an affected male will not have the disease nor will he be a carrier of the pathogenic variant. Women who have an affected son and another affected male relative are obligate heterozygotes. These females may be affected, sometimes with only certain features of the disease, or with milder symptoms. 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 has germline mosaicism. Rarely, the unaffected father of an affected female may have germline mosaicism. A mother of an affected female who has a pathogenic variant may have favorably skewed X-chromosome inactivation that results in her being unaffected or mildly affected. An individual who is the only affected family member (i.e., a simplex case) may have a If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Male sibs who inherit the variant will be affected; female sibs who inherit the variant will be carriers and will usually not be affected. 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 low but greater than that of the general population because of the possibility of maternal germline mosaicism. Daughters of an affected male will be obligate carriers and may or may not be affected; none of his sons will be affected. Each child of an affected female has a 50% chance of inheriting the pathogenic variant. Because of possible skewing of X-chromosome inactivation, variable phenotypes in females are possible. • Most individuals diagnosed as having autosomal dominant leukodystrophy have an affected parent, although occasionally the family history is negative. • Family history may appear to be negative because of early death of a parent, failure to recognize autosomal dominant leukodystrophy in family members, late onset in a parent, reduced penetrance of the mutated allele in an asymptomatic parent, or a • The risk to sibs depends on the genetic status of the proband's parents. • If one of the proband's parents has a mutated allele, the risk to the sibs of inheriting the mutated allele is 50%. • The parents are obligate heterozygotes and therefore carry a single copy of a 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. • Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3. • The father of an affected male will not have the disease nor will he be a carrier of the pathogenic variant. • Women who have an affected son and another affected male relative are obligate heterozygotes. These females may be affected, sometimes with only certain features of the disease, or with milder symptoms. 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 has germline mosaicism. Rarely, the unaffected father of an affected female may have germline mosaicism. • A mother of an affected female who has a pathogenic variant may have favorably skewed X-chromosome inactivation that results in her being unaffected or mildly affected. • An individual who is the only affected family member (i.e., a simplex case) may have a • If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Male sibs who inherit the variant will be affected; female sibs who inherit the variant will be carriers and will usually not be affected. • 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 low but greater than that of the general population because of the possibility of maternal germline mosaicism. • Daughters of an affected male will be obligate carriers and may or may not be affected; none of his sons will be affected. • Each child of an affected female has a 50% chance of inheriting the pathogenic variant. • Because of possible skewing of X-chromosome inactivation, variable phenotypes in females are possible. ## Autosomal Dominant Inheritance Most individuals diagnosed as having autosomal dominant leukodystrophy have an affected parent, although occasionally the family history is negative. Family history may appear to be negative because of early death of a parent, failure to recognize autosomal dominant leukodystrophy in family members, late onset in a parent, reduced penetrance of the mutated allele in an asymptomatic parent, or a The risk to sibs depends on the genetic status of the proband's parents. If one of the proband's parents has a mutated allele, the risk to the sibs of inheriting the mutated allele is 50%. • Most individuals diagnosed as having autosomal dominant leukodystrophy have an affected parent, although occasionally the family history is negative. • Family history may appear to be negative because of early death of a parent, failure to recognize autosomal dominant leukodystrophy in family members, late onset in a parent, reduced penetrance of the mutated allele in an asymptomatic parent, or a • The risk to sibs depends on the genetic status of the proband's parents. • If one of the proband's parents has a mutated allele, the risk to the sibs of inheriting the mutated allele is 50%. ## Autosomal Recessive Inheritance The parents are obligate heterozygotes and therefore carry a single copy of a 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. Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3. • The parents are obligate heterozygotes and therefore carry a single copy of a 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. • Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3. ## X-Linked Inheritance The father of an affected male will not have the disease nor will he be a carrier of the pathogenic variant. Women who have an affected son and another affected male relative are obligate heterozygotes. These females may be affected, sometimes with only certain features of the disease, or with milder symptoms. 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 has germline mosaicism. Rarely, the unaffected father of an affected female may have germline mosaicism. A mother of an affected female who has a pathogenic variant may have favorably skewed X-chromosome inactivation that results in her being unaffected or mildly affected. An individual who is the only affected family member (i.e., a simplex case) may have a If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Male sibs who inherit the variant will be affected; female sibs who inherit the variant will be carriers and will usually not be affected. 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 low but greater than that of the general population because of the possibility of maternal germline mosaicism. Daughters of an affected male will be obligate carriers and may or may not be affected; none of his sons will be affected. Each child of an affected female has a 50% chance of inheriting the pathogenic variant. Because of possible skewing of X-chromosome inactivation, variable phenotypes in females are possible. • The father of an affected male will not have the disease nor will he be a carrier of the pathogenic variant. • Women who have an affected son and another affected male relative are obligate heterozygotes. These females may be affected, sometimes with only certain features of the disease, or with milder symptoms. 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 has germline mosaicism. Rarely, the unaffected father of an affected female may have germline mosaicism. • A mother of an affected female who has a pathogenic variant may have favorably skewed X-chromosome inactivation that results in her being unaffected or mildly affected. • An individual who is the only affected family member (i.e., a simplex case) may have a • If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Male sibs who inherit the variant will be affected; female sibs who inherit the variant will be carriers and will usually not be affected. • 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 low but greater than that of the general population because of the possibility of maternal germline mosaicism. • Daughters of an affected male will be obligate carriers and may or may not be affected; none of his sons will be affected. • Each child of an affected female has a 50% chance of inheriting the pathogenic variant. • Because of possible skewing of X-chromosome inactivation, variable phenotypes in females are possible. ## Related Genetic Counseling Issues ## Prenatal Testing and Preimplantation Genetic Testing 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 leukodystrophy are possible. ## Resources Department of Pediatrics University of Utah P.O. Box 581289 Salt Lake City UT 84158 • • • Department of Pediatrics University of Utah • P.O. Box 581289 • Salt Lake City UT 84158 • • • ## Management Although the underlying mechanisms of leukodystrophies are diverse, many manifestations are similar across this group of disorders. In the great majority of cases, primary treatment is not possible, but management of symptoms can improve the comfort and care of individuals with these complex disorders. Ideally, the child or adult with a leukodystrophy is managed in a multidisciplinary setting by providers experienced in the care of persons with a leukodystrophy. Primary disease manifestations can be prevented in a few of the leukodystrophies: in Standard surveillance includes the following: Routine measurement of weight and height to assess growth and nutritional status Physical examination and/or serial x-rays of the hips and spine to monitor for orthopedic complications Routine history regarding signs and symptoms of seizures Certain disorders require specialized surveillance; for example, monitoring for the development of hydrocephalus in In a number of leukodystrophies anecdotal evidence suggests episodic worsening of manifestations with mild head injuries and infection. While this has been clearly documented only for See Search • Routine measurement of weight and height to assess growth and nutritional status • Physical examination and/or serial x-rays of the hips and spine to monitor for orthopedic complications • Routine history regarding signs and symptoms of seizures ## Treatment of Manifestations Although the underlying mechanisms of leukodystrophies are diverse, many manifestations are similar across this group of disorders. In the great majority of cases, primary treatment is not possible, but management of symptoms can improve the comfort and care of individuals with these complex disorders. Ideally, the child or adult with a leukodystrophy is managed in a multidisciplinary setting by providers experienced in the care of persons with a leukodystrophy. ## Prevention of Primary Manifestations Primary disease manifestations can be prevented in a few of the leukodystrophies: in ## Surveillance Standard surveillance includes the following: Routine measurement of weight and height to assess growth and nutritional status Physical examination and/or serial x-rays of the hips and spine to monitor for orthopedic complications Routine history regarding signs and symptoms of seizures Certain disorders require specialized surveillance; for example, monitoring for the development of hydrocephalus in • Routine measurement of weight and height to assess growth and nutritional status • Physical examination and/or serial x-rays of the hips and spine to monitor for orthopedic complications • Routine history regarding signs and symptoms of seizures ## Agents/Circumstances to Avoid In a number of leukodystrophies anecdotal evidence suggests episodic worsening of manifestations with mild head injuries and infection. While this has been clearly documented only for ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## References ## Literature Cited ## Chapter Notes 30 January 2020 (ma) Retired chapter: Phenotype is too broad. 6 February 2014 (me) Review posted live 14 February 2012 (av) Original submission • 30 January 2020 (ma) Retired chapter: Phenotype is too broad. • 6 February 2014 (me) Review posted live • 14 February 2012 (av) Original submission ## Revision History 30 January 2020 (ma) Retired chapter: Phenotype is too broad. 6 February 2014 (me) Review posted live 14 February 2012 (av) Original submission • 30 January 2020 (ma) Retired chapter: Phenotype is too broad. • 6 February 2014 (me) Review posted live • 14 February 2012 (av) Original submission Hypomyelinating leukodystrophy has T Hypomyelinating leukodystrophy – patterns on MRI A→B. Improvement of myelination over time in C. D. Persistent and severe hypomyelination seen in a school-aged child with E. Cerebellar atrophy seen in F. Basal ganglia involvement seen in Confluent white matter lesions are extensive white matter abnormalities in significant portions of the brain, often affecting specific regions or tracts, although not necessarily perfectly symmetrically. Multifocal white matter lesions are more discrete, often asymmetric and involving a limited area. Demyelinating leukodystrophy – patterns on MRI A. Diffuse cerebral involvement in an individual with B. Primarily frontal involvement in a child with C. Primarily parieto-occipital involvement in a child with D. Primarily temporal involvement in an individual with E. Primarily subcortical involvement in F. Primarily periventricular involvement in an individual with G. Primarily brain stem involvement in an individual with H. Primarily cerebellar and middle cerebellar peduncle involvement in an individual with I. Large, asymmetric lesions in an individual with Algorithm Part 1: Demyelinating and other conditions Adapted from Algorithm Part 2: Hypomyelinating conditions Adapted from Features associated with specific leukodystrophies A. White matter rarefaction and cysts on FLAIR imaging in vanishing white matter disease; arrow indicates cystic rarefaction within abnormal white matter. B. Calcium deposits and hemosiderin deposits visible on CT in C. Contrast enhancement on T D. Cortical gray matter lesions in E. Cerebellar abnormalities seen in the dentate nucleus in L-2-hydroxyglutaric aciduria; arrow indicates symmetric hyperintensity. F. Thinning of the corpus callosum (particularly of the genu) in G. Non-calcifying basal ganglia lesions in H. Typical brain stem involvement in I. Spinal cord involvement in	[ "L Bezman, AB Moser, GV Raymond, P Rinaldo, PA Watkins, KD Smith, NE Kass, HW Moser. Adrenoleukodystrophy: incidence, new mutation rate, and results of extended family screening.. Ann Neurol. 2001;49:512-7", "JL Bonkowsky, C Nelson, JL Kingston, FM Filloux, MB Mundorff, R Srivastava. The burden of inherited leukodystrophies in children.. Neurology 2010;75:718-25", "F Eichler, W Grodd, E Grant, M Sessa, A Biffi, A Bley, A Kohlschuetter, DJ Loes, I Kraegeloh-Mann. Metachromatic leukodystrophy: a scoring system for brain MR imaging observations.. AJNR Am J Neuroradiol 2009;30:1893-7", "P Heim, M Claussen, B Hoffmann, E Conzelmann, J Gärtner, K Harzer, DH Hunneman, W Köhler, G Kurlemann, A Kohlschütter. Leukodystrophy incidence in Germany.. Am J Med Genet 1997;71:475-8", "R Schiffmann, MS van der Knaap. Invited article: an MRI-based approach to the diagnosis of white matter disorders.. Neurology 2009;72:750-9", "MS van der Knaap, SN Breiter, S Naidu, AA Hart, J Valk. Defining and categorizing leukoencephalopathies of unknown origin: MR imaging approach.. Radiology 1999;213:121-33" ]	6/2/2014			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
lgmd-overview	lgmd-overview	[ "LGMD", "LGMD", "Alpha-sarcoglycan", "Anoctamin-5", "Beta-sarcoglycan", "Calpain-3", "Caveolin-3", "Delta-sarcoglycan", "Desmin", "DnaJ homolog subfamily B member 6", "Dysferlin", "E3 ubiquitin-protein ligase TRIM32", "Fukutin", "Fukutin-related protein", "Gamma-sarcoglycan", "Myotilin", "Plectin", "Prelamin-A/C", "Protein O-linked-mannose beta-1,2-N-acetylglucosaminyltransferase 1", "Protein O-mannosyl-transferase 1", "Protein O-mannosyl-transferase 2", "Telethonin", "Titin", "ANO5", "CAPN3", "CAV3", "DES", "DNAJB6", "DYSF", "FKRP", "FKTN", "LMNA", "MYOT", "PLEC", "POMGNT1", "POMT1", "POMT2", "SGCA", "SGCB", "SGCD", "SGCG", "TCAP", "TRIM32", "TTN", "Limb-Girdle Muscular Dystrophy", "Overview" ]	Limb-Girdle Muscular Dystrophy Overview – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY	Elena Pegoraro, Eric P Hoffman	Summary Limb-girdle muscular dystrophy (LGMD) is a purely descriptive term, generally reserved for childhood- or adult-onset muscular dystrophies that are distinct from the much more common X-linked dystrophinopathies. LGMDs are typically nonsyndromic, with clinical involvement typically limited to skeletal muscle. Individuals with LGMD generally show weakness and wasting restricted to the limb musculature, proximal greater than distal, and muscle degeneration/regeneration on muscle biopsy. Most individuals with LGMD show relative sparing of the bulbar muscles, although exceptions occur, depending on the genetic subtype. Onset, progression, and distribution of the weakness and wasting vary considerably among individuals and genetic subtypes. The limb-girdle muscular dystrophies typically show degeneration/regeneration (dystrophic changes) on muscle biopsy, which is usually associated with elevated serum creatine kinase concentration. For any male or female suspected of having limb-girdle muscular dystrophy, it is necessary to first rule out an X-linked dystrophinopathy. Biochemical testing (i.e., protein testing by immunostaining or immunblotting) performed on a muscle biopsy can establish the diagnosis of the following LGMD types: sarcoglycanopathy, calpainopathy, dysferlinopathy, and O-linked glycosylation defects (also known as dystroglycanopathy). In some cases, demonstration of complete or partial deficiencies for any particular protein can then be followed by mutation studies of the corresponding gene. Pathogenic variants in a number of genes have been associated with types of LGMD. The term LGMD1 (including, e.g., LGMD1A, LGMD1B) refers to genetic types showing dominant inheritance, whereas LGMD2 refers to types with autosomal recessive inheritance. Pathogenic variants at more than 50 loci have been reported, making accurate diagnosis and genetic counseling a challenge. In most instances, the proband represents a simplex case, and the families can be counseled for recurrence risks associated with rare autosomal recessive conditions, which leaves a "significant" risk only for the sibs of the proband. If the causative pathogenic variant(s) have been identified in the family, prenatal testing for pregnancies at increased risk is possible. No definitive treatments for the limb-girdle muscular dystrophies exist. Management should be tailored as much as possible to each individual and each specific LGMD type. Management to prolong survival and improve quality of life includes weight control to avoid obesity, physical therapy and stretching exercises to promote mobility and prevent contractures, use of mechanical aids to help ambulation and mobility, surgical intervention for orthopedic complications, use of respiratory aids when indicated, monitoring for cardiomyopathy in LGMD types with cardiac involvement, and social and emotional support and stimulation.	## Definition Limb-girdle muscular dystrophy (LGMD) is a purely descriptive term, generally reserved for childhood- or adult-onset muscular dystrophies that are distinct from the much more common X-linked At one time, the term LGMD was reserved for individuals with onset of weakness in adolescence or adulthood. More severe childhood presentations were previously termed a "severe childhood autosomal recessive muscular dystrophy" (SCARMD); however, SCARMD is now considered a subset of LGMD. The term LGMD1 (including, e.g., LGMD1A, LGMD1B) refers to genetic types showing dominant inheritance, whereas LGMD2 refers to types with autosomal recessive inheritance. Pathogenic variants at more than 50 loci have been shown to cause LGMD. Individuals with LGMD generally show weakness and wasting restricted to the limb musculature, proximal greater than distal. Proximal weakness refers to weakness of the muscles closer to the center of the body (including the shoulder, pelvic girdle, upper thighs, and upper arms). Distal weakness refers to weakness in muscles farther from the center of the body (including lower legs and feet, lower arms and hands). Onset, progression, and distribution of the weakness and wasting may vary considerably among individuals and genetic subtypes. LGMDs are typically nonsyndromic, with clinical involvement typically limited to skeletal muscle. While most individuals with LGMD show relative sparing of the bulbar muscles, exceptions occur, depending on the genetic subtype. The clinical course of the limb-girdle muscular dystrophies is typically progressive, though some individuals may show mild symptoms and/or the disease may stabilize. Serum creatine kinase (CK) concentration is usually elevated. Muscle biopsy typically shows degeneration/regeneration of muscle fibers ("dystrophic changes"). In some LGMDs (i.e., sarcoglycanopathy, In some cases, molecular genetic testing can be used to identify the specific pathogenic variants. Inflammatory myopathy should be excluded during the diagnostic process. The following disorders are included in the differential diagnosis of the limb-girdle muscular dystrophies: Any male or female suspected of having limb-girdle muscular dystrophy must first be evaluated for dystrophinopathy. Males should be evaluated by molecular genetic testing of Females should be evaluated by dystrophin immunostaining of a muscle biopsy or by molecular genetic testing of Because of the heterogeneity of limb-girdle muscular dystrophy and the lack of diagnostic specificity, there are few reports on the prevalence of LGMD. Estimates of prevalence for all forms of LGMD range from one in 14,500 to one in 123,000 [ The estimated prevalence of primary sarcoglycanopathies is approximately one in 178,000 [ • The clinical course of the limb-girdle muscular dystrophies is typically progressive, though some individuals may show mild symptoms and/or the disease may stabilize. • Serum creatine kinase (CK) concentration is usually elevated. • Muscle biopsy typically shows degeneration/regeneration of muscle fibers ("dystrophic changes"). • In some LGMDs (i.e., sarcoglycanopathy, • In some cases, molecular genetic testing can be used to identify the specific pathogenic variants. • Inflammatory myopathy should be excluded during the diagnostic process. • Any male or female suspected of having limb-girdle muscular dystrophy must first be evaluated for dystrophinopathy. • Males should be evaluated by molecular genetic testing of • Females should be evaluated by dystrophin immunostaining of a muscle biopsy or by molecular genetic testing of • Males should be evaluated by molecular genetic testing of • Females should be evaluated by dystrophin immunostaining of a muscle biopsy or by molecular genetic testing of • Males should be evaluated by molecular genetic testing of • Females should be evaluated by dystrophin immunostaining of a muscle biopsy or by molecular genetic testing of ## Clinical Manifestations Individuals with LGMD generally show weakness and wasting restricted to the limb musculature, proximal greater than distal. Proximal weakness refers to weakness of the muscles closer to the center of the body (including the shoulder, pelvic girdle, upper thighs, and upper arms). Distal weakness refers to weakness in muscles farther from the center of the body (including lower legs and feet, lower arms and hands). Onset, progression, and distribution of the weakness and wasting may vary considerably among individuals and genetic subtypes. LGMDs are typically nonsyndromic, with clinical involvement typically limited to skeletal muscle. While most individuals with LGMD show relative sparing of the bulbar muscles, exceptions occur, depending on the genetic subtype. ## Establishing the Diagnosis The clinical course of the limb-girdle muscular dystrophies is typically progressive, though some individuals may show mild symptoms and/or the disease may stabilize. Serum creatine kinase (CK) concentration is usually elevated. Muscle biopsy typically shows degeneration/regeneration of muscle fibers ("dystrophic changes"). In some LGMDs (i.e., sarcoglycanopathy, In some cases, molecular genetic testing can be used to identify the specific pathogenic variants. Inflammatory myopathy should be excluded during the diagnostic process. • The clinical course of the limb-girdle muscular dystrophies is typically progressive, though some individuals may show mild symptoms and/or the disease may stabilize. • Serum creatine kinase (CK) concentration is usually elevated. • Muscle biopsy typically shows degeneration/regeneration of muscle fibers ("dystrophic changes"). • In some LGMDs (i.e., sarcoglycanopathy, • In some cases, molecular genetic testing can be used to identify the specific pathogenic variants. • Inflammatory myopathy should be excluded during the diagnostic process. ## Differential Diagnosis The following disorders are included in the differential diagnosis of the limb-girdle muscular dystrophies: Any male or female suspected of having limb-girdle muscular dystrophy must first be evaluated for dystrophinopathy. Males should be evaluated by molecular genetic testing of Females should be evaluated by dystrophin immunostaining of a muscle biopsy or by molecular genetic testing of • Any male or female suspected of having limb-girdle muscular dystrophy must first be evaluated for dystrophinopathy. • Males should be evaluated by molecular genetic testing of • Females should be evaluated by dystrophin immunostaining of a muscle biopsy or by molecular genetic testing of • Males should be evaluated by molecular genetic testing of • Females should be evaluated by dystrophin immunostaining of a muscle biopsy or by molecular genetic testing of • Males should be evaluated by molecular genetic testing of • Females should be evaluated by dystrophin immunostaining of a muscle biopsy or by molecular genetic testing of ## Prevalence Because of the heterogeneity of limb-girdle muscular dystrophy and the lack of diagnostic specificity, there are few reports on the prevalence of LGMD. Estimates of prevalence for all forms of LGMD range from one in 14,500 to one in 123,000 [ The estimated prevalence of primary sarcoglycanopathies is approximately one in 178,000 [ ## Causes In this section, the type of limb-girdle muscular dystrophy is categorized by mode of inheritance and molecular genetics. Molecular Genetics of Autosomal Recessive Limb-Girdle Muscular Dystrophy (LGMD) See From SCARMD = severe childhood autosomal recessive muscular dystrophy Ranges from 10% in the population of European descent [ MDDG (muscular dystrophy-dystroglycanopathy) [ In nonconsanguineous populations, the relative frequency of pathogenic variants in the four genes is alpha >> beta >> gamma >> delta in an 8:4:2:1 ratio [ To date, two common pathogenic variants, 826C>A and 427C>A, have been observed in individuals with LGMD2I but not in those with MDC1C [ Autosomal Recessive LGMD: Clinical Findings Heart involvement is variable, but typically less severe than in the dystrophinopathies. Cardiomyopathy is common in beta-, delta-, and gamma-sarcoglycanopathy, but rare in alpha-sarcoglycanopathy [ Most individuals with severe, childhood-onset limb-girdle muscular dystrophy have pathogenic variants in Some individuals heterozygous for a pathogenic variant in Genotype/phenotype correlations in large series have been published in multiple populations [ Pelvifemoral LGMD (Leyden-Möbius) phenotype, the most frequently observed calpainopathy phenotype, in which muscle weakness is first evident in the pelvic girdle and later in the shoulder girdle with onset before age 12 years or after age 30 years; Scapulohumeral LGMD (Erb) phenotype, usually a milder phenotype with infrequent early onset, in which muscle weakness is first evident in the shoulder girdle and later in the pelvic girdle; and HyperCKemia, usually observed in children or young individuals, in which symptomatic individuals have only high serum CK concentrations. Clinical findings include the tendency to walk on tiptoes, difficulty in running, scapular winging, waddling gait, and slight hyperlordosis. Early Achilles tendon shortening and scoliosis may be present. Limb-girdle muscular dystrophy syndrome (LGMD2B) with early weakness and atrophy of the pelvic and shoulder girdle muscles in adolescence or young adulthood, with slow progression. Respiratory and cardiac muscles are not involved. Miyoshi myopathy with muscle weakness and atrophy in young adults, most marked in the distal parts of the legs, especially the gastrocnemius and soleus muscles. Over a period of years, the weakness and atrophy spread to the thighs and gluteal muscles. The forearms may become mildly atrophic with decrease in grip strength, but the small muscles of the hands are spared. Two other phenotypes are seen: Distal anterior compartment myopathy (DMAT), which presents in the third decade with weakness of the anterior tibialis muscles. The disease is rapidly progressive resulting in severe proximal weakness of the lower limbs first, followed by the upper limbs [ Dysferlinopathy with rigid spine, which presents with lower limb weakness and atrophy in addition to contractures of the neck, chest, hip, and knee [ Sarcotubular myopathy (STM), caused by the same pathogenic variant in Late onset proximal pelvic girdle muscle weakness with (often asymmetric) atrophy of the quadriceps femoris and biceps brachii Later-onset mild asymmetric calf hypertrophy or early calf weakness without atrophy associated with difficulties walking on tiptoes As disease progresses the phenotypes overlap and merge into a homogeneous clinical entity [ Most of the autosomal dominant limb-girdle muscular dystrophy loci have been described in single extended pedigrees [ Molecular Genetics of Autosomal Dominant LGMD See Locus name given if gene is unknown Autosomal Dominant LGMD: Clinical Findings • Pelvifemoral LGMD (Leyden-Möbius) phenotype, the most frequently observed calpainopathy phenotype, in which muscle weakness is first evident in the pelvic girdle and later in the shoulder girdle with onset before age 12 years or after age 30 years; • Scapulohumeral LGMD (Erb) phenotype, usually a milder phenotype with infrequent early onset, in which muscle weakness is first evident in the shoulder girdle and later in the pelvic girdle; and • HyperCKemia, usually observed in children or young individuals, in which symptomatic individuals have only high serum CK concentrations. • Limb-girdle muscular dystrophy syndrome (LGMD2B) with early weakness and atrophy of the pelvic and shoulder girdle muscles in adolescence or young adulthood, with slow progression. Respiratory and cardiac muscles are not involved. • Miyoshi myopathy with muscle weakness and atrophy in young adults, most marked in the distal parts of the legs, especially the gastrocnemius and soleus muscles. Over a period of years, the weakness and atrophy spread to the thighs and gluteal muscles. The forearms may become mildly atrophic with decrease in grip strength, but the small muscles of the hands are spared. • Distal anterior compartment myopathy (DMAT), which presents in the third decade with weakness of the anterior tibialis muscles. The disease is rapidly progressive resulting in severe proximal weakness of the lower limbs first, followed by the upper limbs [ • Dysferlinopathy with rigid spine, which presents with lower limb weakness and atrophy in addition to contractures of the neck, chest, hip, and knee [ • Late onset proximal pelvic girdle muscle weakness with (often asymmetric) atrophy of the quadriceps femoris and biceps brachii • Later-onset mild asymmetric calf hypertrophy or early calf weakness without atrophy associated with difficulties walking on tiptoes ## Autosomal Recessive Limb-Girdle Muscular Dystrophy Molecular Genetics of Autosomal Recessive Limb-Girdle Muscular Dystrophy (LGMD) See From SCARMD = severe childhood autosomal recessive muscular dystrophy Ranges from 10% in the population of European descent [ MDDG (muscular dystrophy-dystroglycanopathy) [ In nonconsanguineous populations, the relative frequency of pathogenic variants in the four genes is alpha >> beta >> gamma >> delta in an 8:4:2:1 ratio [ To date, two common pathogenic variants, 826C>A and 427C>A, have been observed in individuals with LGMD2I but not in those with MDC1C [ Autosomal Recessive LGMD: Clinical Findings Heart involvement is variable, but typically less severe than in the dystrophinopathies. Cardiomyopathy is common in beta-, delta-, and gamma-sarcoglycanopathy, but rare in alpha-sarcoglycanopathy [ Most individuals with severe, childhood-onset limb-girdle muscular dystrophy have pathogenic variants in Some individuals heterozygous for a pathogenic variant in Genotype/phenotype correlations in large series have been published in multiple populations [ Pelvifemoral LGMD (Leyden-Möbius) phenotype, the most frequently observed calpainopathy phenotype, in which muscle weakness is first evident in the pelvic girdle and later in the shoulder girdle with onset before age 12 years or after age 30 years; Scapulohumeral LGMD (Erb) phenotype, usually a milder phenotype with infrequent early onset, in which muscle weakness is first evident in the shoulder girdle and later in the pelvic girdle; and HyperCKemia, usually observed in children or young individuals, in which symptomatic individuals have only high serum CK concentrations. Clinical findings include the tendency to walk on tiptoes, difficulty in running, scapular winging, waddling gait, and slight hyperlordosis. Early Achilles tendon shortening and scoliosis may be present. Limb-girdle muscular dystrophy syndrome (LGMD2B) with early weakness and atrophy of the pelvic and shoulder girdle muscles in adolescence or young adulthood, with slow progression. Respiratory and cardiac muscles are not involved. Miyoshi myopathy with muscle weakness and atrophy in young adults, most marked in the distal parts of the legs, especially the gastrocnemius and soleus muscles. Over a period of years, the weakness and atrophy spread to the thighs and gluteal muscles. The forearms may become mildly atrophic with decrease in grip strength, but the small muscles of the hands are spared. Two other phenotypes are seen: Distal anterior compartment myopathy (DMAT), which presents in the third decade with weakness of the anterior tibialis muscles. The disease is rapidly progressive resulting in severe proximal weakness of the lower limbs first, followed by the upper limbs [ Dysferlinopathy with rigid spine, which presents with lower limb weakness and atrophy in addition to contractures of the neck, chest, hip, and knee [ Sarcotubular myopathy (STM), caused by the same pathogenic variant in Late onset proximal pelvic girdle muscle weakness with (often asymmetric) atrophy of the quadriceps femoris and biceps brachii Later-onset mild asymmetric calf hypertrophy or early calf weakness without atrophy associated with difficulties walking on tiptoes As disease progresses the phenotypes overlap and merge into a homogeneous clinical entity [ • Pelvifemoral LGMD (Leyden-Möbius) phenotype, the most frequently observed calpainopathy phenotype, in which muscle weakness is first evident in the pelvic girdle and later in the shoulder girdle with onset before age 12 years or after age 30 years; • Scapulohumeral LGMD (Erb) phenotype, usually a milder phenotype with infrequent early onset, in which muscle weakness is first evident in the shoulder girdle and later in the pelvic girdle; and • HyperCKemia, usually observed in children or young individuals, in which symptomatic individuals have only high serum CK concentrations. • Limb-girdle muscular dystrophy syndrome (LGMD2B) with early weakness and atrophy of the pelvic and shoulder girdle muscles in adolescence or young adulthood, with slow progression. Respiratory and cardiac muscles are not involved. • Miyoshi myopathy with muscle weakness and atrophy in young adults, most marked in the distal parts of the legs, especially the gastrocnemius and soleus muscles. Over a period of years, the weakness and atrophy spread to the thighs and gluteal muscles. The forearms may become mildly atrophic with decrease in grip strength, but the small muscles of the hands are spared. • Distal anterior compartment myopathy (DMAT), which presents in the third decade with weakness of the anterior tibialis muscles. The disease is rapidly progressive resulting in severe proximal weakness of the lower limbs first, followed by the upper limbs [ • Dysferlinopathy with rigid spine, which presents with lower limb weakness and atrophy in addition to contractures of the neck, chest, hip, and knee [ • Late onset proximal pelvic girdle muscle weakness with (often asymmetric) atrophy of the quadriceps femoris and biceps brachii • Later-onset mild asymmetric calf hypertrophy or early calf weakness without atrophy associated with difficulties walking on tiptoes ## Molecular Genetics Molecular Genetics of Autosomal Recessive Limb-Girdle Muscular Dystrophy (LGMD) See From SCARMD = severe childhood autosomal recessive muscular dystrophy Ranges from 10% in the population of European descent [ MDDG (muscular dystrophy-dystroglycanopathy) [ In nonconsanguineous populations, the relative frequency of pathogenic variants in the four genes is alpha >> beta >> gamma >> delta in an 8:4:2:1 ratio [ To date, two common pathogenic variants, 826C>A and 427C>A, have been observed in individuals with LGMD2I but not in those with MDC1C [ ## Clinical Findings Autosomal Recessive LGMD: Clinical Findings Heart involvement is variable, but typically less severe than in the dystrophinopathies. Cardiomyopathy is common in beta-, delta-, and gamma-sarcoglycanopathy, but rare in alpha-sarcoglycanopathy [ Most individuals with severe, childhood-onset limb-girdle muscular dystrophy have pathogenic variants in Some individuals heterozygous for a pathogenic variant in Genotype/phenotype correlations in large series have been published in multiple populations [ Pelvifemoral LGMD (Leyden-Möbius) phenotype, the most frequently observed calpainopathy phenotype, in which muscle weakness is first evident in the pelvic girdle and later in the shoulder girdle with onset before age 12 years or after age 30 years; Scapulohumeral LGMD (Erb) phenotype, usually a milder phenotype with infrequent early onset, in which muscle weakness is first evident in the shoulder girdle and later in the pelvic girdle; and HyperCKemia, usually observed in children or young individuals, in which symptomatic individuals have only high serum CK concentrations. Clinical findings include the tendency to walk on tiptoes, difficulty in running, scapular winging, waddling gait, and slight hyperlordosis. Early Achilles tendon shortening and scoliosis may be present. Limb-girdle muscular dystrophy syndrome (LGMD2B) with early weakness and atrophy of the pelvic and shoulder girdle muscles in adolescence or young adulthood, with slow progression. Respiratory and cardiac muscles are not involved. Miyoshi myopathy with muscle weakness and atrophy in young adults, most marked in the distal parts of the legs, especially the gastrocnemius and soleus muscles. Over a period of years, the weakness and atrophy spread to the thighs and gluteal muscles. The forearms may become mildly atrophic with decrease in grip strength, but the small muscles of the hands are spared. Two other phenotypes are seen: Distal anterior compartment myopathy (DMAT), which presents in the third decade with weakness of the anterior tibialis muscles. The disease is rapidly progressive resulting in severe proximal weakness of the lower limbs first, followed by the upper limbs [ Dysferlinopathy with rigid spine, which presents with lower limb weakness and atrophy in addition to contractures of the neck, chest, hip, and knee [ Sarcotubular myopathy (STM), caused by the same pathogenic variant in Late onset proximal pelvic girdle muscle weakness with (often asymmetric) atrophy of the quadriceps femoris and biceps brachii Later-onset mild asymmetric calf hypertrophy or early calf weakness without atrophy associated with difficulties walking on tiptoes As disease progresses the phenotypes overlap and merge into a homogeneous clinical entity [ • Pelvifemoral LGMD (Leyden-Möbius) phenotype, the most frequently observed calpainopathy phenotype, in which muscle weakness is first evident in the pelvic girdle and later in the shoulder girdle with onset before age 12 years or after age 30 years; • Scapulohumeral LGMD (Erb) phenotype, usually a milder phenotype with infrequent early onset, in which muscle weakness is first evident in the shoulder girdle and later in the pelvic girdle; and • HyperCKemia, usually observed in children or young individuals, in which symptomatic individuals have only high serum CK concentrations. • Limb-girdle muscular dystrophy syndrome (LGMD2B) with early weakness and atrophy of the pelvic and shoulder girdle muscles in adolescence or young adulthood, with slow progression. Respiratory and cardiac muscles are not involved. • Miyoshi myopathy with muscle weakness and atrophy in young adults, most marked in the distal parts of the legs, especially the gastrocnemius and soleus muscles. Over a period of years, the weakness and atrophy spread to the thighs and gluteal muscles. The forearms may become mildly atrophic with decrease in grip strength, but the small muscles of the hands are spared. • Distal anterior compartment myopathy (DMAT), which presents in the third decade with weakness of the anterior tibialis muscles. The disease is rapidly progressive resulting in severe proximal weakness of the lower limbs first, followed by the upper limbs [ • Dysferlinopathy with rigid spine, which presents with lower limb weakness and atrophy in addition to contractures of the neck, chest, hip, and knee [ • Late onset proximal pelvic girdle muscle weakness with (often asymmetric) atrophy of the quadriceps femoris and biceps brachii • Later-onset mild asymmetric calf hypertrophy or early calf weakness without atrophy associated with difficulties walking on tiptoes ## Autosomal Dominant Limb-Girdle Muscular Dystrophy Most of the autosomal dominant limb-girdle muscular dystrophy loci have been described in single extended pedigrees [ Molecular Genetics of Autosomal Dominant LGMD See Locus name given if gene is unknown Autosomal Dominant LGMD: Clinical Findings ## Molecular Genetics Molecular Genetics of Autosomal Dominant LGMD See Locus name given if gene is unknown ## Clinical Findings Autosomal Dominant LGMD: Clinical Findings ## Evaluation Strategy Establishing the type of LGMD can be useful in discussions of the clinical course of the disease and for genetic counseling purposes. Establishing the specific type of LGMD in a given individual usually involves obtaining the medical history and family history, performing a physical examination, and laboratory testing (see Note: (1) Only dysferlin immunoblotting of muscle is currently thought to be specific and sensitive. (2) Results of immunostaining of muscle should be confirmed with molecular genetic testing when it is available. Use of molecular genetic testing to establish the specific type of LGMD is problematic: Many genes are involved. Pathogenic variants in no one gene account for the majority of cases. Few clinical or laboratory findings help identify the associated gene for a given individual. The lack of common pathogenic variants prevents efficient screening by genotype. About 50% of currently identified LGMD would have no molecular diagnosis, even if all 20 currently known genes were fully sequenced. For these reasons, clinicians may consider use of limb-girdle muscular dystrophy multigene panels that include a number of genes associated with LGMD. Note: Panels vary by methods used and genes included; thus, the ability of a panel to detect a causative variant(s) in any given individual with LGMD also varies. Testing Used to Establish LGMD Type Muscle protein (biochemical) testing: - Immunochemistry = exposing sections of tissue to an antibody to determine if a specific protein is present or absent; does not quantify the amount of the protein- Immunostaining = use of a dye to detect the antibody - Immunofluorescence = use of a fluorescent dye to detect the antibody - Immunoblot (or western blot) = removing a specific protein from a tissue of interest to quantify the size and amount of the protein Note: Not all protein tests are equally effective in diagnosing each form of LGMD (e.g., immunoblot for dysferlin is both sensitive and specific for diagnosing LGMD2B, whereas immunostaining for dysferlin is sensitive but not specific). Most protein tests are not specific for proteins altered by a pathogenic variant in a particular gene, but the results can help focus molecular genetic testing. Because of the interdependent nature of the sarcoglycan complex, deficiency of any of the four sarcoglycan proteins on immunostaining can be representative of a pathogenic variant in any of the four sarcoglycan genes. Sensitivity and specificity for the sarcoglycanopathies is high, although specificity for the particular form of sarcoglycanopathy is low. Specificity is low. May lead to misclassification as autoimmune disease Immunostaining for dysferlin is much less specific than immunoblotting. Immunoblotting of muscle or white blood cells is highly specific for pathogenic variants in Protein quantification is unreliable; diagnosis relies on molecular genetic testing [ Heterozygotes for a pathogenic variant in Because individuals with Data suggest that immunostaining of frozen muscle is relatively sensitive for detecting primary sarcoglycanopathy; however, it is not specific. • Many genes are involved. • Pathogenic variants in no one gene account for the majority of cases. • Few clinical or laboratory findings help identify the associated gene for a given individual. • The lack of common pathogenic variants prevents efficient screening by genotype. • About 50% of currently identified LGMD would have no molecular diagnosis, even if all 20 currently known genes were fully sequenced. ## Genetic Counseling Limb-girdle muscular dystrophy may be transmitted in an autosomal recessive manner or – less commonly – in an autosomal dominant manner. Difficulties in accurate diagnosis and determination of inheritance in an individual family make genetic counseling particularly complicated. The parents are obligate heterozygotes and therefore carry a single copy of a pathogenic variant. Heterozygotes (carriers) are asymptomatic. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3. Heterozygotes (carriers) are asymptomatic. Clinical severity and disease phenotype often differ among individuals with the same pathogenic variants; thus, age of onset and/or disease progression in affected sibs cannot be predicted. All offspring are obligate carriers. In consanguineous populations with an autosomal recessive disorder, risks to the offspring of a proband should be calculated based on the carrier frequency in the population. If the pathogenic variants in the proband have been identified, carrier testing for at-risk family members is possible through laboratories offering either testing for the gene of interest or custom testing. Most individuals diagnosed as having autosomal dominant limb-girdle muscular dystrophy have an affected parent, although symptoms may be variable among family members. Occasionally the family history is negative. It should be emphasized that an individual with no family history of LGMD may have a Note: Although most individuals diagnosed with autosomal dominant limb-girdle muscular dystrophy have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. The risk to sibs depends on the genetic status of the proband's parents. If one of the proband's parents has a mutated allele, the risk to the sibs of inheriting the mutated allele is 50%. Clinical severity and disease phenotype often differ among individuals with the same pathogenic variant; thus, age of onset and/or disease progression cannot be predicted. When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. Although no instances of germline mosaicism have been reported, it remains a possibility. Individuals with autosomal dominant limb-girdle muscular dystrophy have a 50% chance of transmitting the mutated allele to each child. Clinical severity and disease phenotype often differ among individuals with the same pathogenic variant; thus, age of onset and/or disease progression cannot be predicted. Uncertainties regarding the specificity of protein-based testing of individual muscle biopsies make accurate genetic counseling difficult when based purely on protein testing of muscle biopsy. Often the mode of inheritance cannot be determined. In most instances, the families can be counseled for recurrence risks associated with rare autosomal recessive conditions, which leaves a "significant" risk only for the sibs of the proband. Because many of the LGMDs show a later onset, the parents of the proband may have completed their family by the time that the diagnosis is established. The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once the pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. • The parents are obligate heterozygotes and therefore carry a single copy of a pathogenic variant. • Heterozygotes (carriers) are asymptomatic. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3. • Heterozygotes (carriers) are asymptomatic. • Clinical severity and disease phenotype often differ among individuals with the same pathogenic variants; thus, age of onset and/or disease progression in affected sibs cannot be predicted. • All offspring are obligate carriers. • In consanguineous populations with an autosomal recessive disorder, risks to the offspring of a proband should be calculated based on the carrier frequency in the population. • Most individuals diagnosed as having autosomal dominant limb-girdle muscular dystrophy have an affected parent, although symptoms may be variable among family members. • Occasionally the family history is negative. It should be emphasized that an individual with no family history of LGMD may have a • Note: Although most individuals diagnosed with autosomal dominant limb-girdle muscular dystrophy have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. • The risk to sibs depends on the genetic status of the proband's parents. • If one of the proband's parents has a mutated allele, the risk to the sibs of inheriting the mutated allele is 50%. • Clinical severity and disease phenotype often differ among individuals with the same pathogenic variant; thus, age of onset and/or disease progression cannot be predicted. • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. Although no instances of germline mosaicism have been reported, it remains a possibility. • Individuals with autosomal dominant limb-girdle muscular dystrophy have a 50% chance of transmitting the mutated allele to each child. • Clinical severity and disease phenotype often differ among individuals with the same pathogenic variant; thus, age of onset and/or disease progression cannot be predicted. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance Limb-girdle muscular dystrophy may be transmitted in an autosomal recessive manner or – less commonly – in an autosomal dominant manner. Difficulties in accurate diagnosis and determination of inheritance in an individual family make genetic counseling particularly complicated. ## Risk to Family Members – Autosomal Recessive Limb-Girdle Muscular Dystrophy The parents are obligate heterozygotes and therefore carry a single copy of a pathogenic variant. Heterozygotes (carriers) are asymptomatic. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3. Heterozygotes (carriers) are asymptomatic. Clinical severity and disease phenotype often differ among individuals with the same pathogenic variants; thus, age of onset and/or disease progression in affected sibs cannot be predicted. All offspring are obligate carriers. In consanguineous populations with an autosomal recessive disorder, risks to the offspring of a proband should be calculated based on the carrier frequency in the population. • The parents are obligate heterozygotes and therefore carry a single copy of a pathogenic variant. • Heterozygotes (carriers) are asymptomatic. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3. • Heterozygotes (carriers) are asymptomatic. • Clinical severity and disease phenotype often differ among individuals with the same pathogenic variants; thus, age of onset and/or disease progression in affected sibs cannot be predicted. • All offspring are obligate carriers. • In consanguineous populations with an autosomal recessive disorder, risks to the offspring of a proband should be calculated based on the carrier frequency in the population. ## Carrier Detection If the pathogenic variants in the proband have been identified, carrier testing for at-risk family members is possible through laboratories offering either testing for the gene of interest or custom testing. ## Risk to Family Members – Autosomal Dominant Limb-Girdle Muscular Dystrophy Most individuals diagnosed as having autosomal dominant limb-girdle muscular dystrophy have an affected parent, although symptoms may be variable among family members. Occasionally the family history is negative. It should be emphasized that an individual with no family history of LGMD may have a Note: Although most individuals diagnosed with autosomal dominant limb-girdle muscular dystrophy have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. The risk to sibs depends on the genetic status of the proband's parents. If one of the proband's parents has a mutated allele, the risk to the sibs of inheriting the mutated allele is 50%. Clinical severity and disease phenotype often differ among individuals with the same pathogenic variant; thus, age of onset and/or disease progression cannot be predicted. When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. Although no instances of germline mosaicism have been reported, it remains a possibility. Individuals with autosomal dominant limb-girdle muscular dystrophy have a 50% chance of transmitting the mutated allele to each child. Clinical severity and disease phenotype often differ among individuals with the same pathogenic variant; thus, age of onset and/or disease progression cannot be predicted. • Most individuals diagnosed as having autosomal dominant limb-girdle muscular dystrophy have an affected parent, although symptoms may be variable among family members. • Occasionally the family history is negative. It should be emphasized that an individual with no family history of LGMD may have a • Note: Although most individuals diagnosed with autosomal dominant limb-girdle muscular dystrophy have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. • The risk to sibs depends on the genetic status of the proband's parents. • If one of the proband's parents has a mutated allele, the risk to the sibs of inheriting the mutated allele is 50%. • Clinical severity and disease phenotype often differ among individuals with the same pathogenic variant; thus, age of onset and/or disease progression cannot be predicted. • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. Although no instances of germline mosaicism have been reported, it remains a possibility. • Individuals with autosomal dominant limb-girdle muscular dystrophy have a 50% chance of transmitting the mutated allele to each child. • Clinical severity and disease phenotype often differ among individuals with the same pathogenic variant; thus, age of onset and/or disease progression cannot be predicted. ## Related Genetic Counseling Issues Uncertainties regarding the specificity of protein-based testing of individual muscle biopsies make accurate genetic counseling difficult when based purely on protein testing of muscle biopsy. Often the mode of inheritance cannot be determined. In most instances, the families can be counseled for recurrence risks associated with rare autosomal recessive conditions, which leaves a "significant" risk only for the sibs of the proband. Because many of the LGMDs show a later onset, the parents of the proband may have completed their family by the time that the diagnosis is established. The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. ## Resources 222 South Riverside Plaza Suite 1500 Chicago IL 60606 61A Great Suffolk Street London SE1 0BU United Kingdom • • • • 222 South Riverside Plaza • Suite 1500 • Chicago IL 60606 • • • 61A Great Suffolk Street • London SE1 0BU • United Kingdom • ## Management No definitive treatments for the limb-girdle muscular dystrophies exist. Management should be tailored as much as possible to each individual and each specific LGMD type. A general approach to appropriate management can prolong survival and improve quality of life. This general approach is based on the typical progression and complications of individuals with LGMD as described by Weight control to avoid obesity Physical therapy and stretching exercises to promote mobility and prevent contractures Use of mechanical aids such as canes, walkers, orthotics, and wheelchairs as needed to help ambulation and mobility Surgical intervention as needed for orthopedic complications such as foot deformity and scoliosis Use of respiratory aids when indicated Referral to a cardiologist for standard supportive treatment of cardiomyopathy Social and emotional support and stimulation to maximize a sense of social involvement and productivity and to reduce the sense of social isolation common in these disorders [ Clinical genetics consultation The following are appropriate: Monitoring for orthopedic complications such as foot deformity and scoliosis Monitoring of respiratory function Monitoring for evidence of cardiomyopathy in those LGMD types known to have cardiac involvement Weight should be controlled to avoid obesity. See Search • Weight control to avoid obesity • Physical therapy and stretching exercises to promote mobility and prevent contractures • Use of mechanical aids such as canes, walkers, orthotics, and wheelchairs as needed to help ambulation and mobility • Surgical intervention as needed for orthopedic complications such as foot deformity and scoliosis • Use of respiratory aids when indicated • Referral to a cardiologist for standard supportive treatment of cardiomyopathy • Social and emotional support and stimulation to maximize a sense of social involvement and productivity and to reduce the sense of social isolation common in these disorders [ • Clinical genetics consultation • Monitoring for orthopedic complications such as foot deformity and scoliosis • Monitoring of respiratory function • Monitoring for evidence of cardiomyopathy in those LGMD types known to have cardiac involvement ## Treatment of Manifestations No definitive treatments for the limb-girdle muscular dystrophies exist. Management should be tailored as much as possible to each individual and each specific LGMD type. A general approach to appropriate management can prolong survival and improve quality of life. This general approach is based on the typical progression and complications of individuals with LGMD as described by Weight control to avoid obesity Physical therapy and stretching exercises to promote mobility and prevent contractures Use of mechanical aids such as canes, walkers, orthotics, and wheelchairs as needed to help ambulation and mobility Surgical intervention as needed for orthopedic complications such as foot deformity and scoliosis Use of respiratory aids when indicated Referral to a cardiologist for standard supportive treatment of cardiomyopathy Social and emotional support and stimulation to maximize a sense of social involvement and productivity and to reduce the sense of social isolation common in these disorders [ Clinical genetics consultation • Weight control to avoid obesity • Physical therapy and stretching exercises to promote mobility and prevent contractures • Use of mechanical aids such as canes, walkers, orthotics, and wheelchairs as needed to help ambulation and mobility • Surgical intervention as needed for orthopedic complications such as foot deformity and scoliosis • Use of respiratory aids when indicated • Referral to a cardiologist for standard supportive treatment of cardiomyopathy • Social and emotional support and stimulation to maximize a sense of social involvement and productivity and to reduce the sense of social isolation common in these disorders [ • Clinical genetics consultation ## Surveillance The following are appropriate: Monitoring for orthopedic complications such as foot deformity and scoliosis Monitoring of respiratory function Monitoring for evidence of cardiomyopathy in those LGMD types known to have cardiac involvement • Monitoring for orthopedic complications such as foot deformity and scoliosis • Monitoring of respiratory function • Monitoring for evidence of cardiomyopathy in those LGMD types known to have cardiac involvement ## Agents/Circumstances to Avoid Weight should be controlled to avoid obesity. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## References ## Literature Cited ## Suggested Reading ## Chapter Notes Erynn Gordon, MS, CGC; Children's National Medical Center (2003-2012) Eric P Hoffman, PhD (2000-present) Elena Pegoraro, MD, PhD (2000-present) Cheryl Scacheri, MS; GeneDx, Inc (2000-2003) 17 May 2018 (ma) Retired chapter: outdated; qualified authors not available for update 30 August 2012 (me) Comprehensive update posted live 23 July 2009 (cd) Revision: clinical testing available for LGMD1A, telethoninopathy, LGMD2H, and LGMD 2J 8 June 2007 (cd) Revision: clinical testing available for caveolinopathies 8 February 2006 (cd) Revision: clinical testing available for LGMD2K 3 February 2006 (me) Comprehensive update posted live 14 October 2004 (eh) Revision: Differential Diagnosis 26 July 2004 (eh) Revision: prenatal testing for LGMD1B; changes to Bethlem myopathy 11 February 2004 (eh) Revision: sequence analysis for 14 November 2003 (eh) Revision: molecular genetic testing clinically available 14 August 2003 (me) Comprehensive update posted live 31 January 2001 (eh) Author revisions 8 November 2000 (eh) Author revisions 8 June 2000 (tk, pb) Overview posted live 20 April 2000 (eh) Original submission • 17 May 2018 (ma) Retired chapter: outdated; qualified authors not available for update • 30 August 2012 (me) Comprehensive update posted live • 23 July 2009 (cd) Revision: clinical testing available for LGMD1A, telethoninopathy, LGMD2H, and LGMD 2J • 8 June 2007 (cd) Revision: clinical testing available for caveolinopathies • 8 February 2006 (cd) Revision: clinical testing available for LGMD2K • 3 February 2006 (me) Comprehensive update posted live • 14 October 2004 (eh) Revision: Differential Diagnosis • 26 July 2004 (eh) Revision: prenatal testing for LGMD1B; changes to Bethlem myopathy • 11 February 2004 (eh) Revision: sequence analysis for • 14 November 2003 (eh) Revision: molecular genetic testing clinically available • 14 August 2003 (me) Comprehensive update posted live • 31 January 2001 (eh) Author revisions • 8 November 2000 (eh) Author revisions • 8 June 2000 (tk, pb) Overview posted live • 20 April 2000 (eh) Original submission ## Author History Erynn Gordon, MS, CGC; Children's National Medical Center (2003-2012) Eric P Hoffman, PhD (2000-present) Elena Pegoraro, MD, PhD (2000-present) Cheryl Scacheri, MS; GeneDx, Inc (2000-2003) ## Revision History 17 May 2018 (ma) Retired chapter: outdated; qualified authors not available for update 30 August 2012 (me) Comprehensive update posted live 23 July 2009 (cd) Revision: clinical testing available for LGMD1A, telethoninopathy, LGMD2H, and LGMD 2J 8 June 2007 (cd) Revision: clinical testing available for caveolinopathies 8 February 2006 (cd) Revision: clinical testing available for LGMD2K 3 February 2006 (me) Comprehensive update posted live 14 October 2004 (eh) Revision: Differential Diagnosis 26 July 2004 (eh) Revision: prenatal testing for LGMD1B; changes to Bethlem myopathy 11 February 2004 (eh) Revision: sequence analysis for 14 November 2003 (eh) Revision: molecular genetic testing clinically available 14 August 2003 (me) Comprehensive update posted live 31 January 2001 (eh) Author revisions 8 November 2000 (eh) Author revisions 8 June 2000 (tk, pb) Overview posted live 20 April 2000 (eh) Original submission • 17 May 2018 (ma) Retired chapter: outdated; qualified authors not available for update • 30 August 2012 (me) Comprehensive update posted live • 23 July 2009 (cd) Revision: clinical testing available for LGMD1A, telethoninopathy, LGMD2H, and LGMD 2J • 8 June 2007 (cd) Revision: clinical testing available for caveolinopathies • 8 February 2006 (cd) Revision: clinical testing available for LGMD2K • 3 February 2006 (me) Comprehensive update posted live • 14 October 2004 (eh) Revision: Differential Diagnosis • 26 July 2004 (eh) Revision: prenatal testing for LGMD1B; changes to Bethlem myopathy • 11 February 2004 (eh) Revision: sequence analysis for • 14 November 2003 (eh) Revision: molecular genetic testing clinically available • 14 August 2003 (me) Comprehensive update posted live • 31 January 2001 (eh) Author revisions • 8 November 2000 (eh) Author revisions • 8 June 2000 (tk, pb) Overview posted live • 20 April 2000 (eh) Original submission	[ "J Amberger, C Bocchini, A Hamosh. A new face and new challanges for online Mendelian Inheritance in Man (OMIM®).. Hum Mutat 2011;32:564-7", "C Angelini, M Fanin, E Menegazzo, MP Freda, DJ Duggan, EP Hoffman. Homozygous alpha-sarcoglycan mutation in two siblings: one asymptomatic and one steroid-responsive mild limb-girdle muscular dystrophy patient.. Muscle Nerve 1998;21:769-75", "B Balci, G Uyanik, P Dinçer, C Gross, T Willer, B Talim, G Haliloglu, G Kale, U Hehr, J Winkler, H Topaloglu. An autosomal recessive limb girdle muscular dystrophy (LGMD2) with mild mental retardation is allelic to Walker-Warburg syndrome (WWS) caused by a mutation in the POMT1 gene.. Neuromuscul Disord 2005;15:271-5", "D Bansal, K Miyake, SS Vogel, S Groh, CC Chen, R Williamson, PL McNeil, KP Campbell. Defective membrane repair in dysferlin-deficient muscular dystrophy.. Nature 2003;423:168-72", "BL Banwell, J Russel, T Fukudome, XM Shen, G Stilling, AG Engel. Myopathy, myasthenic syndrome, and epidermolysis bullosa simplex due to plectin deficiency.. J Neuropathol Exp Neurol 1999;58:832-46", "R Biancheri, A Falace, A Tessa, M Pedemonte, S Scapolan, D Cassandrini, C Aiello, A Rossi, P Broda, F Zara, FM Santorelli, C Minetti, C Bruno. POMT2 gene mutation in limb-girdle muscular dystrophy with inflammatory changes.. Biochem Biophys Res Commun 2007;363:1033-7", "L Bisceglia, S Zoccolella, A Toracco, MR Piemontese, R Dell’Aglio, A Amati, P De Bonis, L Artuso, M Copetti, FM Santorelli, L Serlenga, L Zelante, E Bertini, V Petruzzella. A new locus on 3p23-p25 for an autosomal dominant limb-girdle muscular dystrophy, LGMD1H.. Eur J Hum Genet 2010;18:636-41", "CA Boito, P Melacini, A Vianello, P Prandini, BF Gavassini, A Bagattin, G Siciliano, C Angelini, E Pegoraro. Clinical and molecular characterization of patients with limb-girdle muscular dystrophy type 2I.. Arch Neurol 2005;62:1894-9", "V Bolduc, G Marlow, KM Boycott, K Saleki, H Inoue, J Kroon, M Itakura, Y Robitaille, L Parent, F Baas, K Mizuta, N Kamata, I Richard, WHJP Linssen, I Mahjneh, M de Visser, R Bashir, B Brais. Recessive mutations in the putative calcium-activated chloride channel anoctamin 5 cause proximal LGMD2L and distal MMD3 muscular dystrophies.. Am J Hum Genet 2010;86:213-21", "K Borg, R Stucka, M Locke, E Melin, G Ahlberg, U Klutzny, M Hagen, A Huebner, H Lochmuller, K Wrogemann, LE Thornell, DJ Blake, B Schoser. Intragenic deletion of TRIM32 in compound heterozygotes with sarcotubular myopathy/LGMD2H.. Hum Mutat 2009;30:E831-E844", "M Brockington, Y Yuva, P Prandini, SC Brown, S Torelli, MA Benson, R Herrmann, LV Anderson, R Bashir, JM Burgunder, S Fallet, N Romero, M Fardeau, V Straub, G Storey, C Pollitt, I Richard, CA Sewry, K Bushby, T Voit, DJ Blake, F Muntoni. Mutations in the fukutin-related protein gene (FKRP) identify limb girdle muscular dystrophy 2I as a milder allelic variant of congenital muscular dystrophy MDC1C.. Hum Mol Genet 2001;10:2851-9", "H Bourteel, P Vermersch, JM Cuisset, CA Maurage, P Laforet, P Richard, T Stojkovic. Clinical and mutational spectrum of limb-girdle muscular dystrophy type 2I in 11 French patients.. J Neurol Neurosurg Psychiatry 2009;80:1405-8", "KM Bushby. Making sense of the limb-girdle muscular dystrophies.. Brain 1999;122:1403-20", "R Cagliani, F Fortunato, R Giorda, C Rodolico, MC Bonaglia, M Sironi, MG D'Angelo, A Prelle, F Locatelli, A Toscano, N Bresolin, GP Comi. Molecular analysis of LGMD-2B and MM patients: identification of novel DYSF mutations and possible founder effect in the Italian population.. Neuromuscul Disord 2003;13:788-95", "FL Chou, C Angelini, D Daentl, C Garcia, C Greco, I Hausmanowa-Petrusewicz, A Fidzianska, H Wessel, EP Hoffman. Calpain III mutation analysis of a heterogeneous limb-girdle muscular dystrophy population.. Neurology 1999;52:1015-20", "EM Clement, C Godfrey, J Tan, M Brockington, S Torelli, L Feng, SC Brown, C Jimenez-Mallebrera, CA Sewry, C Longman, R Mein, S Abbs, J Vajsar, H Schachter, F Muntoni. Mild POMGnT1 mutations underlie a novel limb-girdle muscular dystrophy variant.. Arch Neurol 2008;65:137-41", "M Cossée, C Lagier-Tourenne, C Seguela, M Mohr, F Leturcq, H Gundesli, J Chelly, C Tranchant, M Koening, JL Mandel. Use of SNP array analysis to identify a novel TRIM32 mutation in limb-girdle muscular dystrophy type 2H.. Neuromuscul Disord 2009;19:255-60", "F de Paula, N Vieira, A Starling, LU Yamamoto, B Lima, R de Cassia Pavanello, M Vainzof, V Nigro, M Zatz. Asymptomatic carriers for homozygous novel mutations in the FKRP gene: the other end of the spectrum.. Eur J Hum Genet 2003;11:923-30", "P Dinçer, F Leturcq, I Richard, F Piccolo, D Yalnizoglu, C de Toma, Z Akcoren, O Broux, N Deburgrave, L Brenguier, C Roudaut, JA Urtizberea, D Jung, E Tan, M Jeanpierre, KP Campbell, JC Kaplan, JS Beckmann, H Topaloglu. A biochemical, genetic, and clinical survey of autosomal recessive limb girdle muscular dystrophies in Turkey.. Ann Neurol 1997;42:222-9", "DJ Duggan, JR Gorospe, M Fanin, EP Hoffman, C Angelini. Mutations in the sarcoglycan genes in patients with myopathy.. N Engl J Med 1997a;336:618-24", "DJ Duggan, D Manchester, KP Stears, DJ Mathews, C Hart, EP Hoffman. Mutations in the delta-sarcoglycan gene are a rare cause of autosomal recessive limb-girdle muscular dystrophy (LGMD2).. Neurogenetics 1997b;1:49-58", "S Eggers, M Zatz. Social adjustment in adult males affected with progressive muscular dystrophy.. Am J Med Genet 1998;81:4-12", "M Fanin, DJ Duggan, ML Mostacciuolo, F Martinello, MP Freda, G Soraru, CP Trevisan, EP Hoffman, C Angelini. Genetic epidemiology of muscular dystrophies resulting from sarcoglycan gene mutations.. J Med Genet 1997;34:973-7", "M Fanin, P Melacini, C Boito, E Pegoraro, C Angelini. LGMD2E patients risk developing dilated cardiomyopathy.. Neuromuscul Disord 2003;13:303-9", "DB Fee, YT So, C Barraza, KP Figueroa, SM Pulst. Phenotypic variability associated with Arg26Gln mutation in caveolin3.. Muscle Nerve 2004;30:375-8", "D Fischer, S Aurino, V Nigro, R Schroder. On symptomatic heterozygous alpha-sarcoglycan gene mutation carriers.. Ann Neurol 2003;54:674-8", "T Foroud, N Pankratz, AP Batchman, MW Pauciulo, R Vidal, L Miravalle, HH Goebel, LJ Cushman, B Azzarelli, H Horak, M Farlow, WC Nichols. A mutation in myotilin causes spheroid body myopathy.. Neurology 2005;65:1936-40", "P Frosk, T Weiler, E Nylen, T Sudha, CR Greenberg, K Morgan, TM Fujiwara, K Wrogemann. Limb-girdle muscular dystrophy type 2H associated with mutation in TRIM32, a putative E3-ubiquitin-ligase gene.. Am J Hum Genet 2002;70:663-72", "J Gamez, C Navarro, AL Andreu, JM Fernandez, L Palenzuela, S Tejeira, R Fernandez-Hojas, S Schwartz, C Karadimas, S DiMauro, M Hirano, C Cervera. Autosomal dominant limb-girdle muscular dystrophy: a large kindred with evidence for anticipation.. Neurology 2001;56:450-4", "JM Gilchrist, M Pericak-Vance, L Silverman, AD Roses. Clinical and genetic investigation in autosomal dominant limb-girdle muscular dystrophy.. Neurology 1988;38:5-9", "C Godfrey, D Escolar, M Brockington, EM Clement, R Mein, C Jimenez-Mallebrera, S Torelli, L Feng, SC Brown, CA Sewry, M Rutheford, Y Shapira, S Abbs, F Muntoni. Fukutin gene mutations in steroid-responsive limb girdle muscular dystrophy.. Ann Neurol 2006;60:603-10", "C Godfrey, E Clement, R Mein, M Brockington, J Smith, B Talim, V Straub, S Robb, R Quinlivan, L Feng, C Jimenez-Mallebrera, E Mercuri, AY Manzur, M Kinali, S Torelli, SC Brown, CA Sewry, K Bushby, H Topaloglu, K North, S Abbs, F Muntoni. Refining genotype phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan.. Brain 2007;130:2725-35", "SA Greenberg, M Salajegheh, DP Judge, MW Feldman, RW Kuncl, Z Waldon, H Steen, KR Wagner. Etiology of limb girdle muscular dystrophy 1D/1E determined by laser capture microdissection proteomics.. Ann Neurol 2012;71:141-5", "H Gundesli, B Talim, P Korkusuz, B Balci-Hayta, S Cirak, NA Akarsu, H Topaloglu, P Dinçer. Mutation in exon 1f of PLEC, leading to disruption of plectin isoform 1f, causes autosomal-recessive limb girdle muscular dystrophy.. Am J Hum Genet 2010;87:834-41", "P Hackman, V Juvonen, J Sarparanta, M Penttinen, T Aarimaa, M Uusitalo, M Auranen, H Pihko, R Alen, M Junes, T Lonnqvist, H Kalimo, B Udd. Enrichment of the R77C alpha-sarcoglycan gene mutation in Finnish LGMD2D patients.. Muscle Nerve 2005;31:199-204", "P Hackman, A Vihola, H Haravuori, S Marchand, J Sarparanta, J De Seze, S Labeit, C Witt, L Peltonen, I Richard, B Udd. Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin.. Am J Hum Genet 2002;71:492-500", "R Han, KP Campbell. Dysferlin and muscle membrane repair.. Curr Opin Cell Biol 2007;19:409-16", "MB Harms, B Sommerville, P Allred, S Bell, D Ma, P Cooper, G Lopate, A Pestronk, CC Weihl, RH Baloh. Exome sequencing reveals. Ann Neurol. 2012;71:407-16", "MA Hauser, CB Conde, V Kowaljow, G Zeppa, AL Taratuto, UM Torian, J Vance, MA Pericak-Vance, MC Speer, AL Rosa. myotilin Mutation found in second pedigree with LGMD1A.. Am J Hum Genet 2002;71:1428-32", "MA Hauser, SK Horrigan, P Salmikangas, UM Torian, KD Viles, R Dancel, RW Tim, A Taivainen, L Bartoloni, JM Gilchrist, JM Stajich, PC Gaskell, JR Gilbert, JM Vance, MA Pericak-Vance, O Carpen, CA Westbrook, MC Speer. Myotilin is mutated in limb girdle muscular dystrophy 1A.. Hum Mol Genet 2000;9:2141-7", "T Hayashi, T Arimura, K Ueda, H Shibata, S Hohda, M Takahashi, H Hori, Y Koga, N Oka, T Imaizumi, M Yasunami, A Kimura. Identification and functional analysis of a caveolin-3 mutation associated with familial hypertrophic cardiomyopathy.. Biochem Biophys Res Commun 2004;313:178-84", "D Hicks, A Sarkozy, N Muelas, K Koehler, A Huebner, G Hudson, PF Chinnery, R Barresi, M Eagle, T Polvikoski, G Bailey, J Miller, A Radunovic, PJ Hughes, R Roberts, S Krause, MC Walter, SH Laval, V Straub, H Lochmuller, K Bushby. A founder mutation in Anoctamin 5 is a major cause of limb-girdle muscular dystrophy.. Brain 2011;134:171-82", "EP Hoffman, K Arahata, C Minetti, E Bonilla, LP Rowland. Dystrophinopathy in isolated cases of myopathy in females.. Neurology 1992;42:967-75", "EP Hoffman, E Pegoraro, P Scacheri, RG Burns, JW Taber, L Weiss, A Spiro, P Blattner. Genetic counseling of isolated carriers of Duchenne muscular dystrophy.. Am J Med Genet 1996;63:573-80", "I Illa, C Serrano-Munuera, E Gallardo, A Lasa, R Rojas-Garcia, J Palmer, P Gallano, M Baiget, C Matsuda, RH Brown. Distal anterior compartment myopathy: a dysferlin mutation causing a new muscular dystrophy phenotype.. Ann Neurol 2001;49:130-4", "M Lommel, S Cirak, T Willer, R Hermann, G Uyanik, H van Bokhoven, C Korner, T Voit, I Baric, U Hehr, S Strahl. Correlation of enzyme activity and clinical phenotypr in POMT1-associated dystroglycanopathies.. Neurology 2010;74:157-64", "C Jimenez-Mallebrera, S Torelli, L Feng, J Kim, C Godfrey, E Clement, R Mein, S Abbs, SC Brown, KP Campbell, S Kröger, B Talim, H Topaloglu, R Quinlivan, H Roper, AM Childs, M Kinali, CA Sewry, F Muntoni. A comparative study of alpha-dystroglycan glycosylation in dystroglycanopathies suggests that the hypoglycosylation of alpha-dystroglycan does not consistently correlate with clinical severity.. Brain Pathol. 2009;19:596-611", "J Kirschner, H Lochmüller. Sarcoglycanopathies.. Handb Clin Neurol 2011;101:41-6", "CM McDonald, ER Johnson, RT Abresch, GT Carter, WM Fowler, DD Kilmer. Profiles of neuromuscular diseases. Limb-girdle syndromes.. Am J Phys Med Rehabil 1995;74:S117-30", "P Melacini, M Fanin, DJ Duggan, MP Freda, A Berardinelli, GA Danieli, A Barchitta, EP Hoffman, S Dalla Volta, C Angelini. Heart involvement in muscular dystrophies due to sarcoglycan gene mutations.. Muscle Nerve 1999;22:473-9", "E Mercuri, M Brockington, V Straub, S Quijano-Roy, Y Yuva, R Herrmann, SC Brown, S Torelli, V Dubowitz, DJ Blake, NB Romero, B Estournet, CA Sewry, P Guicheney, T Voit, F Muntoni. Phenotypic spectrum associated with mutations in the fukutin-related protein gene.. Ann Neurol 2003;53:537-42", "E Mercuri, SC Brown, P Nihoyannopoulos, J Poulton, M Kinali, P Richard, RJ Piercy, S Messina, C Sewry, MM Burke, W McKenna, G Bonne, F Muntoni. Extreme variability of skeletal and cardiac muscle involvement in patients with mutations in exon 11 of the lamin A/C gene.. Muscle Nerve 2005;31:602-9", "L Merlini, JC Kaplan, C Navarro, A Barois, D Bonneau, J Brasa, B Echenne, P Gallano, L Jarre, M Jeanpierre, L Kalaydjieva, F Leturcq, A Levi-Gomes, A Toutain, I Tournev, A Urtizberea, JM Vallat, T Voit, JM Warter. Homogeneous phenotype of the gypsy limb-girdle MD with the gamma- sarcoglycan C283Y mutation.. Neurology 2000;54:1075-9", "C Minetti, F Sotgia, C Bruno, P Scartezzini, P Broda, M Bado, E Masetti, M Mazzocco, A Egeo, MA Donati, D Volonte, F Galbiati, G Cordone, FD Bricarelli, MP Lisanti, F Zara. Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy.. Nat Genet 1998;18:365-8", "ES Moreira, TJ Wiltshire, G Faulkner, A Nilforoushan, M Vainzof, OT Suzuki, G Valle, R Reeves, M Zatz, MR Passos-Bueno, DE Jenne. Limb-girdle muscular dystrophy type 2G is caused by mutations in the gene encoding the sarcomeric protein telethonin.. Nat Genet 2000;24:163-6", "T Müller, M Krasnianski, R Witthaut, M Deschauer, S Zierz. Dilated cardiomyopathy may be an early sign of the C826A Fukutin-related protein mutation.. Neuromuscul Disord 2005;15:372-6", "T Murakami, YK Hayashi, S Noguchi, M Ogawa, I Nonaka, Y Tanabe, M Ogino, F Takada, M Eriguchi, N Kotooka, KP Campbell, M Osawa, I Nishino. Fukutin gene mutations cause dilated cardiomyopathy with minimal muscle weakness.. Ann Neurol 2006;60:597-602", "T Nagashima, T Chuma, Y Mano, Y Goto, YK Hayashi, N Minami, I Nishino, I Nonaka, T Takahashi, H Sawa, M Aoki, K Nagashima. Dysferlinopathy associated with rigid spine syndrome.. Neuropathology 2004;24:341-6", "V Nigro, E de Sa Moreira, G Piluso, M Vainzof, A Belsito, L Politano, AA Puca, MR Passos-Bueno, M Zatz. Autosomal recessive limb-girdle muscular dystrophy, LGMD2F, is caused by a mutation in the delta-sarcoglycan gene.. Nat Genet 1996;14:195-8", "L Palenzuela, AL Andreu, J Gamez, MR Vila, T Kunimatsu, A Meseguer, C Cervera, I Fernandez Cadenas, PF van der Ven, TG Nygaard, E Bonilla, M Hirano. A novel autosomal dominant limb-girdle muscular dystrophy (LGMD 1F) maps to 7q32.1-32.2.. Neurology 2003;61:404-6", "A Palmieri, R Manara, L Bello, G Mento, L Lazzarini, C Borsato, L Bortolussi, C Angelini, E Pegoraro. Cognitive profile and MRI findings in limb-girdle muscular dystrophy 2I.. J Neurol 2011;258:1312-20", "S Penttilä, J Palmio, T Suominen, O Raheem, A Evilä, N Muelas Gomez, G Tasca, LB Waddell, NF Clarke, A Barboi, P Hackman, B Udd. Eight new mutations and the expanding phenotype variability in muscular dystrophy caused by ANO5.. Neurology. 2012;78:897-903", "R Pogue, LV Anderson, A Pyle, C Sewry, C Pollitt, MA Johnson, K Davison, JA Moss, E Mercuri, F Muntoni, KM Bushby. Strategy for mutation analysis in the autosomal recessive limb-girdle muscular dystrophies.. Neuromuscul Disord 2001;11:80-7", "M Poppe, J Bourke, M Eagle, P Frosk, K Wrogemann, C Greenberg, F Muntoni, T Voit, V Straub, D Hilton-Jones, C Shirodaria, K Bushby. Cardiac and respiratory failure in limb-girdle muscular dystrophy 2I.. Ann Neurol 2004;56:738-41", "M Poppe, L Cree, J Bourke, M Eagle, LV Anderson, D Birchall, M Brockington, M Buddles, M Busby, F Muntoni, A Wills, K Bushby. The phenotype of limb-girdle muscular dystrophy type 2I.. Neurology 2003;60:1246-51", "RL Puckett, SA Moore, TL Winder, T Willer, SG Romansky, KK Covault, KP Campbell, JE Abdenur. Further evidence of fukutin mutations as a cause of childhood onset limb-girdle muscular dystrophy without mental retardation.. Neuromusc Disord 2009;19:352-56", "L Pulkkinen, FJD Smith, H Shimizu, S Murata, H Yaoita, H Hachisuka, T Nishikawa, WHI McLean, J Uitto. Homozygous deletion mutations in the plectin gene (PLEC1) in patients with epidermolysis bullosa simplex associated with late-onset muscular dystrophy.. Hum Mol Genet 1996;5:1539-46", "P Reilich, S Krause, N Schramm, U Klutzny, S Bulst, B Zehetmayer, P Schneiderat, MC Walter, B Schoser, H Lochmuller. A novel mutation in the myotilin gene (MYOT) causes a severe form of limb girdle muscular dystrophy 1A (LGMD1A).. J Neurol 2011;258:1437-44", "V Saccone, M Palmieri, L Passamano, G Piluso, G Meroni, L Politano, V Nigro. Mutations that impair interaction properties of TRIM32 associated with limb-girdle muscular dystrophy type 2H.. Hum Mutat 2008;29:240-7", "P Salmikangas, PF van der Ven, M Lalowski, A Taivainen, F Zhao, H Suila, R Schroder, P Lappalainen, DO Furst, O Carpen. Myotilin, the limb-girdle muscular dystrophy 1A (LGMD1A) protein, cross-links actin filaments and controls sarcomere assembly.. Hum Mol Genet 2003;12:189-203", "BG Schoser, P Frosk, AG Engel, U Klutzny, H Lochmuller, K Wrogemann. Commonality of TRIM32 mutation in causing sarcotubular myopathy and LGMD2H.. Ann Neurol 2005;57:591-5", "D Selcen, AG Engel. Mutations in myotilin cause myofibrillar myopathy.. Neurology 2004;62:1363-71", "S Shalaby, H Mitsuhashi, C Matsuda, N Minami, S Noguchi, I Nonaka, I Nishino, YK Hayashi. Defective myotilin homodimerization caused by a novel mutation in MYOT exon 9 in the first Japanese limb girdle muscular dystrophy 1A patient.. J Neuropathol Exp Neurol 2009;68:701-7", "MC Speer, JM Vance, JM Grubber, F Lennon Graham, JM Stajich, KD Viles, A Rogala, R McMichael, J Chutkow, C Goldsmith, RW Tim, MA Pericak-Vance. Identification of a new autosomal dominant limb-girdle muscular dystrophy locus on chromosome 7.. Am J Hum Genet 1999;64:556-62", "A Starling, F Kok, MR Passos-Bueno, M Vainzof, M Zatz. A new form of autosomal dominant limb-girdle muscular dystrophy (LGMD1G) with progressive fingers and toes flexion limitation maps to chromosome 4p21.. Eur J Hum Genet 2004;12:1033-40", "A Todorova, B Halliger-Keller, MC Walter, MC Dabauvalle, H Lochmuller, CR Muller. A synonymous codon change in the LMNA gene alters mRNA splicing and causes limb girdle muscular dystrophy type 1B.. J Med Genet 2003;40", "B Udd, H Kaarianen, H Somer. Muscular dystrophy with separate clinical phenotypes in a large family.. Muscle Nerve 1991;14:1050-8", "M Urtasun, A Saenz, C Roudaut, JJ Poza, JA Urtizberea, AM Cobo, I Richard, F Garcia Bragado, F Leturcq, JC Kaplan, JF Marti Masso, JS Beckmann, A Lopez de Munain. Limb-girdle muscular dystrophy in Guipuzcoa (Basque Country, Spain).. Brain 1998;121:1735-47", "M Vainzof, MR Passos-Bueno, RC Pavanello, SK Marie, AS Oliveira, M Zatz. Sarcoglycanopathies are responsible for 68% of severe autosomal recessive limb-girdle muscular dystrophy in the Brazilian population.. J Neurol Sci 1999;164:44-9", "AJ van der Kooi, PG Barth, HF Busch, R de Haan, HB Ginjaar, AJ van Essen, LJ van Hooff, CJ Howeler, FG Jennekens, P Jongen, HJ Oosterhuis, GW Padberg, F Spaans, AR Wintzen, JH Wokke, E Bakker, GJ van Ommen, PA Bolhuis, M de Visser. The clinical spectrum of limb girdle muscular dystrophy. A survey in The Netherlands.. Brain 1996;119:1471-80", "T Weiler, CR Greenberg, T Zelinski, E Nylen, G Coghlan, MJ Crumley, TM Fujiwara, K Morgan, K Wrogemann. A gene for autosomal recessive limb-girdle muscular dystrophy in Manitoba Hutterites maps to chromosome region 9q31-q33: evidence for another limb-girdle muscular dystrophy locus.. Am J Hum Genet 1998;63:140-7", "SE Woodman, F Sotgia, F Galbiati, C Minetti, MP Lisanti. Caveolinopathies: mutations in caveolin-3 cause four distinct autosomal dominant muscle diseases.. Neurology 2004;62:538-43", "M Zatz, F de Paula, A Starling, M Vainzof. The 10 autosomal recessive limb-girdle muscular dystrophies.. Neuromuscul Disord 2003;13:532-44" ]	8/6/2000	30/8/2012	23/7/2009	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
lgmd2a	lgmd2a	[ "CAPN3-Related HyperCKemia", "Scapulohumeral Limb-Girdle Muscular Dystrophy (Erb LGMD)", "Pelvifemoral Limb-Girdle Muscular Dystrophy (Leyden-Möbius LGMD)", "Calpain-3", "CAPN3", "Calpainopathy" ]	Calpainopathy	Corrado Angelini	Summary Calpainopathy is characterized by symmetric and progressive weakness of proximal limb-girdle muscles. Clinical findings of calpainopathy include the tendency to walk on tiptoe, difficulty in running, scapular winging, waddling gait, laxity of the abdominal muscles, Achilles tendon shortening, and scoliosis. Affected individuals typically do not have cardiac involvement or intellectual disability. Three autosomal recessive calpainopathy phenotypes have been identified based on the distribution of muscle weakness and age at onset: (1) pelvifemoral limb-girdle muscular dystrophy (LGMD) (Leyden-Möbius LGMD) phenotype, the most frequently observed calpainopathy phenotype, in which muscle weakness is first evident in the pelvic girdle and later in the shoulder girdle, with onset that may occur as early as before age 12 years or as late as after age 30 years; (2) scapulohumeral LGMD (Erb LGMD) phenotype, usually a milder phenotype with infrequent early onset, in which muscle weakness is first evident in the shoulder girdle and later in the pelvic girdle; (3) hyperCKemia, usually observed in children or young individuals, in which individuals are asymptomatic and have high serum creatine kinase (CK) concentrations. The autosomal dominant form of calpainopathy is clinically variable, ranging from almost asymptomatic to wheelchair dependence after age 60 years in a few individuals; phenotype is generally milder than the recessive form. The diagnosis of calpainopathy is established by identification of biallelic pathogenic variants in Calpainopathy is typically inherited in an autosomal recessive manner. Less commonly, calpainopathy is inherited in an autosomal dominant manner. Once the	Pelvifemoral limb-girdle muscular dystrophy (Leyden-Möbius LGMD) Scapulohumeral limb-girdle muscular dystrophy (Erb LGMD) HyperCKemia For synonyms and outdated names see For other genetic causes of these phenotypes see • Pelvifemoral limb-girdle muscular dystrophy (Leyden-Möbius LGMD) • Scapulohumeral limb-girdle muscular dystrophy (Erb LGMD) • HyperCKemia ## Diagnosis Calpainopathy is a form of limb-girdle muscular dystrophy (LGMD). Calpainopathy Proximal muscle weakness (pelvic and/or shoulder girdle) with early onset (age 30 years) Symmetric atrophy and wasting of proximal limb and trunk muscles; calf hypertrophy is rarely and sometimes only transiently present [ Scapular winging, scoliosis, Achilles tendon contracture, and other joint contractures (including hip, knee, elbow, finger, and spine) Waddling gait; tiptoe walking; difficulty in running, climbing stairs, lifting weights, and getting up from the floor or from a chair Sparing of facial, ocular, tongue, and neck muscles Absence of cardiomyopathy and intellectual disability Back pain and myalgia; present in 50% of individuals with autosomal dominant calpainopathy [ CT reveals early and striking wasting of muscles predominantly from the posterior compartment of the thighs (but also hip adductors and quadriceps) [ MRI shows the selective muscle involvement and, in some instances, reveals edema-like changes on STIR sequences [ In the dominant form of calpainopathy, the paraspinal muscles are almost completely lost and replaced by fat [ The diagnosis of calpainopathy Biallelic pathogenic (or likely pathogenic) variants in Heterozygous dominantly acting 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 use of a The clinical and laboratory findings in individuals with calpainopathy overlap with other forms of LGMD and other muscular dystrophies. Therefore, use of a multigene panel or comprehensive genomic testing is recommended [ For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Note: Targeted analysis for pathogenic variants can be performed first in individuals of Amish ancestry or individuals from communities with an identified founder variant (e.g., Tlaxcala, Mexico; Mòcheni community, Italy; La Réunion Island; Chioggia, Italy; Guipúzcoa Province, Spain) (see Molecular Genetic Testing Used in Calpainopathy See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click In individuals showing absent or severely reduced calpain-3 protein on immunoblot testing, the probability of identifying In approximately 20%-30% of individuals with calpainopathy, only one Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Large genomic rearrangements involving Muscle biopsy for histopathology and calpain-3 immunoblot analysis should be considered when results of molecular genetic testing are inconclusive. Most individuals have the typical features of an active dystrophic process: increased fiber size variability, increased fibrosis, regenerating fibers, degenerating and necrotic fibers. Others have mild and nonspecific myopathic features: increased central nuclei, fiber splitting, lobulated fibers (misaligned myofibrils that form a lobulated pattern), and type 1 fiber predominance [ The extent of muscle regeneration is less than is typically observed in other LGMDs [ Eosinophilic myositis can be an early and transient feature of calpainopathy and has been reported in individuals with increased CK levels; it is not typically present in muscle from older affected individuals with calpainopathy [ There is considerable muscle fiber atrophy, which correlates with the clinical-functional severity of the disease [ Muscle biopsies from individuals with autosomal dominant calpainopathy show mild myopathic changes (increased internal nuclei, fiber size variability, occasional necrotic fibers, ring fibers, and fibrosis) that appear less severe than muscle biopsy findings in those with autosomal recessive calpainopathy [ Note: The results of calpain-3 immunoblot analysis need to be interpreted with caution, as the analysis is neither completely specific (i.e., it can yield false positive results) nor completely sensitive (i.e., it can yield false negative results). Furthermore, the results must be considered in the context of other muscle proteins [ Issues with lack of specificity include the following: Calpain-3 protein levels can be partially reduced in other muscular dystrophies, such as Although calpain-3 protein is extremely stable in muscle over time, protein quantity can be reduced by artificial degradation that occurs when muscle tissue is handled or stored under conditions that promote rapid calpain-3 autolysis (e.g., partial thawing and exposure to moisture) [ Issues with lack of sensitivity include the following: Approximately 20% of individuals with calpainopathy have normal quantitative protein expression [ When calpain immunoblotting testing shows complete or severe calpain-3 deficiency, the probability that an individual has calpainopathy is very high (84%); the probability decreases as the amount of protein detected increases [ • Proximal muscle weakness (pelvic and/or shoulder girdle) with early onset (age 30 years) • Symmetric atrophy and wasting of proximal limb and trunk muscles; calf hypertrophy is rarely and sometimes only transiently present [ • Scapular winging, scoliosis, Achilles tendon contracture, and other joint contractures (including hip, knee, elbow, finger, and spine) • Waddling gait; tiptoe walking; difficulty in running, climbing stairs, lifting weights, and getting up from the floor or from a chair • Sparing of facial, ocular, tongue, and neck muscles • Absence of cardiomyopathy and intellectual disability • Back pain and myalgia; present in 50% of individuals with autosomal dominant calpainopathy [ • CT reveals early and striking wasting of muscles predominantly from the posterior compartment of the thighs (but also hip adductors and quadriceps) [ • MRI shows the selective muscle involvement and, in some instances, reveals edema-like changes on STIR sequences [ • In the dominant form of calpainopathy, the paraspinal muscles are almost completely lost and replaced by fat [ • Biallelic pathogenic (or likely pathogenic) variants in • Heterozygous dominantly acting • Most individuals have the typical features of an active dystrophic process: increased fiber size variability, increased fibrosis, regenerating fibers, degenerating and necrotic fibers. Others have mild and nonspecific myopathic features: increased central nuclei, fiber splitting, lobulated fibers (misaligned myofibrils that form a lobulated pattern), and type 1 fiber predominance [ • The extent of muscle regeneration is less than is typically observed in other LGMDs [ • Eosinophilic myositis can be an early and transient feature of calpainopathy and has been reported in individuals with increased CK levels; it is not typically present in muscle from older affected individuals with calpainopathy [ • There is considerable muscle fiber atrophy, which correlates with the clinical-functional severity of the disease [ • Muscle biopsies from individuals with autosomal dominant calpainopathy show mild myopathic changes (increased internal nuclei, fiber size variability, occasional necrotic fibers, ring fibers, and fibrosis) that appear less severe than muscle biopsy findings in those with autosomal recessive calpainopathy [ • Issues with lack of specificity include the following: • Calpain-3 protein levels can be partially reduced in other muscular dystrophies, such as • Although calpain-3 protein is extremely stable in muscle over time, protein quantity can be reduced by artificial degradation that occurs when muscle tissue is handled or stored under conditions that promote rapid calpain-3 autolysis (e.g., partial thawing and exposure to moisture) [ • Calpain-3 protein levels can be partially reduced in other muscular dystrophies, such as • Although calpain-3 protein is extremely stable in muscle over time, protein quantity can be reduced by artificial degradation that occurs when muscle tissue is handled or stored under conditions that promote rapid calpain-3 autolysis (e.g., partial thawing and exposure to moisture) [ • Issues with lack of sensitivity include the following: • Approximately 20% of individuals with calpainopathy have normal quantitative protein expression [ • When calpain immunoblotting testing shows complete or severe calpain-3 deficiency, the probability that an individual has calpainopathy is very high (84%); the probability decreases as the amount of protein detected increases [ • Approximately 20% of individuals with calpainopathy have normal quantitative protein expression [ • When calpain immunoblotting testing shows complete or severe calpain-3 deficiency, the probability that an individual has calpainopathy is very high (84%); the probability decreases as the amount of protein detected increases [ • Calpain-3 protein levels can be partially reduced in other muscular dystrophies, such as • Although calpain-3 protein is extremely stable in muscle over time, protein quantity can be reduced by artificial degradation that occurs when muscle tissue is handled or stored under conditions that promote rapid calpain-3 autolysis (e.g., partial thawing and exposure to moisture) [ • Approximately 20% of individuals with calpainopathy have normal quantitative protein expression [ • When calpain immunoblotting testing shows complete or severe calpain-3 deficiency, the probability that an individual has calpainopathy is very high (84%); the probability decreases as the amount of protein detected increases [ ## Suggestive Findings Calpainopathy Proximal muscle weakness (pelvic and/or shoulder girdle) with early onset (age 30 years) Symmetric atrophy and wasting of proximal limb and trunk muscles; calf hypertrophy is rarely and sometimes only transiently present [ Scapular winging, scoliosis, Achilles tendon contracture, and other joint contractures (including hip, knee, elbow, finger, and spine) Waddling gait; tiptoe walking; difficulty in running, climbing stairs, lifting weights, and getting up from the floor or from a chair Sparing of facial, ocular, tongue, and neck muscles Absence of cardiomyopathy and intellectual disability Back pain and myalgia; present in 50% of individuals with autosomal dominant calpainopathy [ CT reveals early and striking wasting of muscles predominantly from the posterior compartment of the thighs (but also hip adductors and quadriceps) [ MRI shows the selective muscle involvement and, in some instances, reveals edema-like changes on STIR sequences [ In the dominant form of calpainopathy, the paraspinal muscles are almost completely lost and replaced by fat [ • Proximal muscle weakness (pelvic and/or shoulder girdle) with early onset (age 30 years) • Symmetric atrophy and wasting of proximal limb and trunk muscles; calf hypertrophy is rarely and sometimes only transiently present [ • Scapular winging, scoliosis, Achilles tendon contracture, and other joint contractures (including hip, knee, elbow, finger, and spine) • Waddling gait; tiptoe walking; difficulty in running, climbing stairs, lifting weights, and getting up from the floor or from a chair • Sparing of facial, ocular, tongue, and neck muscles • Absence of cardiomyopathy and intellectual disability • Back pain and myalgia; present in 50% of individuals with autosomal dominant calpainopathy [ • CT reveals early and striking wasting of muscles predominantly from the posterior compartment of the thighs (but also hip adductors and quadriceps) [ • MRI shows the selective muscle involvement and, in some instances, reveals edema-like changes on STIR sequences [ • In the dominant form of calpainopathy, the paraspinal muscles are almost completely lost and replaced by fat [ ## Establishing the Diagnosis The diagnosis of calpainopathy Biallelic pathogenic (or likely pathogenic) variants in Heterozygous dominantly acting 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 use of a The clinical and laboratory findings in individuals with calpainopathy overlap with other forms of LGMD and other muscular dystrophies. Therefore, use of a multigene panel or comprehensive genomic testing is recommended [ For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Note: Targeted analysis for pathogenic variants can be performed first in individuals of Amish ancestry or individuals from communities with an identified founder variant (e.g., Tlaxcala, Mexico; Mòcheni community, Italy; La Réunion Island; Chioggia, Italy; Guipúzcoa Province, Spain) (see Molecular Genetic Testing Used in Calpainopathy See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click In individuals showing absent or severely reduced calpain-3 protein on immunoblot testing, the probability of identifying In approximately 20%-30% of individuals with calpainopathy, only one Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Large genomic rearrangements involving Muscle biopsy for histopathology and calpain-3 immunoblot analysis should be considered when results of molecular genetic testing are inconclusive. Most individuals have the typical features of an active dystrophic process: increased fiber size variability, increased fibrosis, regenerating fibers, degenerating and necrotic fibers. Others have mild and nonspecific myopathic features: increased central nuclei, fiber splitting, lobulated fibers (misaligned myofibrils that form a lobulated pattern), and type 1 fiber predominance [ The extent of muscle regeneration is less than is typically observed in other LGMDs [ Eosinophilic myositis can be an early and transient feature of calpainopathy and has been reported in individuals with increased CK levels; it is not typically present in muscle from older affected individuals with calpainopathy [ There is considerable muscle fiber atrophy, which correlates with the clinical-functional severity of the disease [ Muscle biopsies from individuals with autosomal dominant calpainopathy show mild myopathic changes (increased internal nuclei, fiber size variability, occasional necrotic fibers, ring fibers, and fibrosis) that appear less severe than muscle biopsy findings in those with autosomal recessive calpainopathy [ Note: The results of calpain-3 immunoblot analysis need to be interpreted with caution, as the analysis is neither completely specific (i.e., it can yield false positive results) nor completely sensitive (i.e., it can yield false negative results). Furthermore, the results must be considered in the context of other muscle proteins [ Issues with lack of specificity include the following: Calpain-3 protein levels can be partially reduced in other muscular dystrophies, such as Although calpain-3 protein is extremely stable in muscle over time, protein quantity can be reduced by artificial degradation that occurs when muscle tissue is handled or stored under conditions that promote rapid calpain-3 autolysis (e.g., partial thawing and exposure to moisture) [ Issues with lack of sensitivity include the following: Approximately 20% of individuals with calpainopathy have normal quantitative protein expression [ When calpain immunoblotting testing shows complete or severe calpain-3 deficiency, the probability that an individual has calpainopathy is very high (84%); the probability decreases as the amount of protein detected increases [ • Biallelic pathogenic (or likely pathogenic) variants in • Heterozygous dominantly acting • Most individuals have the typical features of an active dystrophic process: increased fiber size variability, increased fibrosis, regenerating fibers, degenerating and necrotic fibers. Others have mild and nonspecific myopathic features: increased central nuclei, fiber splitting, lobulated fibers (misaligned myofibrils that form a lobulated pattern), and type 1 fiber predominance [ • The extent of muscle regeneration is less than is typically observed in other LGMDs [ • Eosinophilic myositis can be an early and transient feature of calpainopathy and has been reported in individuals with increased CK levels; it is not typically present in muscle from older affected individuals with calpainopathy [ • There is considerable muscle fiber atrophy, which correlates with the clinical-functional severity of the disease [ • Muscle biopsies from individuals with autosomal dominant calpainopathy show mild myopathic changes (increased internal nuclei, fiber size variability, occasional necrotic fibers, ring fibers, and fibrosis) that appear less severe than muscle biopsy findings in those with autosomal recessive calpainopathy [ • Issues with lack of specificity include the following: • Calpain-3 protein levels can be partially reduced in other muscular dystrophies, such as • Although calpain-3 protein is extremely stable in muscle over time, protein quantity can be reduced by artificial degradation that occurs when muscle tissue is handled or stored under conditions that promote rapid calpain-3 autolysis (e.g., partial thawing and exposure to moisture) [ • Calpain-3 protein levels can be partially reduced in other muscular dystrophies, such as • Although calpain-3 protein is extremely stable in muscle over time, protein quantity can be reduced by artificial degradation that occurs when muscle tissue is handled or stored under conditions that promote rapid calpain-3 autolysis (e.g., partial thawing and exposure to moisture) [ • Issues with lack of sensitivity include the following: • Approximately 20% of individuals with calpainopathy have normal quantitative protein expression [ • When calpain immunoblotting testing shows complete or severe calpain-3 deficiency, the probability that an individual has calpainopathy is very high (84%); the probability decreases as the amount of protein detected increases [ • Approximately 20% of individuals with calpainopathy have normal quantitative protein expression [ • When calpain immunoblotting testing shows complete or severe calpain-3 deficiency, the probability that an individual has calpainopathy is very high (84%); the probability decreases as the amount of protein detected increases [ • Calpain-3 protein levels can be partially reduced in other muscular dystrophies, such as • Although calpain-3 protein is extremely stable in muscle over time, protein quantity can be reduced by artificial degradation that occurs when muscle tissue is handled or stored under conditions that promote rapid calpain-3 autolysis (e.g., partial thawing and exposure to moisture) [ • Approximately 20% of individuals with calpainopathy have normal quantitative protein expression [ • When calpain immunoblotting testing shows complete or severe calpain-3 deficiency, the probability that an individual has calpainopathy is very high (84%); the probability decreases as the amount of protein detected increases [ ## Recommended Molecular Testing For an introduction to multigene panels click For an introduction to comprehensive genomic testing click ## Other Molecular Testing Options Note: Targeted analysis for pathogenic variants can be performed first in individuals of Amish ancestry or individuals from communities with an identified founder variant (e.g., Tlaxcala, Mexico; Mòcheni community, Italy; La Réunion Island; Chioggia, Italy; Guipúzcoa Province, Spain) (see Molecular Genetic Testing Used in Calpainopathy See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click In individuals showing absent or severely reduced calpain-3 protein on immunoblot testing, the probability of identifying In approximately 20%-30% of individuals with calpainopathy, only one Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Large genomic rearrangements involving ## Muscle Biopsy Muscle biopsy for histopathology and calpain-3 immunoblot analysis should be considered when results of molecular genetic testing are inconclusive. Most individuals have the typical features of an active dystrophic process: increased fiber size variability, increased fibrosis, regenerating fibers, degenerating and necrotic fibers. Others have mild and nonspecific myopathic features: increased central nuclei, fiber splitting, lobulated fibers (misaligned myofibrils that form a lobulated pattern), and type 1 fiber predominance [ The extent of muscle regeneration is less than is typically observed in other LGMDs [ Eosinophilic myositis can be an early and transient feature of calpainopathy and has been reported in individuals with increased CK levels; it is not typically present in muscle from older affected individuals with calpainopathy [ There is considerable muscle fiber atrophy, which correlates with the clinical-functional severity of the disease [ Muscle biopsies from individuals with autosomal dominant calpainopathy show mild myopathic changes (increased internal nuclei, fiber size variability, occasional necrotic fibers, ring fibers, and fibrosis) that appear less severe than muscle biopsy findings in those with autosomal recessive calpainopathy [ Note: The results of calpain-3 immunoblot analysis need to be interpreted with caution, as the analysis is neither completely specific (i.e., it can yield false positive results) nor completely sensitive (i.e., it can yield false negative results). Furthermore, the results must be considered in the context of other muscle proteins [ Issues with lack of specificity include the following: Calpain-3 protein levels can be partially reduced in other muscular dystrophies, such as Although calpain-3 protein is extremely stable in muscle over time, protein quantity can be reduced by artificial degradation that occurs when muscle tissue is handled or stored under conditions that promote rapid calpain-3 autolysis (e.g., partial thawing and exposure to moisture) [ Issues with lack of sensitivity include the following: Approximately 20% of individuals with calpainopathy have normal quantitative protein expression [ When calpain immunoblotting testing shows complete or severe calpain-3 deficiency, the probability that an individual has calpainopathy is very high (84%); the probability decreases as the amount of protein detected increases [ • Most individuals have the typical features of an active dystrophic process: increased fiber size variability, increased fibrosis, regenerating fibers, degenerating and necrotic fibers. Others have mild and nonspecific myopathic features: increased central nuclei, fiber splitting, lobulated fibers (misaligned myofibrils that form a lobulated pattern), and type 1 fiber predominance [ • The extent of muscle regeneration is less than is typically observed in other LGMDs [ • Eosinophilic myositis can be an early and transient feature of calpainopathy and has been reported in individuals with increased CK levels; it is not typically present in muscle from older affected individuals with calpainopathy [ • There is considerable muscle fiber atrophy, which correlates with the clinical-functional severity of the disease [ • Muscle biopsies from individuals with autosomal dominant calpainopathy show mild myopathic changes (increased internal nuclei, fiber size variability, occasional necrotic fibers, ring fibers, and fibrosis) that appear less severe than muscle biopsy findings in those with autosomal recessive calpainopathy [ • Issues with lack of specificity include the following: • Calpain-3 protein levels can be partially reduced in other muscular dystrophies, such as • Although calpain-3 protein is extremely stable in muscle over time, protein quantity can be reduced by artificial degradation that occurs when muscle tissue is handled or stored under conditions that promote rapid calpain-3 autolysis (e.g., partial thawing and exposure to moisture) [ • Calpain-3 protein levels can be partially reduced in other muscular dystrophies, such as • Although calpain-3 protein is extremely stable in muscle over time, protein quantity can be reduced by artificial degradation that occurs when muscle tissue is handled or stored under conditions that promote rapid calpain-3 autolysis (e.g., partial thawing and exposure to moisture) [ • Issues with lack of sensitivity include the following: • Approximately 20% of individuals with calpainopathy have normal quantitative protein expression [ • When calpain immunoblotting testing shows complete or severe calpain-3 deficiency, the probability that an individual has calpainopathy is very high (84%); the probability decreases as the amount of protein detected increases [ • Approximately 20% of individuals with calpainopathy have normal quantitative protein expression [ • When calpain immunoblotting testing shows complete or severe calpain-3 deficiency, the probability that an individual has calpainopathy is very high (84%); the probability decreases as the amount of protein detected increases [ • Calpain-3 protein levels can be partially reduced in other muscular dystrophies, such as • Although calpain-3 protein is extremely stable in muscle over time, protein quantity can be reduced by artificial degradation that occurs when muscle tissue is handled or stored under conditions that promote rapid calpain-3 autolysis (e.g., partial thawing and exposure to moisture) [ • Approximately 20% of individuals with calpainopathy have normal quantitative protein expression [ • When calpain immunoblotting testing shows complete or severe calpain-3 deficiency, the probability that an individual has calpainopathy is very high (84%); the probability decreases as the amount of protein detected increases [ ## Clinical Characteristics Calpainopathy is characterized by symmetric and progressive weakness of proximal limb-girdle muscles, symmetric muscle atrophy of the proximal limb and trunk muscles, scapular winging, scoliosis, and joint contractures. The age at onset of muscle weakness ranges from two to 40 years. Early motor milestones are usually normal. Significant intra- and interfamilial clinical variability is seen [ Three phenotypes of autosomal recessive calpainopathy have been identified based on the distribution of muscle weakness and age at onset: Tendency to walk on tiptoe; Difficulty in running; Scapular winging. Waddling gait and slight hyperlordosis Symmetric weakness [ Scapular winging Marked laxity of the abdominal muscles [ Early Achilles tendon shortening and scoliosis Variable findings include the following: Muscle pain, exercise intolerance, and elevated lactate levels in some individuals similar to that seen in a pseudometabolic myopathy [ Eosinophilic myositis with increased serum CK, an early and transient feature that is not present in older individuals [ Significant atrophy of the calf muscle or more rarely calf hypertrophy Rhabdomyolysis (and/or myoglobinuria) triggered by physical exercise; occasionally observed in asymptomatic individuals or in individuals with mild muscle involvement [ The inability to climb stairs, rise up from a chair, lift weights, or get up from the floor Joint contractures (in the hips, knees, elbows, and fingers) Occasionally observed findings: Rigid spine [ Foot drop [ Respiratory insufficiency with reduced lung vital capacity to 30%-50% due to deficiency in diaphragmatic function, weakness in thoracic and abdominal muscles, and scoliosis [ Uncommon findings include cardiomyopathy. In most individuals, cardiac symptoms that precede cardiac morbidity are not present (e.g., chest pain, lower limb edema, palpitations), and cardiac abnormalities may only be identified by echocardiography or electrocardiography. A systematic cardiac evaluation in affected individuals using cardiovascular MR showed no cardiac involvement, even in individuals of advanced age with severe disease [ Note: Intellectual disability is not associated with this disorder. Macroglossia, described in affected individuals from a genetic isolate in the Alps [ The disease is invariably progressive, and loss of ambulation occurs approximately ten to 30 years after the onset of symptoms (range: ages 10-48 years) [ A more rapid progression was observed in males than in females [ Intrafamilial variability in the clinical phenotype has been reported: in sibs with the same pathogenic variants the age at onset and the clinical course can vary considerably [ There are no consistent genotype-phenotype correlations in calpainopathy, although null homozygous variants are generally associated with a severe phenotype and absent calpain-3 protein in muscle [ Individuals who are compound heterozygous for Nearly full penetrance is observed by adulthood. Serum CK concentration is usually increased until the advanced stage of the disease. Calpainopathy was originally called LGMD2A because it was the first form of autosomal recessive LGMD to be mapped [ As both recessive and dominant forms are associated with Calpainopathy is the most common form of LGMD [ A study in northeastern Italy estimated that calpainopathy has a prevalence of approximately 1:100,000 inhabitants (corresponding to a carrier frequency of ~1:160) [ Higher prevalence rates have been calculated in genetically isolated communities; the prevalence of the disease has been estimated at 48:1,000,000 in La Réunion Island [ • Tendency to walk on tiptoe; • Difficulty in running; • Scapular winging. • Waddling gait and slight hyperlordosis • Symmetric weakness [ • Scapular winging • Marked laxity of the abdominal muscles [ • Early Achilles tendon shortening and scoliosis • Muscle pain, exercise intolerance, and elevated lactate levels in some individuals similar to that seen in a pseudometabolic myopathy [ • Eosinophilic myositis with increased serum CK, an early and transient feature that is not present in older individuals [ • Significant atrophy of the calf muscle or more rarely calf hypertrophy • Rhabdomyolysis (and/or myoglobinuria) triggered by physical exercise; occasionally observed in asymptomatic individuals or in individuals with mild muscle involvement [ • The inability to climb stairs, rise up from a chair, lift weights, or get up from the floor • Joint contractures (in the hips, knees, elbows, and fingers) • Rigid spine [ • Foot drop [ • Respiratory insufficiency with reduced lung vital capacity to 30%-50% due to deficiency in diaphragmatic function, weakness in thoracic and abdominal muscles, and scoliosis [ ## Clinical Description Calpainopathy is characterized by symmetric and progressive weakness of proximal limb-girdle muscles, symmetric muscle atrophy of the proximal limb and trunk muscles, scapular winging, scoliosis, and joint contractures. The age at onset of muscle weakness ranges from two to 40 years. Early motor milestones are usually normal. Significant intra- and interfamilial clinical variability is seen [ Three phenotypes of autosomal recessive calpainopathy have been identified based on the distribution of muscle weakness and age at onset: Tendency to walk on tiptoe; Difficulty in running; Scapular winging. Waddling gait and slight hyperlordosis Symmetric weakness [ Scapular winging Marked laxity of the abdominal muscles [ Early Achilles tendon shortening and scoliosis Variable findings include the following: Muscle pain, exercise intolerance, and elevated lactate levels in some individuals similar to that seen in a pseudometabolic myopathy [ Eosinophilic myositis with increased serum CK, an early and transient feature that is not present in older individuals [ Significant atrophy of the calf muscle or more rarely calf hypertrophy Rhabdomyolysis (and/or myoglobinuria) triggered by physical exercise; occasionally observed in asymptomatic individuals or in individuals with mild muscle involvement [ The inability to climb stairs, rise up from a chair, lift weights, or get up from the floor Joint contractures (in the hips, knees, elbows, and fingers) Occasionally observed findings: Rigid spine [ Foot drop [ Respiratory insufficiency with reduced lung vital capacity to 30%-50% due to deficiency in diaphragmatic function, weakness in thoracic and abdominal muscles, and scoliosis [ Uncommon findings include cardiomyopathy. In most individuals, cardiac symptoms that precede cardiac morbidity are not present (e.g., chest pain, lower limb edema, palpitations), and cardiac abnormalities may only be identified by echocardiography or electrocardiography. A systematic cardiac evaluation in affected individuals using cardiovascular MR showed no cardiac involvement, even in individuals of advanced age with severe disease [ Note: Intellectual disability is not associated with this disorder. Macroglossia, described in affected individuals from a genetic isolate in the Alps [ The disease is invariably progressive, and loss of ambulation occurs approximately ten to 30 years after the onset of symptoms (range: ages 10-48 years) [ A more rapid progression was observed in males than in females [ Intrafamilial variability in the clinical phenotype has been reported: in sibs with the same pathogenic variants the age at onset and the clinical course can vary considerably [ • Tendency to walk on tiptoe; • Difficulty in running; • Scapular winging. • Waddling gait and slight hyperlordosis • Symmetric weakness [ • Scapular winging • Marked laxity of the abdominal muscles [ • Early Achilles tendon shortening and scoliosis • Muscle pain, exercise intolerance, and elevated lactate levels in some individuals similar to that seen in a pseudometabolic myopathy [ • Eosinophilic myositis with increased serum CK, an early and transient feature that is not present in older individuals [ • Significant atrophy of the calf muscle or more rarely calf hypertrophy • Rhabdomyolysis (and/or myoglobinuria) triggered by physical exercise; occasionally observed in asymptomatic individuals or in individuals with mild muscle involvement [ • The inability to climb stairs, rise up from a chair, lift weights, or get up from the floor • Joint contractures (in the hips, knees, elbows, and fingers) • Rigid spine [ • Foot drop [ • Respiratory insufficiency with reduced lung vital capacity to 30%-50% due to deficiency in diaphragmatic function, weakness in thoracic and abdominal muscles, and scoliosis [ ## Genotype-Phenotype Correlations There are no consistent genotype-phenotype correlations in calpainopathy, although null homozygous variants are generally associated with a severe phenotype and absent calpain-3 protein in muscle [ Individuals who are compound heterozygous for ## Penetrance Nearly full penetrance is observed by adulthood. Serum CK concentration is usually increased until the advanced stage of the disease. ## Nomenclature Calpainopathy was originally called LGMD2A because it was the first form of autosomal recessive LGMD to be mapped [ As both recessive and dominant forms are associated with ## Prevalence Calpainopathy is the most common form of LGMD [ A study in northeastern Italy estimated that calpainopathy has a prevalence of approximately 1:100,000 inhabitants (corresponding to a carrier frequency of ~1:160) [ Higher prevalence rates have been calculated in genetically isolated communities; the prevalence of the disease has been estimated at 48:1,000,000 in La Réunion Island [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Genes of Interest in the Differential Diagnosis of Calpainopathy AD = autosomal dominant; AR = autosomal recessive; LGMD = limb-girdle muscular dystrophy; LGMDD = autosomal dominant LGMD; LGMDR = autosomal recessive LGMD (LGMD2 in older nomenclature); MOI = mode of inheritance; XL = X-linked Based on Table 1 in FSHD1 is associated with a heterozygous pathogenic contraction of the D4Z4 repeat array in the subtelomeric region of chromosome 4q35 on a chromosome 4 permissive haplotype. FSHD2 is associated with hypomethylation of the D4Z4 repeat array in the subtelomeric region of chromosome 4q35 on a chromosome 4 permissive haplotype. Hypomethylation of the D4Z4 repeat array can be the result of a heterozygous pathogenic variant in FSHD1 is inherited in an autosomal dominant manner. FSHD2 is inherited in a digenic manner. Note: (1) Calpainopathy has been reported in individuals with asthenia, myalgias, exercise intolerance, lower-limb proximal muscle weakness, and excessive lactate production after aerobic exercise [ ## Management Appropriate management, tailored to each individual, can improve quality of life and prolong survival. The general approach is based on the typical progression and complications of individuals with limb-girdle muscular dystrophy (LGMD) as described by To establish the extent of disease and needs in an individual diagnosed with calpainopathy, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Calpainopathy Grading of muscle strength in single upper, lower, proximal, & distal muscles Analysis of several functional performances (e.g., 6MWT, GSGC) Gross motor skills Gait, mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) Cardiac eval Echocardiogram 6MWT = 6-minute walk test; ADL = activities of daily living; GSGC = gait, stairs, gower, chair; MOI = mode of inheritance; PT = physical therapy Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Treatment of Manifestations in Individuals with Calpainopathy Passive PT program & stretching exercises instituted early following diagnosis to promote mobility, prolong walking, & slow disease progression by maintaining joint flexibility Affected persons usually benefit from strengthening & gentle, Additional treatment per PT & OT Maintain appropriate weight for height w/nutrition mgmt as needed. Mobility aids for loss of certain motor abilities; canes, walkers, orthotics, & wheelchairs enable affected persons to regain independence. Knee-ankle-foot orthoses while sleeping to prevent contractures Consider need for positioning & seating devices, as scoliosis occurs mainly after wheelchair dependence. Surgical intervention as needed for orthopedic complications (foot deformities, scoliosis, Achilles tendon contractures) Scapular fixation may be required for problematic scapular winging. Annual influenza vaccination Prompt treatment for chest & respiratory infections w/ mechanical in-exsufflator when needed Nocturnal ventilator assistance (noninvasive ventilation by nasal masks) for those w/nocturnal hypoventilation &/or respiratory failure Respiratory aids for those w/chronic respiratory insufficiency Wheelchair-bound persons may develop weak cough efforts, placing them at risk of atelectasis, pneumonia, progressive mismatch, & respiratory failure. Nocturnal ventilator assistance may be lifesaving in severely affected persons. Respiratory aids may be indicated to prolong survival. Decisions regarding loss of mobility; Need for assistance w/ADL, medical complications, & end-of-life care. ADL = activities of daily living; OT = occupational therapy; PT = physical therapy To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in Recommended Surveillance for Individuals with Calpainopathy Pulmonary eval (incl pulmonary function tests) in those w/nocturnal hypoventilation Note: Forced vital capacity should be measured in sitting & supine position. Strenuous and excessive muscle exercise should be discouraged as it exacerbates muscle necrosis and could precipitate the onset of weakness or accelerate muscle wasting. Although individuals with minimal muscle weakness and functional limitation may be able to perform strenuous exercise, in some instances this may result in rhabdomyolysis and myoglobinuria [ Body weight should be controlled to avoid obesity as well as excessive weight loss (atrophy of muscles can be accelerated by loss of muscle proteins). Physical trauma, bone fractures, and prolonged immobility can induce disuse atrophy and thus should be avoided. Although no association of the disease with malignant hyperthermia is reported, the use of succinylcholine and halogenated anesthetic agents should be avoided when possible (see While the specific mechanism whereby cholesterol-lowering agents (e.g., statins) may produce muscle damage causing pain or weakness is unknown, such drugs should be avoided when possible. It is appropriate to clarify the 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 initiation of evaluation and subsequent surveillance. Evaluations can include: Molecular genetic testing if the pathogenic variant(s) in the family are known; Neurologic examination for muscle weakness if the pathogenic variant(s) in the family are not known. See Women with calpainopathy do not have impaired uterine smooth muscle strength or function and typically have uncomplicated pregnancies. A higher incidence of abnormal fetal presentation was reported in pregnant women with LGMD who were wheelchair bound [ Search • Grading of muscle strength in single upper, lower, proximal, & distal muscles • Analysis of several functional performances (e.g., 6MWT, GSGC) • Gross motor skills • Gait, mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) • Cardiac eval • Echocardiogram • Passive PT program & stretching exercises instituted early following diagnosis to promote mobility, prolong walking, & slow disease progression by maintaining joint flexibility • Affected persons usually benefit from strengthening & gentle, • Additional treatment per PT & OT • Maintain appropriate weight for height w/nutrition mgmt as needed. • Mobility aids for loss of certain motor abilities; canes, walkers, orthotics, & wheelchairs enable affected persons to regain independence. • Knee-ankle-foot orthoses while sleeping to prevent contractures • Consider need for positioning & seating devices, as scoliosis occurs mainly after wheelchair dependence. • Surgical intervention as needed for orthopedic complications (foot deformities, scoliosis, Achilles tendon contractures) • Scapular fixation may be required for problematic scapular winging. • Annual influenza vaccination • Prompt treatment for chest & respiratory infections w/ mechanical in-exsufflator when needed • Nocturnal ventilator assistance (noninvasive ventilation by nasal masks) for those w/nocturnal hypoventilation &/or respiratory failure • Respiratory aids for those w/chronic respiratory insufficiency • Wheelchair-bound persons may develop weak cough efforts, placing them at risk of atelectasis, pneumonia, progressive mismatch, & respiratory failure. • Nocturnal ventilator assistance may be lifesaving in severely affected persons. • Respiratory aids may be indicated to prolong survival. • Decisions regarding loss of mobility; • Need for assistance w/ADL, medical complications, & end-of-life care. • Pulmonary eval (incl pulmonary function tests) in those w/nocturnal hypoventilation • Note: Forced vital capacity should be measured in sitting & supine position. • Molecular genetic testing if the pathogenic variant(s) in the family are known; • Neurologic examination for muscle weakness 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 calpainopathy, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Calpainopathy Grading of muscle strength in single upper, lower, proximal, & distal muscles Analysis of several functional performances (e.g., 6MWT, GSGC) Gross motor skills Gait, mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) Cardiac eval Echocardiogram 6MWT = 6-minute walk test; ADL = activities of daily living; GSGC = gait, stairs, gower, chair; MOI = mode of inheritance; PT = physical therapy Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Grading of muscle strength in single upper, lower, proximal, & distal muscles • Analysis of several functional performances (e.g., 6MWT, GSGC) • Gross motor skills • Gait, mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) • Cardiac eval • Echocardiogram ## Treatment of Manifestations Treatment of Manifestations in Individuals with Calpainopathy Passive PT program & stretching exercises instituted early following diagnosis to promote mobility, prolong walking, & slow disease progression by maintaining joint flexibility Affected persons usually benefit from strengthening & gentle, Additional treatment per PT & OT Maintain appropriate weight for height w/nutrition mgmt as needed. Mobility aids for loss of certain motor abilities; canes, walkers, orthotics, & wheelchairs enable affected persons to regain independence. Knee-ankle-foot orthoses while sleeping to prevent contractures Consider need for positioning & seating devices, as scoliosis occurs mainly after wheelchair dependence. Surgical intervention as needed for orthopedic complications (foot deformities, scoliosis, Achilles tendon contractures) Scapular fixation may be required for problematic scapular winging. Annual influenza vaccination Prompt treatment for chest & respiratory infections w/ mechanical in-exsufflator when needed Nocturnal ventilator assistance (noninvasive ventilation by nasal masks) for those w/nocturnal hypoventilation &/or respiratory failure Respiratory aids for those w/chronic respiratory insufficiency Wheelchair-bound persons may develop weak cough efforts, placing them at risk of atelectasis, pneumonia, progressive mismatch, & respiratory failure. Nocturnal ventilator assistance may be lifesaving in severely affected persons. Respiratory aids may be indicated to prolong survival. Decisions regarding loss of mobility; Need for assistance w/ADL, medical complications, & end-of-life care. ADL = activities of daily living; OT = occupational therapy; PT = physical therapy • Passive PT program & stretching exercises instituted early following diagnosis to promote mobility, prolong walking, & slow disease progression by maintaining joint flexibility • Affected persons usually benefit from strengthening & gentle, • Additional treatment per PT & OT • Maintain appropriate weight for height w/nutrition mgmt as needed. • Mobility aids for loss of certain motor abilities; canes, walkers, orthotics, & wheelchairs enable affected persons to regain independence. • Knee-ankle-foot orthoses while sleeping to prevent contractures • Consider need for positioning & seating devices, as scoliosis occurs mainly after wheelchair dependence. • Surgical intervention as needed for orthopedic complications (foot deformities, scoliosis, Achilles tendon contractures) • Scapular fixation may be required for problematic scapular winging. • Annual influenza vaccination • Prompt treatment for chest & respiratory infections w/ mechanical in-exsufflator when needed • Nocturnal ventilator assistance (noninvasive ventilation by nasal masks) for those w/nocturnal hypoventilation &/or respiratory failure • Respiratory aids for those w/chronic respiratory insufficiency • Wheelchair-bound persons may develop weak cough efforts, placing them at risk of atelectasis, pneumonia, progressive mismatch, & respiratory failure. • Nocturnal ventilator assistance may be lifesaving in severely affected persons. • Respiratory aids may be indicated to prolong survival. • Decisions regarding loss of mobility; • Need for assistance w/ADL, medical complications, & end-of-life care. ## 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 Calpainopathy Pulmonary eval (incl pulmonary function tests) in those w/nocturnal hypoventilation Note: Forced vital capacity should be measured in sitting & supine position. • Pulmonary eval (incl pulmonary function tests) in those w/nocturnal hypoventilation • Note: Forced vital capacity should be measured in sitting & supine position. ## Agents/Circumstances to Avoid Strenuous and excessive muscle exercise should be discouraged as it exacerbates muscle necrosis and could precipitate the onset of weakness or accelerate muscle wasting. Although individuals with minimal muscle weakness and functional limitation may be able to perform strenuous exercise, in some instances this may result in rhabdomyolysis and myoglobinuria [ Body weight should be controlled to avoid obesity as well as excessive weight loss (atrophy of muscles can be accelerated by loss of muscle proteins). Physical trauma, bone fractures, and prolonged immobility can induce disuse atrophy and thus should be avoided. Although no association of the disease with malignant hyperthermia is reported, the use of succinylcholine and halogenated anesthetic agents should be avoided when possible (see While the specific mechanism whereby cholesterol-lowering agents (e.g., statins) may produce muscle damage causing pain or weakness is unknown, such drugs should be avoided when possible. ## Evaluation of Relatives at Risk It is appropriate to clarify the 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 initiation of evaluation and subsequent surveillance. Evaluations can include: Molecular genetic testing if the pathogenic variant(s) in the family are known; Neurologic examination for muscle weakness 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; • Neurologic examination for muscle weakness if the pathogenic variant(s) in the family are not known. ## Pregnancy Management Women with calpainopathy do not have impaired uterine smooth muscle strength or function and typically have uncomplicated pregnancies. A higher incidence of abnormal fetal presentation was reported in pregnant women with LGMD who were wheelchair bound [ ## Therapies Under Investigation Search ## Genetic Counseling Calpainopathy is typically caused by biallelic pathogenic variants and inherited in an autosomal recessive manner. Less commonly, calpainopathy is caused by a heterozygous, dominantly acting pathogenic variant and inherited in an autosomal dominant manner [ The parents of an individual with autosomal recessive calpainopathy 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. Individuals who are heterozygous for a pathogenic variant associated with autosomal recessive calpainopathy are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a pathogenic variant associated with autosomal recessive calpainopathy, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Intrafamilial variability in the clinical phenotype has been reported: in sibs with the same pathogenic variants, the age at onset and the clinical course can vary considerably [ Individuals who are heterozygous for a pathogenic variant associated with autosomal recessive calpainopathy are asymptomatic and are not at risk of developing the disorder. Unless an affected individual's reproductive partner also has calpainopathy or is a carrier, offspring will be obligate heterozygotes for a pathogenic variant in Carrier testing for the reproductive partner of an affected individual should be considered, particularly if consanguinity is likely and/or if both partners are of the same ethnic background. Higher prevalence rates have been calculated in genetically isolated communities (see Note: Carrier testing for the reproductive partner of a known carrier should be considered, particularly if consanguinity is likely and/or if both partners are of the same ethnic background. Higher prevalence rates have been calculated in genetically isolated communities (see All individuals reported to date with autosomal dominant calpainopathy whose parents have undergone molecular genetic testing inherited a To date, If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. If the proband has a known The family history of some individuals diagnosed with autosomal dominant calpainopathy may appear to be negative because of early death of the parent before the onset of symptoms, late onset of the disease in the affected parent (see If a parent of the proband is affected and/or is known to be heterozygous for the If the proband has a known If both parents are clinically unaffected but their genetic status is unknown, the sibs of a proband are still at increased risk for calpainopathy 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, are heterozygous, or are at risk of being heterozygous (e.g., asymptomatic relatives of known 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 testing to be a personal decision, discussion of these issues may be helpful. • The parents of an individual with autosomal recessive calpainopathy 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. • Individuals who are heterozygous for a pathogenic variant associated with autosomal recessive calpainopathy are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a pathogenic variant associated with autosomal recessive calpainopathy, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Intrafamilial variability in the clinical phenotype has been reported: in sibs with the same pathogenic variants, the age at onset and the clinical course can vary considerably [ • Individuals who are heterozygous for a pathogenic variant associated with autosomal recessive calpainopathy are asymptomatic and are not at risk of developing the disorder. • Unless an affected individual's reproductive partner also has calpainopathy or is a carrier, offspring will be obligate heterozygotes for a pathogenic variant in • Carrier testing for the reproductive partner of an affected individual should be considered, particularly if consanguinity is likely and/or if both partners are of the same ethnic background. Higher prevalence rates have been calculated in genetically isolated communities (see • All individuals reported to date with autosomal dominant calpainopathy whose parents have undergone molecular genetic testing inherited a • To date, • If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed 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. • If the proband has a known • The family history of some individuals diagnosed with autosomal dominant calpainopathy may appear to be negative because of early death of the parent before the onset of symptoms, late onset of the disease in the affected parent (see • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If a parent of the proband is affected and/or is known to be heterozygous for the • If the proband has a known • If both parents are clinically unaffected but their genetic status is unknown, the sibs of a proband are still at increased risk for calpainopathy 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, are heterozygous, or are at risk of being heterozygous (e.g., asymptomatic relatives of known affected individuals). ## Mode of Inheritance Calpainopathy is typically caused by biallelic pathogenic variants and inherited in an autosomal recessive manner. Less commonly, calpainopathy is caused by a heterozygous, dominantly acting pathogenic variant and inherited in an autosomal dominant manner [ ## Autosomal Recessive Inheritance – Risk to Family Members The parents of an individual with autosomal recessive calpainopathy 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. Individuals who are heterozygous for a pathogenic variant associated with autosomal recessive calpainopathy are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a pathogenic variant associated with autosomal recessive calpainopathy, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Intrafamilial variability in the clinical phenotype has been reported: in sibs with the same pathogenic variants, the age at onset and the clinical course can vary considerably [ Individuals who are heterozygous for a pathogenic variant associated with autosomal recessive calpainopathy are asymptomatic and are not at risk of developing the disorder. Unless an affected individual's reproductive partner also has calpainopathy or is a carrier, offspring will be obligate heterozygotes for a pathogenic variant in Carrier testing for the reproductive partner of an affected individual should be considered, particularly if consanguinity is likely and/or if both partners are of the same ethnic background. Higher prevalence rates have been calculated in genetically isolated communities (see Note: Carrier testing for the reproductive partner of a known carrier should be considered, particularly if consanguinity is likely and/or if both partners are of the same ethnic background. Higher prevalence rates have been calculated in genetically isolated communities (see • The parents of an individual with autosomal recessive calpainopathy 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. • Individuals who are heterozygous for a pathogenic variant associated with autosomal recessive calpainopathy are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a pathogenic variant associated with autosomal recessive calpainopathy, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Intrafamilial variability in the clinical phenotype has been reported: in sibs with the same pathogenic variants, the age at onset and the clinical course can vary considerably [ • Individuals who are heterozygous for a pathogenic variant associated with autosomal recessive calpainopathy are asymptomatic and are not at risk of developing the disorder. • Unless an affected individual's reproductive partner also has calpainopathy or is a carrier, offspring will be obligate heterozygotes for a pathogenic variant in • Carrier testing for the reproductive partner of an affected individual should be considered, particularly if consanguinity is likely and/or if both partners are of the same ethnic background. Higher prevalence rates have been calculated in genetically isolated communities (see ## Autosomal Dominant Inheritance – Risk to Family Members All individuals reported to date with autosomal dominant calpainopathy whose parents have undergone molecular genetic testing inherited a To date, If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. If the proband has a known The family history of some individuals diagnosed with autosomal dominant calpainopathy may appear to be negative because of early death of the parent before the onset of symptoms, late onset of the disease in the affected parent (see If a parent of the proband is affected and/or is known to be heterozygous for the If the proband has a known If both parents are clinically unaffected but their genetic status is unknown, the sibs of a proband are still at increased risk for calpainopathy because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism. • All individuals reported to date with autosomal dominant calpainopathy whose parents have undergone molecular genetic testing inherited a • To date, • If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed 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. • If the proband has a known • The family history of some individuals diagnosed with autosomal dominant calpainopathy may appear to be negative because of early death of the parent before the onset of symptoms, late onset of the disease in the affected parent (see • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If a parent of the proband is affected and/or is known to be heterozygous for the • If the proband has a known • If both parents are clinically unaffected but their genetic status is unknown, the sibs of a proband are still at increased risk for calpainopathy 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, are heterozygous, or are at risk of being heterozygous (e.g., asymptomatic relatives of known 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, are heterozygous, or are at risk of being heterozygous (e.g., asymptomatic relatives of known 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 testing to be a personal decision, discussion of these issues may be helpful. ## Resources France United Kingdom • • France • • • • • United Kingdom • ## Molecular Genetics Calpainopathy: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Calpainopathy ( Calpain-3 is the muscle-specific member of a family of Ca Most individuals with calpainopathy have complete or partial calpain-3 protein deficiency on muscle biopsy. In 10%-30% of individuals with calpainopathy, muscle biopsy shows a normal amount of protein by western blotting [ The mobility of calpain-3 between the sarcomeric M-lines and the cytosol may have a key role in physical stress, and it is compromised in calpainopathy when its protease activity has been lost. An impairment of calpain proteolytic activity results in sarcomere remodeling by promoting ubiquitin-mediated degradation of sarcomeric proteins [ The majority of The mechanism by which Many deep intronic pathogenic variants that disrupt the correct splicing can be overlooked by sequencing of genomic DNA [ A small number of See AD = autosomal dominant Variants listed in the table have been provided by the author. Variant designation that does not conform to current naming conventions This variant was reported as c.348C>A; however, based on the sequencing trace in • The majority of • The mechanism by which ## Molecular Pathogenesis Calpain-3 is the muscle-specific member of a family of Ca Most individuals with calpainopathy have complete or partial calpain-3 protein deficiency on muscle biopsy. In 10%-30% of individuals with calpainopathy, muscle biopsy shows a normal amount of protein by western blotting [ The mobility of calpain-3 between the sarcomeric M-lines and the cytosol may have a key role in physical stress, and it is compromised in calpainopathy when its protease activity has been lost. An impairment of calpain proteolytic activity results in sarcomere remodeling by promoting ubiquitin-mediated degradation of sarcomeric proteins [ The majority of The mechanism by which Many deep intronic pathogenic variants that disrupt the correct splicing can be overlooked by sequencing of genomic DNA [ A small number of See AD = autosomal dominant Variants listed in the table have been provided by the author. Variant designation that does not conform to current naming conventions This variant was reported as c.348C>A; however, based on the sequencing trace in • The majority of • The mechanism by which ## Chapter Notes Coalition to Cure Calpain 315 Compo ParkwayWestport, CT 06880Web page: Dr Corrado Angelini acknowledges the previous contribution to this chapter by Dr Marina Fanin, a major contributor to calpain research, who first described the intronic variant in calpain-3 in a genetic isolate in the Alps [ Corrado Angelini, MD (2005-present)Marina Fanin, PhD; University of Padova (2005-2022) 1 May 2025 (aa) Revision: ClinGen variant interpretation guidelines 1 December 2022 (sw) Comprehensive update posted live 3 August 2017 (ha) Comprehensive update posted live 5 July 2012 (me) Comprehensive update posted live 3 December 2007 (me) Comprehensive update posted live 10 May 2005 (me) Review posted live 29 November 2004 (ca) Original submission • 1 May 2025 (aa) Revision: ClinGen variant interpretation guidelines • 1 December 2022 (sw) Comprehensive update posted live • 3 August 2017 (ha) Comprehensive update posted live • 5 July 2012 (me) Comprehensive update posted live • 3 December 2007 (me) Comprehensive update posted live • 10 May 2005 (me) Review posted live • 29 November 2004 (ca) Original submission ## Author Notes Coalition to Cure Calpain 315 Compo ParkwayWestport, CT 06880Web page: ## Acknowledgments Dr Corrado Angelini acknowledges the previous contribution to this chapter by Dr Marina Fanin, a major contributor to calpain research, who first described the intronic variant in calpain-3 in a genetic isolate in the Alps [ ## Author History Corrado Angelini, MD (2005-present)Marina Fanin, PhD; University of Padova (2005-2022) ## Revision History 1 May 2025 (aa) Revision: ClinGen variant interpretation guidelines 1 December 2022 (sw) Comprehensive update posted live 3 August 2017 (ha) Comprehensive update posted live 5 July 2012 (me) Comprehensive update posted live 3 December 2007 (me) Comprehensive update posted live 10 May 2005 (me) Review posted live 29 November 2004 (ca) Original submission • 1 May 2025 (aa) Revision: ClinGen variant interpretation guidelines • 1 December 2022 (sw) Comprehensive update posted live • 3 August 2017 (ha) Comprehensive update posted live • 5 July 2012 (me) Comprehensive update posted live • 3 December 2007 (me) Comprehensive update posted live • 10 May 2005 (me) Review posted live • 29 November 2004 (ca) Original submission ## References ## Literature Cited	[]	10/5/2005	1/12/2022	1/5/2025	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
lhon	lhon	[ "Leber's Disease", "Leber's Hereditary Optic Neuropathy", "Leber's Optic Atrophy", "Leber's Optic Neuropathy", "LHON", "LHON", "Leber's Disease", "Leber's Optic Atrophy", "Leber's Optic Neuropathy", "Leber’s Hereditary Optic Neuropathy", "ATP synthase F(0) complex subunit a", "Cytochrome b", "Cytochrome c oxidase subunit 3", "NADH-ubiquinone oxidoreductase chain 1", "NADH-ubiquinone oxidoreductase chain 2", "NADH-ubiquinone oxidoreductase chain 3", "NADH-ubiquinone oxidoreductase chain 4", "NADH-ubiquinone oxidoreductase chain 4L", "NADH-ubiquinone oxidoreductase chain 5", "NADH-ubiquinone oxidoreductase chain 6", "MT-ATP6", "MT-CO3", "MT-CYB", "MT-ND1", "MT-ND2", "MT-ND3", "MT-ND4", "MT-ND4L", "MT-ND5", "MT-ND6", "Leber Hereditary Optic Neuropathy" ]	Leber Hereditary Optic Neuropathy	Patrick Yu-Wai-Man, Patrick F Chinnery	Summary Leber hereditary optic neuropathy (LHON) typically presents in young adults as bilateral, painless, subacute visual failure. The peak age of onset in LHON is in the second and third decades of life, with 90% of those who lose their vision doing so before age 50 years. Very rarely, individuals first manifest LHON in the seventh and eighth decades of life. Males are four to five times more likely to be affected than females, but neither sex nor mutational status significantly influences the timing and severity of the initial visual loss. Neurologic abnormalities such as postural tremor, peripheral neuropathy, nonspecific myopathy, and movement disorders have been reported to be more common in individuals with LHON than in the general population. Some individuals with LHON, usually women, may also develop a multiple sclerosis-like illness. The diagnosis of LHON is established in a proband with a consistent clinical history and/or one of three common mitochondrial DNA (mtDNA) pathogenic variants identified on molecular genetic testing. Referral to a cardiologist for individuals with pre-excitation syndrome on EKG is recommended; treatment for symptomatic individuals is per standard practice. A multidisciplinary approach for those affected individuals with extraocular neurologic features (ataxia, peripheral neuropathy, nonspecific myopathy, and movement disorders) should be considered to minimize the functional consequences of these complications. LHON is caused by pathogenic variants in mtDNA and is transmitted strictly by maternal inheritance. The mother of a proband usually has the mtDNA pathogenic variant and may or may not have developed visual loss. A male (affected or unaffected) with a primary LHON-causing mtDNA pathogenic variant cannot transmit the variant to any of his offspring. A female (affected or unaffected) with a primary LHON-causing mtDNA variant transmits the variant to all of her offspring. In approximately 60% of families, a history of visual loss affecting maternal relatives is present. Genetic counseling for LHON is complicated by the sex- and age-dependent penetrance of the primary mtDNA LHON-causing pathogenic variants and penetrance can vary markedly in different branches of the same family and between families harboring the same LHON-causing mtDNA pathogenic variant. Once a mtDNA LHON-causing variant in the mother has been identified, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible; however, accurate interpretation of a positive prenatal test result is difficult because the mtDNA mutational load in amniocytes and chorionic villi may not correspond to that of other fetal or adult tissues, and the presence of the mtDNA LHON-causing variant does not predict the occurrence, age of onset, severity, or rate of progression of visual loss.	## Diagnosis No consensus clinical diagnostic criteria for Leber hereditary optic neuropathy (LHON) have been published. Leber hereditary optic neuropathy (LHON) Bilateral, painless subacute visual failure that develops during young adult life Visual acuity is severely reduced to 20/200 or worse in the majority of cases. Visual field testing by kinetic or static perimetry shows an enlarging dense central or centrocecal scotoma. Disk hyperemia, edema of the peripapillary retinal nerve fiber layer, retinal telangiectasia, and increased vascular tortuosity Note: Approximately 20% of affected individuals show no fundal abnormalities in the acute stage. Optic disc atrophy Optic nerve dysfunction and absence of other retinal diseases on electrophysiologic studies (pattern electroretinogram and visual evoked potentials) Neurologic abnormalities Postural tremor Peripheral neuropathy Movement disorders Multiple sclerosis-like illness Nonspecific myopathy Cardiac arrhythmias Respiratory Chain Dysfunction in Leber Hereditary Optic Neuropathy See references in MRS = magnetic resonance spectroscopy % of decrease relative to controls The diagnosis of LHON Note: Identification of a mtDNA variant of uncertain significance does not by itself establish or rule out the diagnosis of this disorder. Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click Molecular Genetic Testing Used in Leber Hereditary Optic Neuropathy LHON = Leber hereditary optic neuropathy See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and 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. The three most common pathogenic variants are: Heteroplasmy does not influence the sensitivity of molecular genetic testing for LHON because affected individuals generally have more than 70% mutated mtDNA in leukocytes, which is easily detected by standard techniques. It is likely that the level of heteroplasmy may have a bearing on the risk of developing LHON in the asymptomatic individual and on the risk for transmission [ • Bilateral, painless subacute visual failure that develops during young adult life • Visual acuity is severely reduced to 20/200 or worse in the majority of cases. • Visual field testing by kinetic or static perimetry shows an enlarging dense central or centrocecal scotoma. • Visual acuity is severely reduced to 20/200 or worse in the majority of cases. • Visual field testing by kinetic or static perimetry shows an enlarging dense central or centrocecal scotoma. • Disk hyperemia, edema of the peripapillary retinal nerve fiber layer, retinal telangiectasia, and increased vascular tortuosity • Note: Approximately 20% of affected individuals show no fundal abnormalities in the acute stage. • Optic disc atrophy • Optic nerve dysfunction and absence of other retinal diseases on electrophysiologic studies (pattern electroretinogram and visual evoked potentials) • Visual acuity is severely reduced to 20/200 or worse in the majority of cases. • Visual field testing by kinetic or static perimetry shows an enlarging dense central or centrocecal scotoma. • Neurologic abnormalities • Postural tremor • Peripheral neuropathy • Movement disorders • Multiple sclerosis-like illness • Postural tremor • Peripheral neuropathy • Movement disorders • Multiple sclerosis-like illness • Nonspecific myopathy • Cardiac arrhythmias • Postural tremor • Peripheral neuropathy • Movement disorders • Multiple sclerosis-like illness • Heteroplasmy does not influence the sensitivity of molecular genetic testing for LHON because affected individuals generally have more than 70% mutated mtDNA in leukocytes, which is easily detected by standard techniques. • It is likely that the level of heteroplasmy may have a bearing on the risk of developing LHON in the asymptomatic individual and on the risk for transmission [ ## Suggestive Findings Leber hereditary optic neuropathy (LHON) Bilateral, painless subacute visual failure that develops during young adult life Visual acuity is severely reduced to 20/200 or worse in the majority of cases. Visual field testing by kinetic or static perimetry shows an enlarging dense central or centrocecal scotoma. Disk hyperemia, edema of the peripapillary retinal nerve fiber layer, retinal telangiectasia, and increased vascular tortuosity Note: Approximately 20% of affected individuals show no fundal abnormalities in the acute stage. Optic disc atrophy Optic nerve dysfunction and absence of other retinal diseases on electrophysiologic studies (pattern electroretinogram and visual evoked potentials) Neurologic abnormalities Postural tremor Peripheral neuropathy Movement disorders Multiple sclerosis-like illness Nonspecific myopathy Cardiac arrhythmias Respiratory Chain Dysfunction in Leber Hereditary Optic Neuropathy See references in MRS = magnetic resonance spectroscopy % of decrease relative to controls • Bilateral, painless subacute visual failure that develops during young adult life • Visual acuity is severely reduced to 20/200 or worse in the majority of cases. • Visual field testing by kinetic or static perimetry shows an enlarging dense central or centrocecal scotoma. • Visual acuity is severely reduced to 20/200 or worse in the majority of cases. • Visual field testing by kinetic or static perimetry shows an enlarging dense central or centrocecal scotoma. • Disk hyperemia, edema of the peripapillary retinal nerve fiber layer, retinal telangiectasia, and increased vascular tortuosity • Note: Approximately 20% of affected individuals show no fundal abnormalities in the acute stage. • Optic disc atrophy • Optic nerve dysfunction and absence of other retinal diseases on electrophysiologic studies (pattern electroretinogram and visual evoked potentials) • Visual acuity is severely reduced to 20/200 or worse in the majority of cases. • Visual field testing by kinetic or static perimetry shows an enlarging dense central or centrocecal scotoma. • Neurologic abnormalities • Postural tremor • Peripheral neuropathy • Movement disorders • Multiple sclerosis-like illness • Postural tremor • Peripheral neuropathy • Movement disorders • Multiple sclerosis-like illness • Nonspecific myopathy • Cardiac arrhythmias • Postural tremor • Peripheral neuropathy • Movement disorders • Multiple sclerosis-like illness ## Establishing the Diagnosis The diagnosis of LHON Note: Identification of a mtDNA variant of uncertain significance does not by itself establish or rule out the diagnosis of this disorder. Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click Molecular Genetic Testing Used in Leber Hereditary Optic Neuropathy LHON = Leber hereditary optic neuropathy See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and 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. The three most common pathogenic variants are: Heteroplasmy does not influence the sensitivity of molecular genetic testing for LHON because affected individuals generally have more than 70% mutated mtDNA in leukocytes, which is easily detected by standard techniques. It is likely that the level of heteroplasmy may have a bearing on the risk of developing LHON in the asymptomatic individual and on the risk for transmission [ • Heteroplasmy does not influence the sensitivity of molecular genetic testing for LHON because affected individuals generally have more than 70% mutated mtDNA in leukocytes, which is easily detected by standard techniques. • It is likely that the level of heteroplasmy may have a bearing on the risk of developing LHON in the asymptomatic individual and on the risk for transmission [ ## Step 1 ## Step 2 For an introduction to multigene panels click ## Step 3 Molecular Genetic Testing Used in Leber Hereditary Optic Neuropathy LHON = Leber hereditary optic neuropathy See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and 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. The three most common pathogenic variants are: Heteroplasmy does not influence the sensitivity of molecular genetic testing for LHON because affected individuals generally have more than 70% mutated mtDNA in leukocytes, which is easily detected by standard techniques. It is likely that the level of heteroplasmy may have a bearing on the risk of developing LHON in the asymptomatic individual and on the risk for transmission [ • Heteroplasmy does not influence the sensitivity of molecular genetic testing for LHON because affected individuals generally have more than 70% mutated mtDNA in leukocytes, which is easily detected by standard techniques. • It is likely that the level of heteroplasmy may have a bearing on the risk of developing LHON in the asymptomatic individual and on the risk for transmission [ ## Clinical Characteristics Leber hereditary optic neuropathy (LHON) typically presents in young adults as bilateral painless subacute visual failure. The peak age of onset in LHON is in the second and third decades of life, with 95% of those who lose their vision doing so before age 50 years. Very rarely, individuals first manifest LHON in the seventh and eighth decades of life [ In the Affected individuals are usually entirely asymptomatic until they develop visual blurring affecting the central visual field in one eye ( Broad generalizations with regard to specific LHON-causing pathogenic variants: Variants Variant Following the nadir, visual acuity may improve. Note, however, that recovery of visual function in LHON – if it does occur – is usually incomplete. Reported visual recovery rates in persons with LHON are summarized in In a meta-analysis of 12 retrospective and three prospective studies providing visual function information on 695 affected individuals with the Visual Recovery Rates by Pathogenic Variant in Individuals with Leber Hereditary Optic Neuropathy Different criteria were used to define visual recovery; the range partly reflects this variability. Although published reports would appear to indicate otherwise, the Other predictors of better visual recovery have included an earlier age of onset (≤12 years), a subacute presentation with slow visual deterioration, and a relatively large optic disc [ The lifetime risk of visual failure by sex and age in individuals with a homoplasmic primary LHON-causing pathogenic variant is summarized in Lifetime Risk for Visual Failure in Individuals with a Homoplasmic Primary LHON-Causing Mitochondrial DNA Pathogenic Variant by Study F = female(s); M = male(s) The A multiple sclerosis (MS)-like illness has been reported in association with all three primary mtDNA LHON-causing pathogenic variants ( The pattern of visual loss in LHON-MS appears distinct from classic LHON, being marked by recurrent episodes of visual loss that can be associated with ocular pain, but with incomplete visual recovery and progression to legal blindness in half of all affected persons [ See LHON-causing mtDNA pathogenic variants are characterized by reduced penetrance. An individual can only develop LHON if a pathogenic mtDNA LHON-causing variant is present, but it must be stressed that penetrance can vary markedly in different branches of the same family and between families with the same LHON-causing mtDNA pathogenic variant, which complicates genetic counseling at the individual level. The two most important risk factors for vision loss are sex and age [ Additional genetic and environmental factors interact with the primary mtDNA pathogenic variant and influence whether an individual ultimately develops optic nerve dysfunction and visual failure. In one study, individuals with a In a retrospective analysis of 17 families heteroplasmic for the However, testing to quantify the level of heteroplasmy for the purpose of presymptomatic diagnosis (see In the past, LHON was sometimes referred to as Leber hereditary optic neuroretinopathy; this term is outdated and should not be used. In northeast England, 1:8,500 individuals were found to have a pathogenic LHON-causing variant; 1:31,000 had experienced visual loss as a result of LHON [ Fairly similar figures have been reported in other northern European populations, with a disease prevalence of 1:39,000 in the Netherlands and 1:50,000 in Finland [ • Variants • Variant • In one study, individuals with a • In a retrospective analysis of 17 families heteroplasmic for the • However, testing to quantify the level of heteroplasmy for the purpose of presymptomatic diagnosis (see • In one study, individuals with a • In a retrospective analysis of 17 families heteroplasmic for the • In one study, individuals with a • In a retrospective analysis of 17 families heteroplasmic for the ## Clinical Description Leber hereditary optic neuropathy (LHON) typically presents in young adults as bilateral painless subacute visual failure. The peak age of onset in LHON is in the second and third decades of life, with 95% of those who lose their vision doing so before age 50 years. Very rarely, individuals first manifest LHON in the seventh and eighth decades of life [ In the Affected individuals are usually entirely asymptomatic until they develop visual blurring affecting the central visual field in one eye ( Broad generalizations with regard to specific LHON-causing pathogenic variants: Variants Variant Following the nadir, visual acuity may improve. Note, however, that recovery of visual function in LHON – if it does occur – is usually incomplete. Reported visual recovery rates in persons with LHON are summarized in In a meta-analysis of 12 retrospective and three prospective studies providing visual function information on 695 affected individuals with the Visual Recovery Rates by Pathogenic Variant in Individuals with Leber Hereditary Optic Neuropathy Different criteria were used to define visual recovery; the range partly reflects this variability. Although published reports would appear to indicate otherwise, the Other predictors of better visual recovery have included an earlier age of onset (≤12 years), a subacute presentation with slow visual deterioration, and a relatively large optic disc [ The lifetime risk of visual failure by sex and age in individuals with a homoplasmic primary LHON-causing pathogenic variant is summarized in Lifetime Risk for Visual Failure in Individuals with a Homoplasmic Primary LHON-Causing Mitochondrial DNA Pathogenic Variant by Study F = female(s); M = male(s) The A multiple sclerosis (MS)-like illness has been reported in association with all three primary mtDNA LHON-causing pathogenic variants ( The pattern of visual loss in LHON-MS appears distinct from classic LHON, being marked by recurrent episodes of visual loss that can be associated with ocular pain, but with incomplete visual recovery and progression to legal blindness in half of all affected persons [ • Variants • Variant ## Genotype-Phenotype Correlations See ## Penetrance LHON-causing mtDNA pathogenic variants are characterized by reduced penetrance. An individual can only develop LHON if a pathogenic mtDNA LHON-causing variant is present, but it must be stressed that penetrance can vary markedly in different branches of the same family and between families with the same LHON-causing mtDNA pathogenic variant, which complicates genetic counseling at the individual level. The two most important risk factors for vision loss are sex and age [ Additional genetic and environmental factors interact with the primary mtDNA pathogenic variant and influence whether an individual ultimately develops optic nerve dysfunction and visual failure. In one study, individuals with a In a retrospective analysis of 17 families heteroplasmic for the However, testing to quantify the level of heteroplasmy for the purpose of presymptomatic diagnosis (see • In one study, individuals with a • In a retrospective analysis of 17 families heteroplasmic for the • However, testing to quantify the level of heteroplasmy for the purpose of presymptomatic diagnosis (see • In one study, individuals with a • In a retrospective analysis of 17 families heteroplasmic for the • In one study, individuals with a • In a retrospective analysis of 17 families heteroplasmic for the ## Nomenclature In the past, LHON was sometimes referred to as Leber hereditary optic neuroretinopathy; this term is outdated and should not be used. ## Prevalence In northeast England, 1:8,500 individuals were found to have a pathogenic LHON-causing variant; 1:31,000 had experienced visual loss as a result of LHON [ Fairly similar figures have been reported in other northern European populations, with a disease prevalence of 1:39,000 in the Netherlands and 1:50,000 in Finland [ ## Genetically Related (Allelic) Disorders Mitochondrial DNA pathogenic variants are responsible for a heterogeneous group of inherited diseases (see In a few families, mtDNA complex I pathogenic variants cause optic atrophy in association with severe neurologic deficits including ataxia, dystonia, and encephalopathy [ Two mtDNA complex I single-nucleotide variants, m.3376G>A and m.3697G>A, have also been identified in individuals with a LHON-like optic neuropathy and clinical features of • In a few families, mtDNA complex I pathogenic variants cause optic atrophy in association with severe neurologic deficits including ataxia, dystonia, and encephalopathy [ • Two mtDNA complex I single-nucleotide variants, m.3376G>A and m.3697G>A, have also been identified in individuals with a LHON-like optic neuropathy and clinical features of ## Differential Diagnosis Unilateral optic nerve involvement in Leber hereditary optic neuronopathy (LHON) is exceptionally rare; if it is present, another underlying pathologic process should be actively excluded. If the ophthalmologic assessment (including an assessment of visual acuity, color vision, visual fields, and electrophysiology) and molecular genetic testing leave any uncertainty about the diagnosis of LHON, further investigations are appropriate to exclude other potentially reversible causes of bilateral optic neuropathy and to allow for the initiation of prompt treatment before visual loss becomes irreversible. Depending on the clinical presentation and evolution, the following could be considered: Autoantibody testing and an infectious or vasculitic screen A lumbar puncture to evaluate for unmatched oligoclonal bands when demyelination is suspected or to exclude infection and neoplasia Use of the appropriate neuroimaging modality, ideally reviewed with an experienced neuroradiologist • Autoantibody testing and an infectious or vasculitic screen • A lumbar puncture to evaluate for unmatched oligoclonal bands when demyelination is suspected or to exclude infection and neoplasia • Use of the appropriate neuroimaging modality, ideally reviewed with an experienced neuroradiologist ## Management An international consensus statement on the clinical and therapeutic management of Leber hereditary optic neuropathy (LHON) has been published [ To establish the extent of disease and needs in an individual diagnosed with Leber hereditary optic neuropathy (LHON), the evaluations summarized below (if not performed as part of the evaluation that led to the diagnosis) are recommended: Measurement of best corrected visual acuity Assessment of visual fields with static or kinetic perimetry Measurement of retinal nerve fiber layer thickness with optical coherence tomography imaging EKG. Although a relatively rare finding, an EKG may reveal a pre-excitation syndrome in both symptomatic and asymptomatic individuals who have a LHON-causing mtDNA variant. Even when present, such an EKG finding does not necessitate further intervention in the absence of cardiac symptoms. Screening for possible associated neurologic complications, which can further compound the visual impairment in individuals with LHON 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 LHON in order to facilitate medical and personal decision making Management of affected individuals remains mostly supportive and includes provision of visual aids, occupational rehabilitation, and registration with the relevant local social services. Idebenone (Raxone There is evidence that increased intraocular pressure could be a risk factor triggering visual loss in individuals at risk for developing LHON. Until further evidence becomes available, it is reasonable to set a lower threshold for initiating treatment for increased intraocular pressure in individuals with a LHON-causing variant given the possible deleterious consequences for mitochondrial function and retinal ganglion cell survival [ A minority of individuals with LHON develop neurologic features including ataxia, peripheral neuropathy, nonspecific myopathy, and movement disorders [ In those individuals who are found to have pre-excitation syndrome on EKG, referral to a cardiologist should be considered. Treatment for symptomatic individuals with pre-excitation syndrome is the same as for the general population. Ongoing surveillance of asymptomatic individuals with a LHON-causing mtDNA variant is not necessary; however, they should be advised to seek immediate medical attention if they experience any visual disturbance. The frequency of follow up for affected individuals varies depending on the individual's personal circumstances and the availability of health care locally. Individuals with established LHON-causing mtDNA variants should be strongly advised not to smoke and to moderate their alcohol intake, avoiding binge-drinking episodes [ Although based largely on anecdotal evidence, avoidance of other environmental factors that have been implicated in precipitating visual loss in LHON (e.g., head trauma, industrial toxins, drugs with mitochondrial toxic effects) is reasonable [ See Search • Measurement of best corrected visual acuity • Assessment of visual fields with static or kinetic perimetry • Measurement of retinal nerve fiber layer thickness with optical coherence tomography imaging • EKG. Although a relatively rare finding, an EKG may reveal a pre-excitation syndrome in both symptomatic and asymptomatic individuals who have a LHON-causing mtDNA variant. Even when present, such an EKG finding does not necessitate further intervention in the absence of cardiac symptoms. • Screening for possible associated neurologic complications, which can further compound the visual impairment in individuals with LHON • 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 LHON in order to facilitate medical and personal decision making ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Leber hereditary optic neuropathy (LHON), the evaluations summarized below (if not performed as part of the evaluation that led to the diagnosis) are recommended: Measurement of best corrected visual acuity Assessment of visual fields with static or kinetic perimetry Measurement of retinal nerve fiber layer thickness with optical coherence tomography imaging EKG. Although a relatively rare finding, an EKG may reveal a pre-excitation syndrome in both symptomatic and asymptomatic individuals who have a LHON-causing mtDNA variant. Even when present, such an EKG finding does not necessitate further intervention in the absence of cardiac symptoms. Screening for possible associated neurologic complications, which can further compound the visual impairment in individuals with LHON 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 LHON in order to facilitate medical and personal decision making • Measurement of best corrected visual acuity • Assessment of visual fields with static or kinetic perimetry • Measurement of retinal nerve fiber layer thickness with optical coherence tomography imaging • EKG. Although a relatively rare finding, an EKG may reveal a pre-excitation syndrome in both symptomatic and asymptomatic individuals who have a LHON-causing mtDNA variant. Even when present, such an EKG finding does not necessitate further intervention in the absence of cardiac symptoms. • Screening for possible associated neurologic complications, which can further compound the visual impairment in individuals with LHON • 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 LHON in order to facilitate medical and personal decision making ## Treatment of Manifestations Management of affected individuals remains mostly supportive and includes provision of visual aids, occupational rehabilitation, and registration with the relevant local social services. Idebenone (Raxone There is evidence that increased intraocular pressure could be a risk factor triggering visual loss in individuals at risk for developing LHON. Until further evidence becomes available, it is reasonable to set a lower threshold for initiating treatment for increased intraocular pressure in individuals with a LHON-causing variant given the possible deleterious consequences for mitochondrial function and retinal ganglion cell survival [ A minority of individuals with LHON develop neurologic features including ataxia, peripheral neuropathy, nonspecific myopathy, and movement disorders [ In those individuals who are found to have pre-excitation syndrome on EKG, referral to a cardiologist should be considered. Treatment for symptomatic individuals with pre-excitation syndrome is the same as for the general population. ## Surveillance Ongoing surveillance of asymptomatic individuals with a LHON-causing mtDNA variant is not necessary; however, they should be advised to seek immediate medical attention if they experience any visual disturbance. The frequency of follow up for affected individuals varies depending on the individual's personal circumstances and the availability of health care locally. ## Agents/Circumstances to Avoid Individuals with established LHON-causing mtDNA variants should be strongly advised not to smoke and to moderate their alcohol intake, avoiding binge-drinking episodes [ Although based largely on anecdotal evidence, avoidance of other environmental factors that have been implicated in precipitating visual loss in LHON (e.g., head trauma, industrial toxins, drugs with mitochondrial toxic effects) is reasonable [ ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Leber hereditary optic neuropathy (LHON) is caused by pathogenic variants in mitochondrial DNA (mtDNA) and is transmitted strictly by maternal inheritance. 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 developed visual loss. In approximately 60% of families, a history of visual loss affecting maternal relatives is present. Up to 40% of individuals with LHON have no known family history of LHON. The explanation for apparently simplex cases may be absence of a comprehensive and/or reliable family history or, in rare cases, a Maternal testing is not considered necessary for recurrence risk counseling as the mtDNA LHON-causing variant is usually homoplasmic or present at high levels in the proband [ All sibs of a proband will inherit the mtDNA LHON-causing variant and may or may not have symptoms (see Penetrance can vary markedly between sibs with the same LHON-causing mtDNA pathogenic variant (see A male (affected or unaffected) with a primary LHON-causing mtDNA variant A female (affected or unaffected) with a primary LHON-causing mtDNA variant will transmit the variant to all of her offspring. The presence of the mtDNA pathogenic variant does not predict the occurrence, age of onset, severity, or rate of progression of visual loss. See If a female proband is heteroplasmic for the mtDNA LHON-causing variant, she may transmit a lower level of mutated mtDNA to her offspring, conferring a low disease risk [ Large studies have established accurate risks for the m.11778G>A and m.14484T>C pathogenic variants (reviewed in The identification of the familial LHON-related pathogenic variant confers a lifetime risk; however, such testing is not useful in predicting the age of onset or the visual outcome in family members. The most important factors determining risk are sex and age (see It must be stressed that the penetrance can vary markedly in different branches of the same family and between families with the same LHON-causing mtDNA 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. Once a mtDNA LHON-causing variant in the mother has been identified, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing [ Accurate interpretation of a positive prenatal test result is difficult for the following reasons: The majority of mothers will be homoplasmic for the mtDNA LHON-causing variant. For mothers who are heteroplasmic, the mtDNA mutational load in amniocytes and chorionic villi may not correspond to that of other fetal or adult tissues due to mitotic segregation. The presence of the mtDNA LHON-causing variant does not predict the occurrence, age of onset, severity, or rate of progression of visual loss in this mitochondrial genetic disorder. 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. For more information, see the National Society of Genetic Counselors • 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 developed visual loss. • In approximately 60% of families, a history of visual loss affecting maternal relatives is present. • Up to 40% of individuals with LHON have no known family history of LHON. The explanation for apparently simplex cases may be absence of a comprehensive and/or reliable family history or, in rare cases, a • Maternal testing is not considered necessary for recurrence risk counseling as the mtDNA LHON-causing variant is usually homoplasmic or present at high levels in the proband [ • All sibs of a proband will inherit the mtDNA LHON-causing variant and may or may not have symptoms (see • Penetrance can vary markedly between sibs with the same LHON-causing mtDNA pathogenic variant (see • A male (affected or unaffected) with a primary LHON-causing mtDNA variant • A female (affected or unaffected) with a primary LHON-causing mtDNA variant will transmit the variant to all of her offspring. • The presence of the mtDNA pathogenic variant does not predict the occurrence, age of onset, severity, or rate of progression of visual loss. See • If a female proband is heteroplasmic for the mtDNA LHON-causing variant, she may transmit a lower level of mutated mtDNA to her offspring, conferring a low disease risk [ • Large studies have established accurate risks for the m.11778G>A and m.14484T>C pathogenic variants (reviewed in • The identification of the familial LHON-related pathogenic variant confers a lifetime risk; however, such testing is not useful in predicting the age of onset or the visual outcome in family members. The most important factors determining risk are sex and age (see • It must be stressed that the penetrance can vary markedly in different branches of the same family and between families with the same LHON-causing mtDNA 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. • The majority of mothers will be homoplasmic for the mtDNA LHON-causing variant. For mothers who are heteroplasmic, the mtDNA mutational load in amniocytes and chorionic villi may not correspond to that of other fetal or adult tissues due to mitotic segregation. • The presence of the mtDNA LHON-causing variant does not predict the occurrence, age of onset, severity, or rate of progression of visual loss in this mitochondrial genetic disorder. See ## Mode of Inheritance Leber hereditary optic neuropathy (LHON) is caused by pathogenic variants in mitochondrial DNA (mtDNA) and is transmitted strictly by maternal inheritance. ## Risk to Family Members The father of a proband is not at risk of having the mtDNA pathogenic variant. The mother of a proband usually has the mtDNA pathogenic variant and may or may not have developed visual loss. In approximately 60% of families, a history of visual loss affecting maternal relatives is present. Up to 40% of individuals with LHON have no known family history of LHON. The explanation for apparently simplex cases may be absence of a comprehensive and/or reliable family history or, in rare cases, a Maternal testing is not considered necessary for recurrence risk counseling as the mtDNA LHON-causing variant is usually homoplasmic or present at high levels in the proband [ All sibs of a proband will inherit the mtDNA LHON-causing variant and may or may not have symptoms (see Penetrance can vary markedly between sibs with the same LHON-causing mtDNA pathogenic variant (see A male (affected or unaffected) with a primary LHON-causing mtDNA variant A female (affected or unaffected) with a primary LHON-causing mtDNA variant will transmit the variant to all of her offspring. The presence of the mtDNA pathogenic variant does not predict the occurrence, age of onset, severity, or rate of progression of visual loss. See If a female proband is heteroplasmic for the mtDNA LHON-causing variant, she may transmit a lower level of mutated mtDNA to her offspring, conferring a low disease risk [ • 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 developed visual loss. • In approximately 60% of families, a history of visual loss affecting maternal relatives is present. • Up to 40% of individuals with LHON have no known family history of LHON. The explanation for apparently simplex cases may be absence of a comprehensive and/or reliable family history or, in rare cases, a • Maternal testing is not considered necessary for recurrence risk counseling as the mtDNA LHON-causing variant is usually homoplasmic or present at high levels in the proband [ • All sibs of a proband will inherit the mtDNA LHON-causing variant and may or may not have symptoms (see • Penetrance can vary markedly between sibs with the same LHON-causing mtDNA pathogenic variant (see • A male (affected or unaffected) with a primary LHON-causing mtDNA variant • A female (affected or unaffected) with a primary LHON-causing mtDNA variant will transmit the variant to all of her offspring. • The presence of the mtDNA pathogenic variant does not predict the occurrence, age of onset, severity, or rate of progression of visual loss. See • If a female proband is heteroplasmic for the mtDNA LHON-causing variant, she may transmit a lower level of mutated mtDNA to her offspring, conferring a low disease risk [ ## Related Genetic Counseling Issues Large studies have established accurate risks for the m.11778G>A and m.14484T>C pathogenic variants (reviewed in The identification of the familial LHON-related pathogenic variant confers a lifetime risk; however, such testing is not useful in predicting the age of onset or the visual outcome in family members. The most important factors determining risk are sex and age (see It must be stressed that the penetrance can vary markedly in different branches of the same family and between families with the same LHON-causing mtDNA 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. • Large studies have established accurate risks for the m.11778G>A and m.14484T>C pathogenic variants (reviewed in • The identification of the familial LHON-related pathogenic variant confers a lifetime risk; however, such testing is not useful in predicting the age of onset or the visual outcome in family members. The most important factors determining risk are sex and age (see • It must be stressed that the penetrance can vary markedly in different branches of the same family and between families with the same LHON-causing mtDNA 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. ## Prenatal Testing and Preimplantation Genetic Testing Once a mtDNA LHON-causing variant in the mother has been identified, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing [ Accurate interpretation of a positive prenatal test result is difficult for the following reasons: The majority of mothers will be homoplasmic for the mtDNA LHON-causing variant. For mothers who are heteroplasmic, the mtDNA mutational load in amniocytes and chorionic villi may not correspond to that of other fetal or adult tissues due to mitotic segregation. The presence of the mtDNA LHON-causing variant does not predict the occurrence, age of onset, severity, or rate of progression of visual loss in this mitochondrial genetic disorder. 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. For more information, see the National Society of Genetic Counselors • The majority of mothers will be homoplasmic for the mtDNA LHON-causing variant. For mothers who are heteroplasmic, the mtDNA mutational load in amniocytes and chorionic villi may not correspond to that of other fetal or adult tissues due to mitotic segregation. • The presence of the mtDNA LHON-causing variant does not predict the occurrence, age of onset, severity, or rate of progression of visual loss in this mitochondrial genetic disorder. See ## Resources United Kingdom NY • • • • United Kingdom • • • • • NY • • • ## Molecular Genetics Leber Hereditary Optic Neuropathy: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Leber Hereditary Optic Neuropathy ( See The ocular pathology in Leber hereditary optic neuropathy (LHON) is limited to the retinal ganglion cell layer with sparing of the retinal pigment epithelium and photoreceptor layers. There is marked cell body and axonal degeneration, with associated demyelination, extending to the lateral geniculate bodies. A number of pathologic factors have been implicated, including a reduction in the amount of ATP being produced by the mitochondrial respiratory chain ( Although LHON has a well-defined clinical and molecular genetic phenotype, the pathophysiology is complex and the selective vulnerability of retinal ganglion cells in this mitochondrial disorder remains unexplained [ Mitochondrial DNA Variants Identified in Individuals with LHON From Core genes Mitochondrial DNA variants that affect function. They have been identified in at least two independent LHON pedigrees and segregate with affected disease status. ## Molecular Pathogenesis See The ocular pathology in Leber hereditary optic neuropathy (LHON) is limited to the retinal ganglion cell layer with sparing of the retinal pigment epithelium and photoreceptor layers. There is marked cell body and axonal degeneration, with associated demyelination, extending to the lateral geniculate bodies. A number of pathologic factors have been implicated, including a reduction in the amount of ATP being produced by the mitochondrial respiratory chain ( Although LHON has a well-defined clinical and molecular genetic phenotype, the pathophysiology is complex and the selective vulnerability of retinal ganglion cells in this mitochondrial disorder remains unexplained [ Mitochondrial DNA Variants Identified in Individuals with LHON From Core genes Mitochondrial DNA variants that affect function. They have been identified in at least two independent LHON pedigrees and segregate with affected disease status. ## Chapter Notes 11 March 2021 (bp) Comprehensive update posted live 23 June 2016 (ma) Comprehensive update posted live 19 September 2013 (me) Comprehensive update posted live 19 April 2012 (cd/pc) Revision: prenatal testing no longer listed in GeneTests Laboratory Directory; addition to 7 July 2011 (me) Comprehensive update posted live 10 March 2008 (me) Comprehensive update posted live 3 October 2005 (pc) Revision: mitochondrial gene 12 April 2005 (me) Comprehensive update posted live 7 March 2003 (me) Comprehensive update posted live 14 January 2002 (pc) Author revisions 27 August 2001 (pc) Author revisions 26 October 2000 (me) Review posted live May 2000 (pc) Original submission • 11 March 2021 (bp) Comprehensive update posted live • 23 June 2016 (ma) Comprehensive update posted live • 19 September 2013 (me) Comprehensive update posted live • 19 April 2012 (cd/pc) Revision: prenatal testing no longer listed in GeneTests Laboratory Directory; addition to • 7 July 2011 (me) Comprehensive update posted live • 10 March 2008 (me) Comprehensive update posted live • 3 October 2005 (pc) Revision: mitochondrial gene • 12 April 2005 (me) Comprehensive update posted live • 7 March 2003 (me) Comprehensive update posted live • 14 January 2002 (pc) Author revisions • 27 August 2001 (pc) Author revisions • 26 October 2000 (me) Review posted live • May 2000 (pc) Original submission ## Revision History 11 March 2021 (bp) Comprehensive update posted live 23 June 2016 (ma) Comprehensive update posted live 19 September 2013 (me) Comprehensive update posted live 19 April 2012 (cd/pc) Revision: prenatal testing no longer listed in GeneTests Laboratory Directory; addition to 7 July 2011 (me) Comprehensive update posted live 10 March 2008 (me) Comprehensive update posted live 3 October 2005 (pc) Revision: mitochondrial gene 12 April 2005 (me) Comprehensive update posted live 7 March 2003 (me) Comprehensive update posted live 14 January 2002 (pc) Author revisions 27 August 2001 (pc) Author revisions 26 October 2000 (me) Review posted live May 2000 (pc) Original submission • 11 March 2021 (bp) Comprehensive update posted live • 23 June 2016 (ma) Comprehensive update posted live • 19 September 2013 (me) Comprehensive update posted live • 19 April 2012 (cd/pc) Revision: prenatal testing no longer listed in GeneTests Laboratory Directory; addition to • 7 July 2011 (me) Comprehensive update posted live • 10 March 2008 (me) Comprehensive update posted live • 3 October 2005 (pc) Revision: mitochondrial gene • 12 April 2005 (me) Comprehensive update posted live • 7 March 2003 (me) Comprehensive update posted live • 14 January 2002 (pc) Author revisions • 27 August 2001 (pc) Author revisions • 26 October 2000 (me) Review posted live • May 2000 (pc) Original submission ## References ## Published Guidelines / Consensus Statements ## Literature Cited	[]	26/10/2000	11/3/2021	19/4/2012	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
li-ar	li-ar	[ "Arachidonate 12-lipoxygenase, 12R-type", "Caspase-14", "Ceramide synthase 3", "Glucosylceramide transporter ABCA12", "Hydroperoxide isomerase ALOXE3", "Lipase member N", "Long-chain fatty acid transport protein 4", "Magnesium transporter NIPA4", "Omega-hydroxyceramide transacylase", "Protein-glutamine gamma-glutamyltransferase K", "Short-chain dehydrogenase/reductase family 9C member 7", "Sulfotransferase 2B1", "Ultra-long-chain fatty acid omega-hydroxylase", "ABCA12", "ALOX12B", "ALOXE3", "CASP14", "CERS3", "CYP4F22", "LIPN", "NIPAL4", "PNPLA1", "SDR9C7", "SLC27A4", "SULT2B1", "TGM1", "Autosomal Recessive Congenital Ichthyosis", "Overview" ]	Autosomal Recessive Congenital Ichthyosis	Gabriele Richard	Summary The purpose of this overview is to: Briefly describe the Review the Review the Provide an Review Inform	## Clinical Characteristics of Autosomal Recessive Congenital Ichthyosis Autosomal recessive congenital ichthyoses (ARCI) are lifelong skin disorders with generalized scaling and variable erythema that typically manifest at birth or early infancy. ARCI encompass several forms of nonsyndromic ichthyosis, which vary significantly in clinical presentation and severity, including the most severe and sometimes fatal form, harlequin ichthyosis; lamellar ichthyosis (LI); (nonbullous) congenital ichthyosiform erythroderma (CIE); and intermediate phenotypes with variable degrees of erythema and size and quality of scale. While these phenotypes fall on a continuum, the phenotypic descriptions are clinically useful for clarifying prognosis and management for affected individuals. Children with ARCI are often born prematurely encased in a In the rarest form of ARCI, Babies with In about 10% of babies with a collodion membrane, a milder "self-healing" phenotype known as "self-improving collodion ichthyosis" occurs [ Histologic findings in ARCI are mostly nonspecific, showing epidermal hyperplasia and ortho-hyperkeratosis (thickened stratum corneum, the uppermost layer of the epidermis) with an underlying acanthosis. Harlequin ichthyosis is characterized by extreme hyperkeratosis and follicular plugging. Electron microscopy shows absence of lamellar bodies and lipid bilayers. • Histologic findings in ARCI are mostly nonspecific, showing epidermal hyperplasia and ortho-hyperkeratosis (thickened stratum corneum, the uppermost layer of the epidermis) with an underlying acanthosis. • Harlequin ichthyosis is characterized by extreme hyperkeratosis and follicular plugging. Electron microscopy shows absence of lamellar bodies and lipid bilayers. ## Presentation at Birth Children with ARCI are often born prematurely encased in a In the rarest form of ARCI, Babies with ## Postnatal Features In about 10% of babies with a collodion membrane, a milder "self-healing" phenotype known as "self-improving collodion ichthyosis" occurs [ Histologic findings in ARCI are mostly nonspecific, showing epidermal hyperplasia and ortho-hyperkeratosis (thickened stratum corneum, the uppermost layer of the epidermis) with an underlying acanthosis. Harlequin ichthyosis is characterized by extreme hyperkeratosis and follicular plugging. Electron microscopy shows absence of lamellar bodies and lipid bilayers. • Histologic findings in ARCI are mostly nonspecific, showing epidermal hyperplasia and ortho-hyperkeratosis (thickened stratum corneum, the uppermost layer of the epidermis) with an underlying acanthosis. • Harlequin ichthyosis is characterized by extreme hyperkeratosis and follicular plugging. Electron microscopy shows absence of lamellar bodies and lipid bilayers. ## Genetic Causes of Autosomal Recessive Congenital Ichthyosis Autosomal Recessive Congenital Ichthyosis: Genes and Distinguishing Clinical Features Accounts for >93% of HI; biallelic complete loss-of-function variants were assoc w/most severe HI. CIE or LI presented in those w/variants w/partial function; often assoc w/severe erythroderma & PPK. Albeit extremely rare, a mosaic form of CIE due to postzygotic somatic mosaicism has been observed. ~4% of distinct variants are large deletions/duplications. Missense variants in the region coding for the 1st nuclear binding fold were assoc w/LI & predicted to interfere w/specific functions of this protein domain. >75% of affected persons w/ Persons w/self-improving collodion ichthyosis ~2% of distinct variants are large deletions/duplications. The variant p.Tyr521Cys accounts for 22% of disease alleles. >33% of affected persons w/ Intermediate phenotypes Persons w/self-improving collodion ichthyosis More common in Austria ~10% of distinct variants are large deletions/duplications. The variant p.Pro630Leu accounts for 40% of disease alleles & p.Arg234Ter accounts for 21%. 1 homozygous frameshift variant was observed in 2 Algerian families. To date, no large deletions/duplications have been reported. Collodion membrane at birth, erythema & fine scales on face & trunk, larger, gray-brown scales on lower limbs, & hyperlinear palms/soles A distinct feature is keratotic lichenification w/prematurely aged appearance of skin. More common in Iran (5.6% of variants) 1 multigene deletion reported incl See also footnote 4. Typically, erythroderma at birth but w/o collodion membrane & later in life present w/LI w/larger, white-gray scales & hyperlinear palms/soles Persons w/self-improving collodion ichthyosis ~3% of distinct variants are large deletions/duplications. Less common in northern Europeans 5% of variants in Middle Eastern populations To date, no large deletions/duplications have been reported. <30% of persons w/ Congenital ichthyosis w/coarse, gray-white scales, mild-to-moderate erythroderma, & sparing of face Yellowish PPK & hypohidrosis Specific electron microscopic (EM) abnormalities (classified as ARCI EM type 3) w/abnormal lamellar bodies & elongated perinuclear membranes in granular layer More common in Scandinavia (12.5%) Higher prevalence in Sweden, Denmark, & Norway, where The variant p.Asn176Asp is a mutation hot spot, observed in 87% of disease alleles & 70% of persons tested. To date, no large deletions/duplications have been reported. Typically, collodion membrane at birth & then transition to CIE phenotype w/scalp involvement & hyperlinear palms/soles Mild disease w/generalized fine exfoliation & hyperkeratotic plaques over knees resembling progressive symmetric erythrokeratoderma Ectropion, eclabium, & alopecia are lacking. More common in Iran (15% of variants) Higher prevalence in northern Africa, Spain, & Iran, likely due to founder variants To date, no large deletions/duplications have been reported. More common in Austria (6% of variants) To date, no large deletions/duplications have been reported. IPS: polyhydramnios & premature birth Severe perinatal presentation w/respiratory asphyxia & thick, vernix caseosa-like scale or cobblestone-like hyperkeratosis on scalp, forehead, & trunk Skin findings resolve over several weeks, transitioning to mild generalized follicular hyperkeratosis Mainly in persons from Scandinavia & northern Europe The variant c.504C>A (p.Cys168Ter) is a founder variant in persons of Scandinavian ancestry. A deletion of exon 3 has been reported. ~70%-90% of persons w/LI phenotype have Persons w/"bathing suit ichthyosis" Persons w/self-improving collodion ichthyosis More common in Scandinavia & Galicia The variant c.877-2A>G is a Norwegian/German founder variant & is common in Norway, Finland, & North America. The variants c.2278C>T (p.Arg760Ter) & c.1223_1227delACACA are founder variants in Galician population of Spain. <1% of variants are large deletions/duplications. ARCI = autosomal recessive congenital ichthyosis; CIE = congenital ichthyosiform erythroderma; HI = harlequin ichthyosis; IPS = ichthyosis-prematurity syndrome; LI = lamellar ichthyosis; PPK = palmoplantar keratoderma Genes are listed alphabetically. Does not represent the overall percentage of deletions/duplications among probands/families; data derived from the subscription-based professional view of Human Gene Mutation Database [ Large contiguous deletions reported including Based on several studies using multigene testing, 7%-17% of individuals with congenital ichthyosis do not have pathogenic variants in any of the known genes [ • Accounts for >93% of HI; biallelic complete loss-of-function variants were assoc w/most severe HI. • CIE or LI presented in those w/variants w/partial function; often assoc w/severe erythroderma & PPK. • Albeit extremely rare, a mosaic form of CIE due to postzygotic somatic mosaicism has been observed. • ~4% of distinct variants are large deletions/duplications. • Missense variants in the region coding for the 1st nuclear binding fold were assoc w/LI & predicted to interfere w/specific functions of this protein domain. • >75% of affected persons w/ • Persons w/self-improving collodion ichthyosis • ~2% of distinct variants are large deletions/duplications. • The variant p.Tyr521Cys accounts for 22% of disease alleles. • >33% of affected persons w/ • Intermediate phenotypes • Persons w/self-improving collodion ichthyosis • More common in Austria • ~10% of distinct variants are large deletions/duplications. • The variant p.Pro630Leu accounts for 40% of disease alleles & p.Arg234Ter accounts for 21%. • 1 homozygous frameshift variant was observed in 2 Algerian families. • To date, no large deletions/duplications have been reported. • Collodion membrane at birth, erythema & fine scales on face & trunk, larger, gray-brown scales on lower limbs, & hyperlinear palms/soles • A distinct feature is keratotic lichenification w/prematurely aged appearance of skin. • More common in Iran (5.6% of variants) • 1 multigene deletion reported incl • See also footnote 4. • Typically, erythroderma at birth but w/o collodion membrane & later in life present w/LI w/larger, white-gray scales & hyperlinear palms/soles • Persons w/self-improving collodion ichthyosis • ~3% of distinct variants are large deletions/duplications. • Less common in northern Europeans • 5% of variants in Middle Eastern populations • To date, no large deletions/duplications have been reported. • <30% of persons w/ • Congenital ichthyosis w/coarse, gray-white scales, mild-to-moderate erythroderma, & sparing of face • Yellowish PPK & hypohidrosis • Specific electron microscopic (EM) abnormalities (classified as ARCI EM type 3) w/abnormal lamellar bodies & elongated perinuclear membranes in granular layer • More common in Scandinavia (12.5%) • Higher prevalence in Sweden, Denmark, & Norway, where • The variant p.Asn176Asp is a mutation hot spot, observed in 87% of disease alleles & 70% of persons tested. • To date, no large deletions/duplications have been reported. • Typically, collodion membrane at birth & then transition to CIE phenotype w/scalp involvement & hyperlinear palms/soles • Mild disease w/generalized fine exfoliation & hyperkeratotic plaques over knees resembling progressive symmetric erythrokeratoderma • Ectropion, eclabium, & alopecia are lacking. • More common in Iran (15% of variants) • Higher prevalence in northern Africa, Spain, & Iran, likely due to founder variants • To date, no large deletions/duplications have been reported. • More common in Austria (6% of variants) • To date, no large deletions/duplications have been reported. • IPS: polyhydramnios & premature birth • Severe perinatal presentation w/respiratory asphyxia & thick, vernix caseosa-like scale or cobblestone-like hyperkeratosis on scalp, forehead, & trunk • Skin findings resolve over several weeks, transitioning to mild generalized follicular hyperkeratosis • Mainly in persons from Scandinavia & northern Europe • The variant c.504C>A (p.Cys168Ter) is a founder variant in persons of Scandinavian ancestry. • A deletion of exon 3 has been reported. • ~70%-90% of persons w/LI phenotype have • Persons w/"bathing suit ichthyosis" • Persons w/self-improving collodion ichthyosis • More common in Scandinavia & Galicia • The variant c.877-2A>G is a Norwegian/German founder variant & is common in Norway, Finland, & North America. • The variants c.2278C>T (p.Arg760Ter) & c.1223_1227delACACA are founder variants in Galician population of Spain. • <1% of variants are large deletions/duplications. ## Differential Diagnosis of Autosomal Recessive Congenital Ichthyosis Differential Diagnosis of Autosomal Recessive Congenital Ichthyosis: Genetic Disorders with Ichthyosis Present at Birth IUGR & prematurity ≥1 of the following: brittle sulfur-deficient hair, nail dystrophy, photosensitivity ( Widespread lipid deposits result in hepatomegaly & fibrosis, cataracts, & sensorineural hearing loss. DD is common. Variable findings incl microcephaly, ataxia, short stature, splenomegaly, & renal insufficiency. Lipid vacuoles in circulating granulocytes & monocytes on fresh peripheral blood smear In females, punctuate calcification in epiphyseal cartilage, asymmetric rhizomelic limb shortening, short stature, cataracts, & sensorineural hearing loss Early gestational male lethality Neonates may be diagnosed because of peeling skin (like that of "postmature" babies) & periorbital hyperpigmentation. Later, persons develop dry skin & chronic eczema. ↓ ability to sweat; sparse scalp & body hair, & congenital absence of teeth Cardinal features of classic HED become obvious during childhood. Skin fragility, blistering, & erythema at birth & during infancy; transitions to pronounced ridged or cobblestone-like hyperkeratosis Severe PPK is common in No collodion membrane at birth Life-threatening complications in neonates are sepsis & fluid & electrolyte imbalances. Later complications incl recurrent blistering & skin infections, heat intolerance, body odor, & gait abnormalities. CIE often w/continuous skin peeling Atopic manifestations Hair shaft anomalies & poor weight gain Life-threatening complications during infancy incl temperature & electrolyte imbalance, recurrent infections, & sepsis. Congenital ichthyosis w/white, fine scale & scalp involvement & possibly sparing of flexures Follicular atrophoderma w/pitted ("orange peel") appearance of skin in face & dorsal hands Generalized, diffuse, non-scarring hypotrichosis that improves w/age Scalp hair is light colored, sparse, lusterless, & curly. Hypohidrosis; eye involvement incl photophobia &/or inflammation of eyelids AD = autosomal dominant; AR = autosomal recessive; CIE = congenital ichthyosiform erythroderma; DD = developmental delay; ID = intellectual disability; IUGR = intrauterine growth restriction; MOI = mode of inheritance; PPK = palmoplantar keratoderma; XL = X-linked Trichothiodystrophy is inherited in an autosomal recessive manner with the exception of • IUGR & prematurity • ≥1 of the following: brittle sulfur-deficient hair, nail dystrophy, photosensitivity ( • Widespread lipid deposits result in hepatomegaly & fibrosis, cataracts, & sensorineural hearing loss. • DD is common. • Variable findings incl microcephaly, ataxia, short stature, splenomegaly, & renal insufficiency. • Lipid vacuoles in circulating granulocytes & monocytes on fresh peripheral blood smear • In females, punctuate calcification in epiphyseal cartilage, asymmetric rhizomelic limb shortening, short stature, cataracts, & sensorineural hearing loss • Early gestational male lethality • Neonates may be diagnosed because of peeling skin (like that of "postmature" babies) & periorbital hyperpigmentation. • Later, persons develop dry skin & chronic eczema. • ↓ ability to sweat; sparse scalp & body hair, & congenital absence of teeth • Cardinal features of classic HED become obvious during childhood. • Skin fragility, blistering, & erythema at birth & during infancy; transitions to pronounced ridged or cobblestone-like hyperkeratosis • Severe PPK is common in • No collodion membrane at birth • Life-threatening complications in neonates are sepsis & fluid & electrolyte imbalances. • Later complications incl recurrent blistering & skin infections, heat intolerance, body odor, & gait abnormalities. • CIE often w/continuous skin peeling • Atopic manifestations • Hair shaft anomalies & poor weight gain • Life-threatening complications during infancy incl temperature & electrolyte imbalance, recurrent infections, & sepsis. • Congenital ichthyosis w/white, fine scale & scalp involvement & possibly sparing of flexures • Follicular atrophoderma w/pitted ("orange peel") appearance of skin in face & dorsal hands • Generalized, diffuse, non-scarring hypotrichosis that improves w/age • Scalp hair is light colored, sparse, lusterless, & curly. • Hypohidrosis; eye involvement incl photophobia &/or inflammation of eyelids ## Evaluation Strategies to Identify the Genetic Cause of Autosomal Recessive Congenital Ichthyosis in a Proband Establishing a specific genetic cause of autosomal recessive congenital ichthyosis (ARCI): Can aid in discussions of prognosis (which are beyond the scope of this Usually involves a medical history, physical examination, family history, and molecular genetic testing. For an introduction to multigene panels click In individuals with harlequin ichthyosis, analysis of In individuals with ARCI and without harlequin presentation at birth, analysis of In individuals with ichthyosis-prematurity syndrome, molecular genetic testing should start with For an introduction to comprehensive genomic testing click • Can aid in discussions of prognosis (which are beyond the scope of this • Usually involves a medical history, physical examination, family history, and molecular genetic testing. • For an introduction to multigene panels click • In individuals with harlequin ichthyosis, analysis of • In individuals with ARCI and without harlequin presentation at birth, analysis of • In individuals with ichthyosis-prematurity syndrome, molecular genetic testing should start with • In individuals with harlequin ichthyosis, analysis of • In individuals with ARCI and without harlequin presentation at birth, analysis of • In individuals with ichthyosis-prematurity syndrome, molecular genetic testing should start with • For an introduction to comprehensive genomic testing click • In individuals with harlequin ichthyosis, analysis of • In individuals with ARCI and without harlequin presentation at birth, analysis of • In individuals with ichthyosis-prematurity syndrome, molecular genetic testing should start with ## Management Guidelines for the management of congenital ichthyosis have been published [ To establish the extent of disease and needs in an individual diagnosed with autosomal recessive congenital ichthyosis (ARCI), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Autosomal Recessive Congenital Ichthyosis Assessment of transepidermal water loss & hydration status Assessment of feeding & nutrition status Community or Social work involvement for parental support; Home nursing referral. ARCI = autosomal recessive congenital ichthyosis; HI = harlequin ichthyosis; IPS = ichthyosis-prematurity syndrome; MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse Treatment of ARCI is mainly symptomatic, as no curative therapies exist. Treatment of Manifestations in Individuals with Autosomal Recessive Congenital Ichthyosis Provide moist environment in highly humidified incubator (50%-70% humidity). Prevent infection using hygienic standard precautions. Perform regular bacteriologic samplings to monitor for skin & systemic infections. Monitor & maintain body temperature to avoid hypothermia or overheating. Monitor & maintain weight & water & electrolyte balance to avoid hypernatremia or dehydration. Manage pain as needed. Admission to NICU Interdisciplinary approach w/involvement of parents in care Avoidance of invasive procedures (due to ↑ risk of infections) In young children, topical salicylic acid preparations should be avoided because of absorption through skin leading to toxicity. Topical use of tacrolimus or vitamin D should be considered w/caution due to skin absorption. Skin irritation may limit use of keratolytics. For long-term use of systemic retinoids, important safety & health concerns must be considered. Treatment requires careful risk vs benefit assessment & monitoring, & should be performed by dermatologist familiar w/congenital ichthyosis. Oral retinoid therapy should be used w/caution in women of child-bearing age because of teratogenicity (see Additional side effects of retinoids incl hypertriglyceridemia, hepatotoxicity, bone toxicity & ligamentous calcifications, dry eyes, night blindness, & retinal dysfunction from long-term use. For a detailed review of choice of retinoid, dosage, treatment duration, toxicity, monitoring, & disease-specific considerations for ARCI, see Moderate to severe ARCI often necessitates systemic (oral) retinoid therapy. Oral retinoids (isotretinoin, etretinate) can effectively ↓ hyperkeratosis & scaling but are less beneficial in suppressing erythroderma. Monitor weight daily as indicator for sufficient fluid & nutrient intake. High-calorie diet; nutritional support via oro- or nasogastric tube may be necessary due to high caloric demand, &/or complications from eclabium. Prevent dehydration. Antiseptics, antifungal topicals in macerated skin areas Prompt treatment of skin or systemic bacterial infection according to antibiotic sensitivity profile Patient advocacy groups to provide family support & other resources Disability resources & information Financial aid programs Children's camps (Camp Discovery, Camp Wonder) HI = harlequin ichthyosis; NICU = neonatal intensive care unit 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 Autosomal Recessive Congenital Ichthyosis Every 4-6 mos after starting systemic retinoid therapy Every 6-12 mos in persons on long-term systemic retinoid therapy Invasive procedures in infants with complications related to prematurity should be avoided because of increased risk of infections related to such procedures. Skin irritants and overheating should be avoided. Topical salicylic acid preparations in children should be avoided because of absorption through the skin leading to toxicity. Topical use of tacrolimus or vitamin D should be considered with caution due to skin absorption. See Affected mothers are at no specific disease-related risks during pregnancy, but overheating should be avoided during pregnancy. Systemic retinoids are known to be teratogenic to a developing fetus and pose a high risk for birth defects. Therefore, women who are using systemic retinoids should be appropriately counseled about pregnancy risks and the need for highly effective contraception; regular monitoring with pregnancy tests is indicated. Systemic retinoids should be administered only by physicians who are knowledgeable regarding their risks and benefits. To access isotretinoin in the US, women and their prescribing providers must be enrolled in the See Advances in understanding the genetics and pathophysiology of ichthyosis paired with new biotechnology approaches have led to the exploration and development of pathogenesis-based therapies for ichthyoses. Among those are enzyme replacement therapy (ERT) and lipid replacement therapy (LRT); repurposing of biologic therapeutics; and gene replacement and gene editing therapies. It can be expected that some of these new therapies will prove their efficacy and will be incorporated in the treatment of ichthyosis. Nevertheless, there are only a few ongoing, registered clinical trials for treatment of ARCI. Results have not been published, and no conclusions regarding the long-term safety and efficacy can be made at this time. For a detailed review, see Phase I open-label and long-term extension study using subcutaneous injection of human monoclonal antibody targeting IL-12/IL-23 (ustekinumab) ( Phase II multicenter, randomized, double-blind, placebo-controlled dosage study using subcutaneous injection of humanized monoclonal antibody ANB019 targeting IL-36 receptor (imsidolimab) ( Phase IV experimental non-randomized clinical study comparing the effect of subcutaneous injections with either secukinumab, ustekinumab, or dupilumab with symptomatic treatment in children with congenital ichthyosis ( These trials are based on the pivotal finding that congenital ichthyoses demonstrate an interleukin 17-dominant immune profile with marked elevations in Th17/IL-23 pathway cytokines and chemokines reminiscent of the inflammatory pattern of psoriasis [ In a subsequent double-blind placebo-controlled Phase II trial with secukinumab ( Search • Assessment of transepidermal water loss & hydration status • Assessment of feeding & nutrition status • Community or • Social work involvement for parental support; • Home nursing referral. • Provide moist environment in highly humidified incubator (50%-70% humidity). • Prevent infection using hygienic standard precautions. • Perform regular bacteriologic samplings to monitor for skin & systemic infections. • Monitor & maintain body temperature to avoid hypothermia or overheating. • Monitor & maintain weight & water & electrolyte balance to avoid hypernatremia or dehydration. • Manage pain as needed. • Admission to NICU • Interdisciplinary approach w/involvement of parents in care • Avoidance of invasive procedures (due to ↑ risk of infections) • In young children, topical salicylic acid preparations should be avoided because of absorption through skin leading to toxicity. • Topical use of tacrolimus or vitamin D should be considered w/caution due to skin absorption. • Skin irritation may limit use of keratolytics. • For long-term use of systemic retinoids, important safety & health concerns must be considered. • Treatment requires careful risk vs benefit assessment & monitoring, & should be performed by dermatologist familiar w/congenital ichthyosis. • Oral retinoid therapy should be used w/caution in women of child-bearing age because of teratogenicity (see • Additional side effects of retinoids incl hypertriglyceridemia, hepatotoxicity, bone toxicity & ligamentous calcifications, dry eyes, night blindness, & retinal dysfunction from long-term use. • For a detailed review of choice of retinoid, dosage, treatment duration, toxicity, monitoring, & disease-specific considerations for ARCI, see • Moderate to severe ARCI often necessitates systemic (oral) retinoid therapy. • Oral retinoids (isotretinoin, etretinate) can effectively ↓ hyperkeratosis & scaling but are less beneficial in suppressing erythroderma. • Monitor weight daily as indicator for sufficient fluid & nutrient intake. • High-calorie diet; nutritional support via oro- or nasogastric tube may be necessary due to high caloric demand, &/or complications from eclabium. • Prevent dehydration. • Antiseptics, antifungal topicals in macerated skin areas • Prompt treatment of skin or systemic bacterial infection according to antibiotic sensitivity profile • Patient advocacy groups to provide family support & other resources • Disability resources & information • Financial aid programs • Children's camps (Camp Discovery, Camp Wonder) • Every 4-6 mos after starting systemic retinoid therapy • Every 6-12 mos in persons on long-term systemic retinoid therapy • Phase I open-label and long-term extension study using subcutaneous injection of human monoclonal antibody targeting IL-12/IL-23 (ustekinumab) ( • Phase II multicenter, randomized, double-blind, placebo-controlled dosage study using subcutaneous injection of humanized monoclonal antibody ANB019 targeting IL-36 receptor (imsidolimab) ( • Phase IV experimental non-randomized clinical study comparing the effect of subcutaneous injections with either secukinumab, ustekinumab, or dupilumab with symptomatic treatment in children with congenital ichthyosis ( ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with autosomal recessive congenital ichthyosis (ARCI), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Autosomal Recessive Congenital Ichthyosis Assessment of transepidermal water loss & hydration status Assessment of feeding & nutrition status Community or Social work involvement for parental support; Home nursing referral. ARCI = autosomal recessive congenital ichthyosis; HI = harlequin ichthyosis; IPS = ichthyosis-prematurity syndrome; MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Assessment of transepidermal water loss & hydration status • Assessment of feeding & nutrition status • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Treatment of ARCI is mainly symptomatic, as no curative therapies exist. Treatment of Manifestations in Individuals with Autosomal Recessive Congenital Ichthyosis Provide moist environment in highly humidified incubator (50%-70% humidity). Prevent infection using hygienic standard precautions. Perform regular bacteriologic samplings to monitor for skin & systemic infections. Monitor & maintain body temperature to avoid hypothermia or overheating. Monitor & maintain weight & water & electrolyte balance to avoid hypernatremia or dehydration. Manage pain as needed. Admission to NICU Interdisciplinary approach w/involvement of parents in care Avoidance of invasive procedures (due to ↑ risk of infections) In young children, topical salicylic acid preparations should be avoided because of absorption through skin leading to toxicity. Topical use of tacrolimus or vitamin D should be considered w/caution due to skin absorption. Skin irritation may limit use of keratolytics. For long-term use of systemic retinoids, important safety & health concerns must be considered. Treatment requires careful risk vs benefit assessment & monitoring, & should be performed by dermatologist familiar w/congenital ichthyosis. Oral retinoid therapy should be used w/caution in women of child-bearing age because of teratogenicity (see Additional side effects of retinoids incl hypertriglyceridemia, hepatotoxicity, bone toxicity & ligamentous calcifications, dry eyes, night blindness, & retinal dysfunction from long-term use. For a detailed review of choice of retinoid, dosage, treatment duration, toxicity, monitoring, & disease-specific considerations for ARCI, see Moderate to severe ARCI often necessitates systemic (oral) retinoid therapy. Oral retinoids (isotretinoin, etretinate) can effectively ↓ hyperkeratosis & scaling but are less beneficial in suppressing erythroderma. Monitor weight daily as indicator for sufficient fluid & nutrient intake. High-calorie diet; nutritional support via oro- or nasogastric tube may be necessary due to high caloric demand, &/or complications from eclabium. Prevent dehydration. Antiseptics, antifungal topicals in macerated skin areas Prompt treatment of skin or systemic bacterial infection according to antibiotic sensitivity profile Patient advocacy groups to provide family support & other resources Disability resources & information Financial aid programs Children's camps (Camp Discovery, Camp Wonder) HI = harlequin ichthyosis; NICU = neonatal intensive care unit • Provide moist environment in highly humidified incubator (50%-70% humidity). • Prevent infection using hygienic standard precautions. • Perform regular bacteriologic samplings to monitor for skin & systemic infections. • Monitor & maintain body temperature to avoid hypothermia or overheating. • Monitor & maintain weight & water & electrolyte balance to avoid hypernatremia or dehydration. • Manage pain as needed. • Admission to NICU • Interdisciplinary approach w/involvement of parents in care • Avoidance of invasive procedures (due to ↑ risk of infections) • In young children, topical salicylic acid preparations should be avoided because of absorption through skin leading to toxicity. • Topical use of tacrolimus or vitamin D should be considered w/caution due to skin absorption. • Skin irritation may limit use of keratolytics. • For long-term use of systemic retinoids, important safety & health concerns must be considered. • Treatment requires careful risk vs benefit assessment & monitoring, & should be performed by dermatologist familiar w/congenital ichthyosis. • Oral retinoid therapy should be used w/caution in women of child-bearing age because of teratogenicity (see • Additional side effects of retinoids incl hypertriglyceridemia, hepatotoxicity, bone toxicity & ligamentous calcifications, dry eyes, night blindness, & retinal dysfunction from long-term use. • For a detailed review of choice of retinoid, dosage, treatment duration, toxicity, monitoring, & disease-specific considerations for ARCI, see • Moderate to severe ARCI often necessitates systemic (oral) retinoid therapy. • Oral retinoids (isotretinoin, etretinate) can effectively ↓ hyperkeratosis & scaling but are less beneficial in suppressing erythroderma. • Monitor weight daily as indicator for sufficient fluid & nutrient intake. • High-calorie diet; nutritional support via oro- or nasogastric tube may be necessary due to high caloric demand, &/or complications from eclabium. • Prevent dehydration. • Antiseptics, antifungal topicals in macerated skin areas • Prompt treatment of skin or systemic bacterial infection according to antibiotic sensitivity profile • Patient advocacy groups to provide family support & other resources • Disability resources & information • Financial aid programs • Children's camps (Camp Discovery, Camp Wonder) ## 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 Autosomal Recessive Congenital Ichthyosis Every 4-6 mos after starting systemic retinoid therapy Every 6-12 mos in persons on long-term systemic retinoid therapy • Every 4-6 mos after starting systemic retinoid therapy • Every 6-12 mos in persons on long-term systemic retinoid therapy ## Agents/Circumstances to Avoid Invasive procedures in infants with complications related to prematurity should be avoided because of increased risk of infections related to such procedures. Skin irritants and overheating should be avoided. Topical salicylic acid preparations in children should be avoided because of absorption through the skin leading to toxicity. Topical use of tacrolimus or vitamin D should be considered with caution due to skin absorption. ## Evaluation of Relatives at Risk See ## Pregnancy Management Affected mothers are at no specific disease-related risks during pregnancy, but overheating should be avoided during pregnancy. Systemic retinoids are known to be teratogenic to a developing fetus and pose a high risk for birth defects. Therefore, women who are using systemic retinoids should be appropriately counseled about pregnancy risks and the need for highly effective contraception; regular monitoring with pregnancy tests is indicated. Systemic retinoids should be administered only by physicians who are knowledgeable regarding their risks and benefits. To access isotretinoin in the US, women and their prescribing providers must be enrolled in the See ## Therapies Under Investigation Advances in understanding the genetics and pathophysiology of ichthyosis paired with new biotechnology approaches have led to the exploration and development of pathogenesis-based therapies for ichthyoses. Among those are enzyme replacement therapy (ERT) and lipid replacement therapy (LRT); repurposing of biologic therapeutics; and gene replacement and gene editing therapies. It can be expected that some of these new therapies will prove their efficacy and will be incorporated in the treatment of ichthyosis. Nevertheless, there are only a few ongoing, registered clinical trials for treatment of ARCI. Results have not been published, and no conclusions regarding the long-term safety and efficacy can be made at this time. For a detailed review, see Phase I open-label and long-term extension study using subcutaneous injection of human monoclonal antibody targeting IL-12/IL-23 (ustekinumab) ( Phase II multicenter, randomized, double-blind, placebo-controlled dosage study using subcutaneous injection of humanized monoclonal antibody ANB019 targeting IL-36 receptor (imsidolimab) ( Phase IV experimental non-randomized clinical study comparing the effect of subcutaneous injections with either secukinumab, ustekinumab, or dupilumab with symptomatic treatment in children with congenital ichthyosis ( These trials are based on the pivotal finding that congenital ichthyoses demonstrate an interleukin 17-dominant immune profile with marked elevations in Th17/IL-23 pathway cytokines and chemokines reminiscent of the inflammatory pattern of psoriasis [ In a subsequent double-blind placebo-controlled Phase II trial with secukinumab ( Search • Phase I open-label and long-term extension study using subcutaneous injection of human monoclonal antibody targeting IL-12/IL-23 (ustekinumab) ( • Phase II multicenter, randomized, double-blind, placebo-controlled dosage study using subcutaneous injection of humanized monoclonal antibody ANB019 targeting IL-36 receptor (imsidolimab) ( • Phase IV experimental non-randomized clinical study comparing the effect of subcutaneous injections with either secukinumab, ustekinumab, or dupilumab with symptomatic treatment in children with congenital ichthyosis ( ## Genetic Counseling By definition, autosomal recessive congenital ichthyosis (ARCI) is inherited in an autosomal recessive manner. The parents of an affected child are presumed to be heterozygous for an ARCI-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 an ARCI-related pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an ARCI-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Carrier testing for at-risk relatives requires prior identification of the ARCI-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. Gene-targeted testing for the reproductive partners of known carriers, and for the reproductive partners of individuals affected with ARCI should be considered, particularly if both partners are of the same ethnic background. ARCI-related founder variants have been identified in individuals of Scandinavian, Norwegian/German, and Galician heritage (see 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 ARCI-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 an ARCI-related pathogenic variant and to allow reliable recurrence risk assessment. • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an ARCI-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • Gene-targeted testing for the reproductive partners of known carriers, and for the reproductive partners of individuals affected with ARCI should be considered, particularly if both partners are of the same ethnic background. ARCI-related founder variants have been identified in individuals of Scandinavian, Norwegian/German, and Galician heritage (see ## Mode of Inheritance By definition, autosomal recessive congenital ichthyosis (ARCI) is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected child are presumed to be heterozygous for an ARCI-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 an ARCI-related pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an ARCI-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The parents of an affected child are presumed to be heterozygous for an ARCI-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 an ARCI-related pathogenic variant and to allow reliable recurrence risk assessment. • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an ARCI-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ARCI-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. Gene-targeted testing for the reproductive partners of known carriers, and for the reproductive partners of individuals affected with ARCI should be considered, particularly if both partners are of the same ethnic background. ARCI-related founder variants have been identified in individuals of Scandinavian, Norwegian/German, and Galician heritage (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. • Gene-targeted testing for the reproductive partners of known carriers, and for the reproductive partners of individuals affected with ARCI should be considered, particularly if both partners are of the same ethnic background. ARCI-related founder variants have been identified in individuals of Scandinavian, Norwegian/German, and Galician heritage (see ## 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 • • • • • • • • • • ## Chapter Notes Dr Gabriele Richard, a trained dermatologist and PhD medical geneticist, has more than 20 years' experience in clinical and molecular genetic studies of ichthyoses and other disorders of cornification. Her prior research studies helped elucidate the molecular basis of numerous inherited ichthyoses and other skin disorders, and she is now dedicated to the rapid molecular diagnosis of these conditions in a diagnostic laboratory, using next-generation sequencing panels and exome and genome sequencing. She has contributed to more than 100 scientific publications, review articles, and book chapters. Dr Richard thanks the Foundation for Ichthyosis and Related Skin Types. Sherri J Bale, PhD, FACMG; GeneDx (2001-2017)Gabriele Richard, MD, FACMG (2001-present) 20 April 2023 (sw) Comprehensive update posted live; scope changed to overview 18 May 2017 (ha) Comprehensive update posted live 28 August 2014 (me) Comprehensive update posted live 19 April 2012 (me) Comprehensive update posted live 29 October 2007 (me) Comprehensive update posted live 29 December 2004 (me) Comprehensive update posted live 30 January 2003 (me) Comprehensive update posted live 10 January 2001 (me) Review posted live June 2000 (sb) Original submission • 20 April 2023 (sw) Comprehensive update posted live; scope changed to overview • 18 May 2017 (ha) Comprehensive update posted live • 28 August 2014 (me) Comprehensive update posted live • 19 April 2012 (me) Comprehensive update posted live • 29 October 2007 (me) Comprehensive update posted live • 29 December 2004 (me) Comprehensive update posted live • 30 January 2003 (me) Comprehensive update posted live • 10 January 2001 (me) Review posted live • June 2000 (sb) Original submission ## Author Notes Dr Gabriele Richard, a trained dermatologist and PhD medical geneticist, has more than 20 years' experience in clinical and molecular genetic studies of ichthyoses and other disorders of cornification. Her prior research studies helped elucidate the molecular basis of numerous inherited ichthyoses and other skin disorders, and she is now dedicated to the rapid molecular diagnosis of these conditions in a diagnostic laboratory, using next-generation sequencing panels and exome and genome sequencing. She has contributed to more than 100 scientific publications, review articles, and book chapters. ## Acknowledgments Dr Richard thanks the Foundation for Ichthyosis and Related Skin Types. ## Author History Sherri J Bale, PhD, FACMG; GeneDx (2001-2017)Gabriele Richard, MD, FACMG (2001-present) ## Revision History 20 April 2023 (sw) Comprehensive update posted live; scope changed to overview 18 May 2017 (ha) Comprehensive update posted live 28 August 2014 (me) Comprehensive update posted live 19 April 2012 (me) Comprehensive update posted live 29 October 2007 (me) Comprehensive update posted live 29 December 2004 (me) Comprehensive update posted live 30 January 2003 (me) Comprehensive update posted live 10 January 2001 (me) Review posted live June 2000 (sb) Original submission • 20 April 2023 (sw) Comprehensive update posted live; scope changed to overview • 18 May 2017 (ha) Comprehensive update posted live • 28 August 2014 (me) Comprehensive update posted live • 19 April 2012 (me) Comprehensive update posted live • 29 October 2007 (me) Comprehensive update posted live • 29 December 2004 (me) Comprehensive update posted live • 30 January 2003 (me) Comprehensive update posted live • 10 January 2001 (me) Review posted live • June 2000 (sb) Original submission ## References ## Literature Cited	[]	10/1/2001	20/4/2023		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
li-fraumeni	li-fraumeni	[ "Cellular tumor antigen p53", "TP53", "Li-Fraumeni Syndrome" ]	Li-Fraumeni Syndrome	Katherine Schneider, Kristin Zelley, Kim E Nichols, Alison Schwartz Levine, Judy Garber	Summary Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with high risks for a broad spectrum of cancers including early-onset cancers. Five cancer types account for the majority of LFS tumors: adrenocortical carcinomas, breast cancer, central nervous system tumors, osteosarcomas, and soft-tissue sarcomas. Other cancers associated with LFS include leukemia, colorectal cancer, stomach cancer, lung cancer, melanoma, pediatric head and neck cancers, pancreatic cancer, and prostate cancer. Cancer survivors are at increased risk for developing additional primary cancers and treatment-related secondary cancers. The lifetime risks of cancer for women and men with classic LFS are 90% and 70%, respectively, and 50% of cancers occur prior to age 40 years. The clinical diagnosis of LFS can be established in a proband who meets clinical diagnostic criteria, or the molecular diagnosis is established in a proband with a germline pathogenic variant in LFS is inherited in an autosomal dominant manner. Most individuals diagnosed with LFS inherited a	## Diagnosis Consensus clinical diagnostic criteria for Li-Fraumeni syndrome (LFS) have been published [ LFS A proband with a tumor belonging to the classic LFS tumor spectrum (e.g., premenopausal breast cancer, soft-tissue sarcoma, osteosarcoma, central nervous system [CNS] tumor, adrenocortical carcinoma [ACC]) before age 46 years A proband with multiple tumors (except multiple breast tumors), two of which belong to the classic LFS tumor spectrum and the first of which occurred before age 46 years; A proband with ACC, choroid plexus tumor, or rhabdomyosarcoma (embryonal anaplastic subtype), irrespective of family history; A proband with breast cancer before age 31 years Human epidermal growth factor receptor 2 (HER2)-positive breast cancer before age 40 years [ Pediatric low-hypodiploid acute lymphoblastic leukemia (ALL) [ Pediatric unexplained sonic hedgehog-activated medulloblastoma or jaw osteosarcoma that is not explained by another tumor predisposition syndrome, such as Second primary tumor occurring within the radiation field following treatment of a classic LFS tumor, with the initial tumor diagnosed before age 46 years [ Any pediatric cancer in an individual of southern or southeastern Brazilian ancestry (See The identification of a A proband with a sarcoma diagnosed before age 45 years; A first-degree relative with any cancer diagnosed before age 45 years; A first- or second-degree relative with any cancer diagnosed before age 45 years or a sarcoma diagnosed at any age. 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 Note: Targeted testing for the For an introduction to multigene panels click Molecular Genetic Testing Used in Li-Fraumeni Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Sequence analysis of the entire Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. LFS can be caused by a deletion involving the coding region of To date, • A proband with a tumor belonging to the classic LFS tumor spectrum (e.g., premenopausal breast cancer, soft-tissue sarcoma, osteosarcoma, central nervous system [CNS] tumor, adrenocortical carcinoma [ACC]) before age 46 years • A proband with multiple tumors (except multiple breast tumors), two of which belong to the classic LFS tumor spectrum and the first of which occurred before age 46 years; • A proband with ACC, choroid plexus tumor, or rhabdomyosarcoma (embryonal anaplastic subtype), irrespective of family history; • A proband with breast cancer before age 31 years • Human epidermal growth factor receptor 2 (HER2)-positive breast cancer before age 40 years [ • Pediatric low-hypodiploid acute lymphoblastic leukemia (ALL) [ • Pediatric unexplained sonic hedgehog-activated medulloblastoma or jaw osteosarcoma that is not explained by another tumor predisposition syndrome, such as • Second primary tumor occurring within the radiation field following treatment of a classic LFS tumor, with the initial tumor diagnosed before age 46 years [ • Any pediatric cancer in an individual of southern or southeastern Brazilian ancestry (See • The identification of a • A proband with a sarcoma diagnosed before age 45 years; • A first-degree relative with any cancer diagnosed before age 45 years; • A first- or second-degree relative with any cancer diagnosed before age 45 years or a sarcoma diagnosed at any age. • Note: Targeted testing for the • For an introduction to multigene panels click ## Suggestive Findings LFS A proband with a tumor belonging to the classic LFS tumor spectrum (e.g., premenopausal breast cancer, soft-tissue sarcoma, osteosarcoma, central nervous system [CNS] tumor, adrenocortical carcinoma [ACC]) before age 46 years A proband with multiple tumors (except multiple breast tumors), two of which belong to the classic LFS tumor spectrum and the first of which occurred before age 46 years; A proband with ACC, choroid plexus tumor, or rhabdomyosarcoma (embryonal anaplastic subtype), irrespective of family history; A proband with breast cancer before age 31 years Human epidermal growth factor receptor 2 (HER2)-positive breast cancer before age 40 years [ Pediatric low-hypodiploid acute lymphoblastic leukemia (ALL) [ Pediatric unexplained sonic hedgehog-activated medulloblastoma or jaw osteosarcoma that is not explained by another tumor predisposition syndrome, such as Second primary tumor occurring within the radiation field following treatment of a classic LFS tumor, with the initial tumor diagnosed before age 46 years [ Any pediatric cancer in an individual of southern or southeastern Brazilian ancestry (See The identification of a • A proband with a tumor belonging to the classic LFS tumor spectrum (e.g., premenopausal breast cancer, soft-tissue sarcoma, osteosarcoma, central nervous system [CNS] tumor, adrenocortical carcinoma [ACC]) before age 46 years • A proband with multiple tumors (except multiple breast tumors), two of which belong to the classic LFS tumor spectrum and the first of which occurred before age 46 years; • A proband with ACC, choroid plexus tumor, or rhabdomyosarcoma (embryonal anaplastic subtype), irrespective of family history; • A proband with breast cancer before age 31 years • Human epidermal growth factor receptor 2 (HER2)-positive breast cancer before age 40 years [ • Pediatric low-hypodiploid acute lymphoblastic leukemia (ALL) [ • Pediatric unexplained sonic hedgehog-activated medulloblastoma or jaw osteosarcoma that is not explained by another tumor predisposition syndrome, such as • Second primary tumor occurring within the radiation field following treatment of a classic LFS tumor, with the initial tumor diagnosed before age 46 years [ • Any pediatric cancer in an individual of southern or southeastern Brazilian ancestry (See • The identification of a ## Establishing the Diagnosis A proband with a sarcoma diagnosed before age 45 years; A first-degree relative with any cancer diagnosed before age 45 years; A first- or second-degree relative with any cancer diagnosed before age 45 years or a sarcoma diagnosed at any age. 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 Note: Targeted testing for the For an introduction to multigene panels click Molecular Genetic Testing Used in Li-Fraumeni Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Sequence analysis of the entire Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. LFS can be caused by a deletion involving the coding region of To date, • A proband with a sarcoma diagnosed before age 45 years; • A first-degree relative with any cancer diagnosed before age 45 years; • A first- or second-degree relative with any cancer diagnosed before age 45 years or a sarcoma diagnosed at any age. • Note: Targeted testing for the • For an introduction to multigene panels click ## Clinical Characteristics Li-Fraumeni syndrome (LFS) is associated with a high risk for a broad spectrum of cancers. The five core LFS-related cancers are adrenocortical carcinomas (ACC), breast cancer, central nervous system (CNS) tumors, osteosarcomas, and soft-tissue sarcomas [ Childhood (age 0-15 years): ACC, choroid plexus carcinoma, rhabdomyosarcoma, and medulloblastoma Adolescent to adulthood (16-50 years): breast cancer, osteosarcoma, soft-tissue sarcoma, leukemia, astrocytoma, glioblastoma, colorectal cancer, and lung cancer Late adulthood (51-80 years): pancreatic cancer and prostate cancer There continues to be debate regarding genotype-phenotype correlations in LFS. Nonsense, frameshift, and missense pathogenic variants that cause complete loss of p53 function or a dominant-negative effect are associated with a more severe phenotype compared to pathogenic variants that cause partial loss of p53 function [ Additional missense pathogenic variants are associated with lower risk of cancer and older age of onset compared to other One study suggested that Penetrance in LFS is variable and is partially due to the type of pathogenic variant (see Genetic modifiers of LFS-associated cancer risk include the following: Additional epigenetic modifiers are being investigated, including variants in the WNT signaling pathway, which appear to decrease cancer risk, and inherited epimutations in As the clinical and molecular definitions of LFS have expanded, alternate terms have been proposed, including "Li-Fraumeni spectrum" and "heritable The prevalence of germline The • Childhood (age 0-15 years): ACC, choroid plexus carcinoma, rhabdomyosarcoma, and medulloblastoma • Adolescent to adulthood (16-50 years): breast cancer, osteosarcoma, soft-tissue sarcoma, leukemia, astrocytoma, glioblastoma, colorectal cancer, and lung cancer • Late adulthood (51-80 years): pancreatic cancer and prostate cancer ## Clinical Description Li-Fraumeni syndrome (LFS) is associated with a high risk for a broad spectrum of cancers. The five core LFS-related cancers are adrenocortical carcinomas (ACC), breast cancer, central nervous system (CNS) tumors, osteosarcomas, and soft-tissue sarcomas [ Childhood (age 0-15 years): ACC, choroid plexus carcinoma, rhabdomyosarcoma, and medulloblastoma Adolescent to adulthood (16-50 years): breast cancer, osteosarcoma, soft-tissue sarcoma, leukemia, astrocytoma, glioblastoma, colorectal cancer, and lung cancer Late adulthood (51-80 years): pancreatic cancer and prostate cancer • Childhood (age 0-15 years): ACC, choroid plexus carcinoma, rhabdomyosarcoma, and medulloblastoma • Adolescent to adulthood (16-50 years): breast cancer, osteosarcoma, soft-tissue sarcoma, leukemia, astrocytoma, glioblastoma, colorectal cancer, and lung cancer • Late adulthood (51-80 years): pancreatic cancer and prostate cancer ## Genotype-Phenotype Correlations There continues to be debate regarding genotype-phenotype correlations in LFS. Nonsense, frameshift, and missense pathogenic variants that cause complete loss of p53 function or a dominant-negative effect are associated with a more severe phenotype compared to pathogenic variants that cause partial loss of p53 function [ Additional missense pathogenic variants are associated with lower risk of cancer and older age of onset compared to other One study suggested that ## Penetrance Penetrance in LFS is variable and is partially due to the type of pathogenic variant (see ## Genetic Modifiers Genetic modifiers of LFS-associated cancer risk include the following: Additional epigenetic modifiers are being investigated, including variants in the WNT signaling pathway, which appear to decrease cancer risk, and inherited epimutations in ## Nomenclature As the clinical and molecular definitions of LFS have expanded, alternate terms have been proposed, including "Li-Fraumeni spectrum" and "heritable ## Prevalence The prevalence of germline The ## Genetically Related (Allelic) Disorders Ancillary evaluation to determine constitutional or somatic status of a No phenotypes other than those discussed in this ## Differential Diagnosis Other Genes of Interest in the Differential Diagnosis of Li-Fraumeni Syndrome ACC = adrenocortical carcinoma; AD = autosomal dominant; AR = autosomal recessive; CLL = chronic lymphocytic leukemia; CNS = central nervous system; ER = estrogen receptor; GI = gastrointestinal; HER2 = human epidermal growth factor receptor 2; LFS = Li-Fraumeni syndrome; MOI = mode of inheritance; PR = progesterone receptor ## Management Clinical practice guidelines for Li-Fraumeni syndrome (LFS) have been published [ To establish the extent of disease and needs in an individual diagnosed with LFS, the evaluations summarized in Li-Fraumeni Syndrome: Recommended Evaluations Following Initial Diagnosis Complete physical exam w/high index of suspicion for cancer (incl blood pressure, full neurologic exam, & assessment of growth, sudden weight gain or loss, cushingoid appearance, or signs of virilization in a child) Whole-body MRI w/o contrast Clinical breast exam Breast MRI w/& w/o contrast Neurologic exam Brain MRI w/contrast Community or Social work involvement for parental support CNS = central nervous system; GI = gastrointestinal; LFS = Li-Fraumeni syndrome; MOI = mode of inheritance Individuals with a family history of LFS should begin surveillance at the ages listed in this table or 5-10 years before the onset of the cancer in the family, whichever comes first. Evidence supports the use of whole-body MRI for surveillance in individuals with LFS [ Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Individuals with LFS may need mental health support and resources due to the burden of intensive surveillance protocols and their personal and family cancer experiences [ Radiation therapy should be avoided if possible to reduce the risk of secondary malignancies [ The use of conventional cytotoxic chemotherapy may also pose an increased secondary cancer risk [ Otherwise, standard oncologic management is recommended. Note: In some hereditary cancer syndromes, tumor tissue testing for loss of heterozygosity (LOH) and other features in the tumor can be informative; however, this is not usually the case in LFS. Thus, molecular analysis of tumor tissue to identify LOH of Surveillance guidelines for adults and children with LFS have been developed and modified from the Toronto protocol [ Li-Fraumeni Syndrome: Recommended Surveillance Every 3-4 mos from birth to age 18 yrs Every 6 mos from age ≥18 yrs ACC = adrenocortical carcinomas; CNS = central nervous system; EUS = endoscopic ultrasound; MRCP = magnetic resonance cholangiopancreatography; GI = gastrointestinal; NA = not applicable; PSA = prostate-specific antigen Individuals with a family history of LFS should begin surveillance at the ages listed in this table or 5-10 years before the onset of the cancer in the family, whichever comes first. Evidence supports the role of whole-body MRI in individuals with LFS [ The first brain MRI should be done with contrast, and subsequent brain MRIs may be done without contrast if the previous MRI was normal and there are no new clinical manifestations [ Interim blood counts and inflammatory biomarkers have not been shown to have independent benefit for cancer detection [ National Comprehensive Cancer Network (NCCN) guidelines suggest pancreatic cancer surveillance only if the individual has ≥1 first- or second-degree relative with exocrine pancreatic cancer ( Individuals with LFS recognize the value of surveillance but may need additional mental health support and resources due to the burden of intensive surveillance protocols and their personal and family cancer experiences. More research is needed in this area [ Individuals with LFS are encouraged to avoid or minimize exposures to known or suspected carcinogens, including ionizing radiation, unprotected sun exposure, tobacco use, occupational exposures, and excessive alcohol use, because the effects of carcinogenic exposures and germline Since the risks of LFS-related cancers are increased at all ages, including infancy and childhood, it is recommended that See There are efforts to identify medications that can reduce the risk of cancer in individuals with LFS. One medication that looks promising is metformin; additional clinical trials investigating metformin are planned by groups in the United States, Canada, Germany, and the United Kingdom [ There are also studies evaluating the clinical application and utility of cell-free DNA for early cancer detection in individuals with LFS. One study looked at the efficacy of a multimodal liquid biopsy assay in a longitudinal cohort of 89 individuals with LFS. The results showed that cancer-associated signal(s) were detected in individuals with LFS prior to identification of cancer by conventional screening (positive predictive value = 67.6%; negative predictive value = 96.5%) [ Search Additional resources include the Li-Fraumeni Exploration (LiFE) Research Consortium, Li-Fraumeni syndrome association (LFSA), Living LFS, and the LiFT Up study. • Complete physical exam w/high index of suspicion for cancer (incl blood pressure, full neurologic exam, & assessment of growth, sudden weight gain or loss, cushingoid appearance, or signs of virilization in a child) • Whole-body MRI w/o contrast • Clinical breast exam • Breast MRI w/& w/o contrast • Neurologic exam • Brain MRI w/contrast • Community or • Social work involvement for parental support • Radiation therapy should be avoided if possible to reduce the risk of secondary malignancies [ • The use of conventional cytotoxic chemotherapy may also pose an increased secondary cancer risk [ • Otherwise, standard oncologic management is recommended. • Every 3-4 mos from birth to age 18 yrs • Every 6 mos from age ≥18 yrs ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with LFS, the evaluations summarized in Li-Fraumeni Syndrome: Recommended Evaluations Following Initial Diagnosis Complete physical exam w/high index of suspicion for cancer (incl blood pressure, full neurologic exam, & assessment of growth, sudden weight gain or loss, cushingoid appearance, or signs of virilization in a child) Whole-body MRI w/o contrast Clinical breast exam Breast MRI w/& w/o contrast Neurologic exam Brain MRI w/contrast Community or Social work involvement for parental support CNS = central nervous system; GI = gastrointestinal; LFS = Li-Fraumeni syndrome; MOI = mode of inheritance Individuals with a family history of LFS should begin surveillance at the ages listed in this table or 5-10 years before the onset of the cancer in the family, whichever comes first. Evidence supports the use of whole-body MRI for surveillance in individuals with LFS [ Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Individuals with LFS may need mental health support and resources due to the burden of intensive surveillance protocols and their personal and family cancer experiences [ • Complete physical exam w/high index of suspicion for cancer (incl blood pressure, full neurologic exam, & assessment of growth, sudden weight gain or loss, cushingoid appearance, or signs of virilization in a child) • Whole-body MRI w/o contrast • Clinical breast exam • Breast MRI w/& w/o contrast • Neurologic exam • Brain MRI w/contrast • Community or • Social work involvement for parental support ## Treatment of Manifestations Radiation therapy should be avoided if possible to reduce the risk of secondary malignancies [ The use of conventional cytotoxic chemotherapy may also pose an increased secondary cancer risk [ Otherwise, standard oncologic management is recommended. Note: In some hereditary cancer syndromes, tumor tissue testing for loss of heterozygosity (LOH) and other features in the tumor can be informative; however, this is not usually the case in LFS. Thus, molecular analysis of tumor tissue to identify LOH of • Radiation therapy should be avoided if possible to reduce the risk of secondary malignancies [ • The use of conventional cytotoxic chemotherapy may also pose an increased secondary cancer risk [ • Otherwise, standard oncologic management is recommended. ## Prevention of Primary Manifestations ## Surveillance Surveillance guidelines for adults and children with LFS have been developed and modified from the Toronto protocol [ Li-Fraumeni Syndrome: Recommended Surveillance Every 3-4 mos from birth to age 18 yrs Every 6 mos from age ≥18 yrs ACC = adrenocortical carcinomas; CNS = central nervous system; EUS = endoscopic ultrasound; MRCP = magnetic resonance cholangiopancreatography; GI = gastrointestinal; NA = not applicable; PSA = prostate-specific antigen Individuals with a family history of LFS should begin surveillance at the ages listed in this table or 5-10 years before the onset of the cancer in the family, whichever comes first. Evidence supports the role of whole-body MRI in individuals with LFS [ The first brain MRI should be done with contrast, and subsequent brain MRIs may be done without contrast if the previous MRI was normal and there are no new clinical manifestations [ Interim blood counts and inflammatory biomarkers have not been shown to have independent benefit for cancer detection [ National Comprehensive Cancer Network (NCCN) guidelines suggest pancreatic cancer surveillance only if the individual has ≥1 first- or second-degree relative with exocrine pancreatic cancer ( Individuals with LFS recognize the value of surveillance but may need additional mental health support and resources due to the burden of intensive surveillance protocols and their personal and family cancer experiences. More research is needed in this area [ • Every 3-4 mos from birth to age 18 yrs • Every 6 mos from age ≥18 yrs ## Agents/Circumstances to Avoid Individuals with LFS are encouraged to avoid or minimize exposures to known or suspected carcinogens, including ionizing radiation, unprotected sun exposure, tobacco use, occupational exposures, and excessive alcohol use, because the effects of carcinogenic exposures and germline ## Evaluation of Relatives at Risk Since the risks of LFS-related cancers are increased at all ages, including infancy and childhood, it is recommended that See ## Pregnancy Management ## Therapies Under Investigation There are efforts to identify medications that can reduce the risk of cancer in individuals with LFS. One medication that looks promising is metformin; additional clinical trials investigating metformin are planned by groups in the United States, Canada, Germany, and the United Kingdom [ There are also studies evaluating the clinical application and utility of cell-free DNA for early cancer detection in individuals with LFS. One study looked at the efficacy of a multimodal liquid biopsy assay in a longitudinal cohort of 89 individuals with LFS. The results showed that cancer-associated signal(s) were detected in individuals with LFS prior to identification of cancer by conventional screening (positive predictive value = 67.6%; negative predictive value = 96.5%) [ Search ## Other Additional resources include the Li-Fraumeni Exploration (LiFE) Research Consortium, Li-Fraumeni syndrome association (LFSA), Living LFS, and the LiFT Up study. ## Genetic Counseling Li-Fraumeni syndrome (LFS) is inherited in an autosomal dominant manner. Most individuals diagnosed with LFS inherited a Some individuals diagnosed with LFS have the disorder as the result of a If a If a If a The proband has a The proband inherited a pathogenic variant from a parent with gonadal mosaicism [ The family history of some individuals diagnosed with LFS may appear to be negative because of failure to recognize the disorder in family members, a small family size, variable expressivity, early death of the parent before the onset of symptoms, or late onset of cancer in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless a molecular diagnosis has been established in the proband and molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband. If a If a molecular diagnosis of LFS has been established in the proband (i.e., the proband has a known germline A parent of the proband is heterozygous for the The If a clinical diagnosis of LFS has been established in the proband but a Each child of an individual with a molecular diagnosis of LFS has a 50% risk of inheriting the Each child of an individual with a clinical diagnosis of LFS (in whom a The risk to other family members (e.g., aunts, uncles, cousins) depends on the genetic status of the proband's parents: if a parent has the If the Molecular genetic testing can be used with certainty to clarify the genetic status of at-risk family members if a clinically diagnosed relative has undergone molecular genetic testing and is found to have a pathogenic variant in The use of molecular genetic testing for determining the genetic status of at-risk relatives when a Because cancer screening for individuals with LFS begins in infancy, molecular genetic testing is offered to at-risk children and adolescents. Parents are motivated to arrange testing for their offspring to clarify their child's cancer risk status and the need for enhanced surveillance. Special consideration should be given to education of the children and their parents prior to genetic testing, and older children and adolescents should be given the option of assenting to the test. The method of results disclosure should be discussed and agreed upon by the provider, parent(s), and older child/adolescent. Living with a diagnosis of LFS can take an emotional toll on individuals, especially those in the adolescent / young adult age group. Individuals in this age group describe the burden of coping with one or more cancer diagnoses and/or living with the anticipation and fear of cancer as well as a range of family communication challenges [ Obtaining a family history in a proband suspected of having LFS includes obtaining information on all childhood- and adult-onset malignancies (e.g., age of onset, type of malignancy) among first-, second-, and third-degree relatives. Family history may be incorrect or incomplete for a variety of reasons (e.g., the topic of cancer may be avoided or a death in the family may have led to estrangement). In addition, obtaining a cancer history for a proband with suspected LFS is often emotionally charged because of the number of cancer-related illnesses and deaths among close relatives. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. If a Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • Most individuals diagnosed with LFS inherited a • Some individuals diagnosed with LFS have the disorder as the result of a • If a • If a • If a • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal mosaicism [ • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal mosaicism [ • The family history of some individuals diagnosed with LFS may appear to be negative because of failure to recognize the disorder in family members, a small family size, variable expressivity, early death of the parent before the onset of symptoms, or late onset of cancer in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless a molecular diagnosis has been established in the proband and molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband. • If a • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal mosaicism [ • If a molecular diagnosis of LFS has been established in the proband (i.e., the proband has a known germline • A parent of the proband is heterozygous for the • The • A parent of the proband is heterozygous for the • The • If a clinical diagnosis of LFS has been established in the proband but a • A parent of the proband is heterozygous for the • The • Each child of an individual with a molecular diagnosis of LFS has a 50% risk of inheriting the • Each child of an individual with a clinical diagnosis of LFS (in whom a • The risk to other family members (e.g., aunts, uncles, cousins) depends on the genetic status of the proband's parents: if a parent has the • If the • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance Li-Fraumeni syndrome (LFS) is inherited in an autosomal dominant manner. ## Risk to Family Members Most individuals diagnosed with LFS inherited a Some individuals diagnosed with LFS have the disorder as the result of a If a If a If a The proband has a The proband inherited a pathogenic variant from a parent with gonadal mosaicism [ The family history of some individuals diagnosed with LFS may appear to be negative because of failure to recognize the disorder in family members, a small family size, variable expressivity, early death of the parent before the onset of symptoms, or late onset of cancer in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless a molecular diagnosis has been established in the proband and molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband. If a If a molecular diagnosis of LFS has been established in the proband (i.e., the proband has a known germline A parent of the proband is heterozygous for the The If a clinical diagnosis of LFS has been established in the proband but a Each child of an individual with a molecular diagnosis of LFS has a 50% risk of inheriting the Each child of an individual with a clinical diagnosis of LFS (in whom a The risk to other family members (e.g., aunts, uncles, cousins) depends on the genetic status of the proband's parents: if a parent has the If the • Most individuals diagnosed with LFS inherited a • Some individuals diagnosed with LFS have the disorder as the result of a • If a • If a • If a • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal mosaicism [ • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal mosaicism [ • The family history of some individuals diagnosed with LFS may appear to be negative because of failure to recognize the disorder in family members, a small family size, variable expressivity, early death of the parent before the onset of symptoms, or late onset of cancer in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless a molecular diagnosis has been established in the proband and molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband. • If a • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal mosaicism [ • If a molecular diagnosis of LFS has been established in the proband (i.e., the proband has a known germline • A parent of the proband is heterozygous for the • The • A parent of the proband is heterozygous for the • The • If a clinical diagnosis of LFS has been established in the proband but a • A parent of the proband is heterozygous for the • The • Each child of an individual with a molecular diagnosis of LFS has a 50% risk of inheriting the • Each child of an individual with a clinical diagnosis of LFS (in whom a • The risk to other family members (e.g., aunts, uncles, cousins) depends on the genetic status of the proband's parents: if a parent has the • If the ## Related Genetic Counseling Issues Molecular genetic testing can be used with certainty to clarify the genetic status of at-risk family members if a clinically diagnosed relative has undergone molecular genetic testing and is found to have a pathogenic variant in The use of molecular genetic testing for determining the genetic status of at-risk relatives when a Because cancer screening for individuals with LFS begins in infancy, molecular genetic testing is offered to at-risk children and adolescents. Parents are motivated to arrange testing for their offspring to clarify their child's cancer risk status and the need for enhanced surveillance. Special consideration should be given to education of the children and their parents prior to genetic testing, and older children and adolescents should be given the option of assenting to the test. The method of results disclosure should be discussed and agreed upon by the provider, parent(s), and older child/adolescent. Living with a diagnosis of LFS can take an emotional toll on individuals, especially those in the adolescent / young adult age group. Individuals in this age group describe the burden of coping with one or more cancer diagnoses and/or living with the anticipation and fear of cancer as well as a range of family communication challenges [ Obtaining a family history in a proband suspected of having LFS includes obtaining information on all childhood- and adult-onset malignancies (e.g., age of onset, type of malignancy) among first-, second-, and third-degree relatives. Family history may be incorrect or incomplete for a variety of reasons (e.g., the topic of cancer may be avoided or a death in the family may have led to estrangement). In addition, obtaining a cancer history for a proband with suspected LFS is often emotionally charged because of the number of cancer-related illnesses and deaths among close relatives. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is 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 If a Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • • • • • • • • • • • • • ## Molecular Genetics Li-Fraumeni Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Li-Fraumeni Syndrome ( It has been proposed that p53 is a central driver in creating a cellular microenvironment that is conducive to tumor formation and growth. This theory, termed the precancerous niche hypothesis, may eventually lead to possible treatment options [ Identification of a See Variants listed in the table have been provided by the authors. ACC = adrenocortical carcinoma; LFS = Li-Fraumeni syndrome Variant designation that does not conform to current naming conventions ## Molecular Pathogenesis It has been proposed that p53 is a central driver in creating a cellular microenvironment that is conducive to tumor formation and growth. This theory, termed the precancerous niche hypothesis, may eventually lead to possible treatment options [ Identification of a See Variants listed in the table have been provided by the authors. ACC = adrenocortical carcinoma; LFS = Li-Fraumeni syndrome Variant designation that does not conform to current naming conventions ## Chapter Notes Dr Nichols is a pediatric oncologist with clinical and research interests in cancer predisposition and primary immunodeficiency. We wish to acknowledge Dr Frederick P Li, Dr Joseph F Fraumeni, and Dr. Thierry Frebourg for their contributions. Judy Garber, MD, MPH (2010-present)Frederick P Li, MD; Dana Farber Cancer Institute (1998-2010)Kim E Nichols, MD (2013-present)Katherine A Schneider, MPH (1998-present)Alison Schwartz Levine, MS, LGC (2024-present)Kristin Zelley, MS (2013-present) 1 May 2025 (aa) Revision: ClinGen variant interpretation guidelines 5 September 2024 (sw) Comprehensive update posted live 21 November 2019 (sw) Comprehensive update posted live 11 April 2013 (me) Comprehensive update posted live 9 February 2010 (me) Comprehensive update posted live 12 October 2004 (me) Comprehensive update posted live 3 October 2002 (me) Comprehensive update posted live 19 January 1999 (me) Review posted live 24 July 1998 (ks) Original submission • 1 May 2025 (aa) Revision: ClinGen variant interpretation guidelines • 5 September 2024 (sw) Comprehensive update posted live • 21 November 2019 (sw) Comprehensive update posted live • 11 April 2013 (me) Comprehensive update posted live • 9 February 2010 (me) Comprehensive update posted live • 12 October 2004 (me) Comprehensive update posted live • 3 October 2002 (me) Comprehensive update posted live • 19 January 1999 (me) Review posted live • 24 July 1998 (ks) Original submission ## Author Notes Dr Nichols is a pediatric oncologist with clinical and research interests in cancer predisposition and primary immunodeficiency. ## Acknowledgments We wish to acknowledge Dr Frederick P Li, Dr Joseph F Fraumeni, and Dr. Thierry Frebourg for their contributions. ## Author History Judy Garber, MD, MPH (2010-present)Frederick P Li, MD; Dana Farber Cancer Institute (1998-2010)Kim E Nichols, MD (2013-present)Katherine A Schneider, MPH (1998-present)Alison Schwartz Levine, MS, LGC (2024-present)Kristin Zelley, MS (2013-present) ## Revision History 1 May 2025 (aa) Revision: ClinGen variant interpretation guidelines 5 September 2024 (sw) Comprehensive update posted live 21 November 2019 (sw) Comprehensive update posted live 11 April 2013 (me) Comprehensive update posted live 9 February 2010 (me) Comprehensive update posted live 12 October 2004 (me) Comprehensive update posted live 3 October 2002 (me) Comprehensive update posted live 19 January 1999 (me) Review posted live 24 July 1998 (ks) Original submission • 1 May 2025 (aa) Revision: ClinGen variant interpretation guidelines • 5 September 2024 (sw) Comprehensive update posted live • 21 November 2019 (sw) Comprehensive update posted live • 11 April 2013 (me) Comprehensive update posted live • 9 February 2010 (me) Comprehensive update posted live • 12 October 2004 (me) Comprehensive update posted live • 3 October 2002 (me) Comprehensive update posted live • 19 January 1999 (me) Review posted live • 24 July 1998 (ks) Original submission ## References ## Literature Cited	[]	19/1/1999	5/9/2024	1/5/2025	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
lipoid-p	lipoid-p	[ "Hyalinosis Cutis et Mucosae", "Urbach-Wiethe Disease", "Hyalinosis Cutis et Mucosae", "Urbach-Wiethe Disease", "Extracellular matrix protein 1", "ECM1", "Lipoid Proteinosis" ]	Lipoid Proteinosis	Hassan Vahidnezhad, Leila Youssefian, Jouni Uitto	Summary Lipoid proteinosis (LP) is characterized by deposition of hyaline-like material in various tissues resulting in a hoarse voice from early infancy, vesicles and hemorrhagic crusts in the mouth and on the face and extremities, verrucous and keratotic cutaneous lesions on extensor surfaces (especially the elbows), and moniliform blepharosis (multiple beaded papules along the eyelid margins and inner canthus). Extracutaneous manifestations may include epilepsy, neuropsychiatric disorders, spontaneous CNS hemorrhage, and asymptomatic multiple yellowish nodules throughout the gastrointestinal tract. Generally, the disease course is chronic and fluctuating. Males and females are affected equally. Affected individuals have a normal life span unless they experience laryngeal obstruction. The diagnosis of lipoid proteinosis is established in a proband with characteristic clinical findings and either biallelic LP is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an	## Diagnosis Lipoid proteinosis (LP), which is characterized by deposition of hyaline-like material in the larynx, oral cavity, skin, and internal organs, First, vesicles and hemorrhagic crusts, often caused by minor trauma or friction, appear in the mouth and on the face and extremities ( Later, with increasing hyaline deposition in the dermis, the skin becomes diffusely thickened and appears waxy with a yellowish discoloration; papules, nodules, and plaques appear on the face and lips ( The diagnosis of lipoid proteinosis Biallelic pathogenic variants in Characteristic histologic findings and/or immunolabeling on skin biopsy (See Note: Identification of biallelic Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Lipoid Proteinosis See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and 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. Gross deletions and duplications have been reported in several individuals [ Hematoxylin and eosin (H&E) staining shows hyperkeratosis and accumulation of hyaline-like material in the dermis. Periodic acid-Schiff (PAS)-diastase staining shows PAS-positive, diastase-resistant basement membrane thickening and reduplication at the dermal-epidermal junction around blood vessels [ Immunolabeling using polyclonal anti-ECM1 antibody shows reduced levels of ECM1 protein, providing a means of rapid diagnosis especially in the early stages of the disease [ • First, vesicles and hemorrhagic crusts, often caused by minor trauma or friction, appear in the mouth and on the face and extremities ( • Later, with increasing hyaline deposition in the dermis, the skin becomes diffusely thickened and appears waxy with a yellowish discoloration; papules, nodules, and plaques appear on the face and lips ( • First, vesicles and hemorrhagic crusts, often caused by minor trauma or friction, appear in the mouth and on the face and extremities ( • Later, with increasing hyaline deposition in the dermis, the skin becomes diffusely thickened and appears waxy with a yellowish discoloration; papules, nodules, and plaques appear on the face and lips ( • First, vesicles and hemorrhagic crusts, often caused by minor trauma or friction, appear in the mouth and on the face and extremities ( • Later, with increasing hyaline deposition in the dermis, the skin becomes diffusely thickened and appears waxy with a yellowish discoloration; papules, nodules, and plaques appear on the face and lips ( • Biallelic pathogenic variants in • Characteristic histologic findings and/or immunolabeling on skin biopsy (See ## Suggestive Findings Lipoid proteinosis (LP), which is characterized by deposition of hyaline-like material in the larynx, oral cavity, skin, and internal organs, First, vesicles and hemorrhagic crusts, often caused by minor trauma or friction, appear in the mouth and on the face and extremities ( Later, with increasing hyaline deposition in the dermis, the skin becomes diffusely thickened and appears waxy with a yellowish discoloration; papules, nodules, and plaques appear on the face and lips ( • First, vesicles and hemorrhagic crusts, often caused by minor trauma or friction, appear in the mouth and on the face and extremities ( • Later, with increasing hyaline deposition in the dermis, the skin becomes diffusely thickened and appears waxy with a yellowish discoloration; papules, nodules, and plaques appear on the face and lips ( • First, vesicles and hemorrhagic crusts, often caused by minor trauma or friction, appear in the mouth and on the face and extremities ( • Later, with increasing hyaline deposition in the dermis, the skin becomes diffusely thickened and appears waxy with a yellowish discoloration; papules, nodules, and plaques appear on the face and lips ( • First, vesicles and hemorrhagic crusts, often caused by minor trauma or friction, appear in the mouth and on the face and extremities ( • Later, with increasing hyaline deposition in the dermis, the skin becomes diffusely thickened and appears waxy with a yellowish discoloration; papules, nodules, and plaques appear on the face and lips ( ## Establishing the Diagnosis The diagnosis of lipoid proteinosis Biallelic pathogenic variants in Characteristic histologic findings and/or immunolabeling on skin biopsy (See Note: Identification of biallelic Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Lipoid Proteinosis See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and 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. Gross deletions and duplications have been reported in several individuals [ Hematoxylin and eosin (H&E) staining shows hyperkeratosis and accumulation of hyaline-like material in the dermis. Periodic acid-Schiff (PAS)-diastase staining shows PAS-positive, diastase-resistant basement membrane thickening and reduplication at the dermal-epidermal junction around blood vessels [ Immunolabeling using polyclonal anti-ECM1 antibody shows reduced levels of ECM1 protein, providing a means of rapid diagnosis especially in the early stages of the disease [ • Biallelic pathogenic variants in • Characteristic histologic findings and/or immunolabeling on skin biopsy (See ## Option 1 For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Lipoid Proteinosis See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and 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. Gross deletions and duplications have been reported in several individuals [ ## Skin Biopsy Hematoxylin and eosin (H&E) staining shows hyperkeratosis and accumulation of hyaline-like material in the dermis. Periodic acid-Schiff (PAS)-diastase staining shows PAS-positive, diastase-resistant basement membrane thickening and reduplication at the dermal-epidermal junction around blood vessels [ Immunolabeling using polyclonal anti-ECM1 antibody shows reduced levels of ECM1 protein, providing a means of rapid diagnosis especially in the early stages of the disease [ ## Clinical Characteristics Lipoid proteinosis (LP) is characterized by deposition of hyaline-like material that results in a hoarse voice from early infancy and characteristic skin lesions. To date, more than 400 individuals have been identified with biallelic pathogenic variants in Lipoid Proteinosis: Frequency of Select Features Recurrent episodes of parotitis caused by stenosis of the parotid duct and submandibular gland inflammation are reported. Infiltration of the tongue may destroy the dorsal papillae, causing the tongue to have a smooth surface. Dental health is often poor [ During childhood the skin may be easily damaged by minor trauma or friction, resulting in blisters and scar formation. Pock-like or acneiform scars, vesicles, and hemorrhagic crust are particularly evident on the face and extremities ( At later stages with increasing hyaline-like deposition within the dermis, skin becomes diffusely thickened and appears waxy with yellowish discoloration; papules, nodules, and plaques appear on the face and the lips ( Hyperkeratotic and verrucous lesions may appear in regions exposed to mechanical trauma, such as the hands, elbows, knees, buttocks, and axillae ( Patchy and diffuse alopecia of the scalp, beard, eyelashes, and eyebrows may be present; however, alopecia is not a significant finding in most. Nail dystrophy has been reported [ Extracutaneous manifestations may include the following: No More than 400 individuals with lipoid proteinosis (LP) have been reported worldwide [ LP tends to be more common in countries with extensive consanguinity and/or in areas (e.g., South Africa) in which a founder variant has been postulated [ • During childhood the skin may be easily damaged by minor trauma or friction, resulting in blisters and scar formation. Pock-like or acneiform scars, vesicles, and hemorrhagic crust are particularly evident on the face and extremities ( • At later stages with increasing hyaline-like deposition within the dermis, skin becomes diffusely thickened and appears waxy with yellowish discoloration; papules, nodules, and plaques appear on the face and the lips ( ## Clinical Description Lipoid proteinosis (LP) is characterized by deposition of hyaline-like material that results in a hoarse voice from early infancy and characteristic skin lesions. To date, more than 400 individuals have been identified with biallelic pathogenic variants in Lipoid Proteinosis: Frequency of Select Features Recurrent episodes of parotitis caused by stenosis of the parotid duct and submandibular gland inflammation are reported. Infiltration of the tongue may destroy the dorsal papillae, causing the tongue to have a smooth surface. Dental health is often poor [ During childhood the skin may be easily damaged by minor trauma or friction, resulting in blisters and scar formation. Pock-like or acneiform scars, vesicles, and hemorrhagic crust are particularly evident on the face and extremities ( At later stages with increasing hyaline-like deposition within the dermis, skin becomes diffusely thickened and appears waxy with yellowish discoloration; papules, nodules, and plaques appear on the face and the lips ( Hyperkeratotic and verrucous lesions may appear in regions exposed to mechanical trauma, such as the hands, elbows, knees, buttocks, and axillae ( Patchy and diffuse alopecia of the scalp, beard, eyelashes, and eyebrows may be present; however, alopecia is not a significant finding in most. Nail dystrophy has been reported [ Extracutaneous manifestations may include the following: • During childhood the skin may be easily damaged by minor trauma or friction, resulting in blisters and scar formation. Pock-like or acneiform scars, vesicles, and hemorrhagic crust are particularly evident on the face and extremities ( • At later stages with increasing hyaline-like deposition within the dermis, skin becomes diffusely thickened and appears waxy with yellowish discoloration; papules, nodules, and plaques appear on the face and the lips ( ## Genotype-Phenotype Correlations No ## Prevalence More than 400 individuals with lipoid proteinosis (LP) have been reported worldwide [ LP tends to be more common in countries with extensive consanguinity and/or in areas (e.g., South Africa) in which a founder variant has been postulated [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Genes and Disorders of Interest in the Differential Diagnosis of Lipoid Proteinosis LP is characterized by moniliform blepharosis. PXE is characterized by subretinal neovascularization w/hemorrhage that can cause significant visual impairment. Hepatic dysfunction is rare in LP but may occur in 20%-30% of those w/EPP. Hoarseness & moniliform blepharosis (features characteristic of LP) are not found in those w/EPP. AR = autosomal recessive; LP = lipoid proteinosis; MOI = mode of inheritance • LP is characterized by moniliform blepharosis. • PXE is characterized by subretinal neovascularization w/hemorrhage that can cause significant visual impairment. • Hepatic dysfunction is rare in LP but may occur in 20%-30% of those w/EPP. • Hoarseness & moniliform blepharosis (features characteristic of LP) are not found in those w/EPP. ## Management No clinical practice guidelines for lipoid proteinosis (LP) have been published. To establish the extent of disease and needs in an individual diagnosed with LP, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Lipoid Proteinosis (LP) Use of community or Need for social work involvement for parental support; Need for home nursing referral. MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse There is no curative therapy for LP. Treatment of Manifestations in Individuals with Lipoid Proteinosis (LP) Some persons are resistant to ASMs. Successful treatment w/ASMs incl Tegretol ASM = anti-seizure medication Recommended Surveillance for Individuals with Lipoid Proteinosis (LP) See Search • Use of community or • Need for social work involvement for parental support; • Need for home nursing referral. • Some persons are resistant to ASMs. • Successful treatment w/ASMs incl Tegretol ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with LP, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Lipoid Proteinosis (LP) Use of community or Need for social work involvement for parental support; Need for home nursing referral. MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Use of community or • Need for social work involvement for parental support; • Need for home nursing referral. ## Treatment of Manifestations There is no curative therapy for LP. Treatment of Manifestations in Individuals with Lipoid Proteinosis (LP) Some persons are resistant to ASMs. Successful treatment w/ASMs incl Tegretol ASM = anti-seizure medication • Some persons are resistant to ASMs. • Successful treatment w/ASMs incl Tegretol ## Surveillance Recommended Surveillance for Individuals with Lipoid Proteinosis (LP) ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Lipoid proteinosis (LP) is inherited in an autosomal recessive manner. The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes are typically asymptomatic but may have variable findings. If both parents are known to be heterozygous for an A wide range of clinical manifestations and disease progression may be observed in sibs with the same Heterozygotes are typically asymptomatic but may have variable findings. Carrier testing for at-risk relatives requires prior identification of the The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one • 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 are typically asymptomatic but may have variable findings. • 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 • A wide range of clinical manifestations and disease progression may be observed in sibs with the same • Heterozygotes are typically asymptomatic but may have variable findings. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including 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 Lipoid proteinosis (LP) is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes are typically asymptomatic but may have variable findings. If both parents are known to be heterozygous for an A wide range of clinical manifestations and disease progression may be observed in sibs with the same Heterozygotes are typically asymptomatic but may have variable findings. • The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes are typically asymptomatic but may have variable findings. • 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 • A wide range of clinical manifestations and disease progression may be observed in sibs with the same • Heterozygotes are typically asymptomatic but may have variable findings. ## 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 and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including 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 Lipoid Proteinosis: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Lipoid Proteinosis ( Lipoid proteinosis (LP) is characterized by deposition of hyaline-like material in the larynx, oral cavity, skin, and internal organs and caused by pathogenic variants in Three transcripts of The ECM1 protein structure has four functional domains including a cysteine-free N-terminal segment, two tandem repeats, and a C-terminal segment. The tandem domains contain highly conserved sequence and numerous cysteine residues that are involved in protein-protein interactions and allow the ECM1 protein to function as a transport protein or to be involved in binding of growth or differentiation factors [ Notable Variants listed in the table have been provided by the authors. No correlation between increased cancer incidence and lipoid proteinosis has been reported; however, evidence linking expression of ECM1 with aspects of malignancy has emerged as ECM1 is dysregulated in some carcinomas [ ## Molecular Pathogenesis Lipoid proteinosis (LP) is characterized by deposition of hyaline-like material in the larynx, oral cavity, skin, and internal organs and caused by pathogenic variants in Three transcripts of The ECM1 protein structure has four functional domains including a cysteine-free N-terminal segment, two tandem repeats, and a C-terminal segment. The tandem domains contain highly conserved sequence and numerous cysteine residues that are involved in protein-protein interactions and allow the ECM1 protein to function as a transport protein or to be involved in binding of growth or differentiation factors [ Notable Variants listed in the table have been provided by the authors. ## Cancer and Benign Tumors No correlation between increased cancer incidence and lipoid proteinosis has been reported; however, evidence linking expression of ECM1 with aspects of malignancy has emerged as ECM1 is dysregulated in some carcinomas [ ## Chapter Notes Leila Youssefian and Hassan Vahidnezhad contributed equally to this work. Carol Kelly assisted in manuscript preparation. 22 July 2021 (ha) Comprehensive update posted live 21 January 2016 (bp) Review posted live 28 July 2015 (ju) Original submission • 22 July 2021 (ha) Comprehensive update posted live • 21 January 2016 (bp) Review posted live • 28 July 2015 (ju) Original submission ## Author Notes Leila Youssefian and Hassan Vahidnezhad contributed equally to this work. ## Acknowledgments Carol Kelly assisted in manuscript preparation. ## Revision History 22 July 2021 (ha) Comprehensive update posted live 21 January 2016 (bp) Review posted live 28 July 2015 (ju) Original submission • 22 July 2021 (ha) Comprehensive update posted live • 21 January 2016 (bp) Review posted live • 28 July 2015 (ju) Original submission ## References ## Literature Cited Clinical manifestations of lipoid proteinosis a. Vesicles and hemorrhagic crusts and scars on the face b. Hyperkeratotic wart-like or nodular lesions on the fingers c. Reduced tongue movement due to thickening of the sub-lingual frenulum d, e. Papular thickening of the upper and lower eyelids, and moniliform blepharosis (beaded papules on the eyelid margins) f. Warty skin thickening and infiltration on the elbow g. Warty nodules over infiltrated plaques on knees h. Axial CT showing bilateral symmetric amygdalae calcifications	[ "PM Agredano, CM Del Barrio, MC Martinez, CA Cabrera. Intracranial calcifications associated with epilepsy: a case report of lipoid proteinosis.. Seizure. 2020;83:172-4", "I An, ME Güldür, M Aksoy, Y Yeşilova, M Ozturk. Histopathological findings in patients with lipoid proteinosis.. Turk J Dermatol. 2019;13:99", "MJ Belliveau, A Alkhotani, A Ali. Moniliform blepharosis of lipoid proteinosis.. JAMA Ophthalmol. 2015;133", "D Caccamo, A Jaen, M Telenta, E Varela, O Tiscornia. Lipoid proteinosis of the small bowel.. Arch Pathol Lab Med. 1994;118:572-4", "I. Chan. The role of extracellular matrix protein 1 in human skin.. Clin Exp Dermatol. 2004;29:52-6", "I Chan, L Liu, T Hamada, G Sethuraman, JA McGrath. The molecular basis of lipoid proteinosis: mutations in extracellular matrix protein 1.. Exp Dermatol. 2007;16:881-90", "I Chan, AP South, JA McGrath, N Oyama, BS Bhogal, MM Black, T Hamada. Rapid diagnosis of lipoid proteinosis using an anti-extracellular matrix protein 1 (ECM1) antibody.. J Dermatol Sci. 2004;35:151-3", "KG Claeys, LR Claes, JW Van Goethem, S Sercu, J Merregaert, J Lambert, EA Van Marck, PM Parizel, P De Jonghe. Epilepsy and migraine in a patient with Urbach-Wiethe disease.. Seizure. 2007;16:465-8", "J Custódio Lima, CK Nagasako, CG Montes, IH Barcelos, RB de Carvalho, MA Mesquita. Gastrointestinal involvement in lipoid proteinosis: a ten-year follow-up of a Brazilian female patient.. Case Rep Med. 2014;2014", "N Fujimoto, J Terlizzi, S Aho, R Brittingham, A Fertala, N Oyama, JA McGrath, J Uitto. Extracellular matrix protein 1 inhibits the activity of matrix metalloproteinase 9 through high-affinity protein/protein interactions.. Exp Dermatol. 2006;15:300-7", "N Fujimoto, J Terlizzi, R Brittingham, A Fertala, JA McGrath, J Uitto. Extracellular matrix protein 1 interacts with the domain III of fibulin-1C and 1D variants through its central tandem repeat 2.. Biochem Biophys Res Commun. 2005;333:1327-33", "P Gómez-Contreras, JM Ramiro-Díaz, A Sierra, C Stipp, FE Domann, RJ Weigel, G Lal. Extracellular matrix 1 (ECM1) regulates the actin cytoskeletal architecture of aggressive breast cancer cells in part via S100A4 and Rho-family GTPases.. Clin Exp Metastasis. 2017;34:37-49", "FG Gonçalves, MB de Melo, V del Matos, FR Barra, RE Figueroa. Amygdalae and striatum calcification in lipoid proteinosis.. AJNR Am J Neuroradiol. 2010;31:88-90", "T Hamada, WH McLean, M Ramsay, GH Ashton, A Nanda, T Jenkins, I Edelstein, AP South, O Bleck, V Wessagowit, R Mallipeddi, GE Orchard, H Wan, PJ Dopping-Hepenstal, JE Mellerio, NV Whittock, CS Munro, MA van Steensel, PM Steijlen, J Ni, L Zhang, T Hashimoto, RA Eady, JA McGrath. Lipoid proteinosis maps to 1q21 and is caused by mutations in the extracellular matrix protein 1 gene (ECM1).. Hum Mol Genet. 2002;11:833-40", "T Hamada, V Wessagowit, AP South, GH Ashton, I Chan, N Oyama, A Siriwattana, P Jewhasuchin, S Charuwichitratana, DM Thappa, B Jeevankumar, P Lenane, B Krafchik, K Kulthanan, H Shimizu, TI Kaya, ME Erdal, M Paradisi, AS Paller, M Seishima, T Hashimoto, JA McGrath. Extracellular matrix protein 1 gene (ECM1) mutations in lipoid proteinosis and genotype-phenotype correlation.. J Invest Dermatol. 2003;120:345-50", "T. Hamada. Lipoid proteinosis.. Clin Exp Dermatol. 2002;27:624-9", "A Hameed, M Nasir, M Ajmal, L Latif. Novel human pathological mutations. Gene symbol: ECM1. Disease: Lipoid Proteinosis.. Hum Genet. 2009;126:336", "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", "KM Lee, K Nam, S Oh, J Lim, RK Kim, D Shim, JH Choi, SJ Lee, JH Yu, JW Lee, SH Ahn, I Shin. ECM1 regulates tumor metastasis and CSC-like property through stabilization of β-catenin.. Oncogene. 2015b;34:6055-65", "MY Lee, HJ Wang, Y Han, Y Zhou, JH Zhao, LN Duo, C Feng, H Hua, HW Liu, ZM Lin, Y Yang. Lipoid proteinosis resulting from a large homozygous deletion affecting part of the ECM1 gene and adjacent long non-coding RNA.. Acta Derm Venereol. 2015a;95:608-10", "MJ Messina, G Nuzzaco, A Barbieri, M Scarlato, S Gerevini, V Martinelli, G Comi, M Sessa. Spontaneous intracerebral hemorrhage in Urbach-Wiethe disease.. Neurology. 2012;79:1740-1", "M Nasir, A Latif, M Ajmal, M Ismail, A. Hameed. A novel homozygous 62-bp insertion in ECM1 causes lipoid proteinosis in a multigeneration Pakistani family.. Br J Dermatol. 2009;161:688-90", "M Nasir, SB Rahman, CM Sieber, A Mir, A Latif, N Ahmad, SA Malik, A Hameed. Identification of recurrent c. 742G> T nonsense mutation in ECM1 in Pakistani families suffering from lipoid proteinosis.. Mol Biol Rep. 2014;41:2085-92", "HG Omrani, M Tajdini, B Ghelichnia, SM Hosseini, A Tafakhori, E Rahimian, V Aghamollaii. Should we think of Urbach–Wiethe disease in refractory epilepsy? Case report and review of the literature.. J Neurol Sci. 2012;320:149-52", "S Ravi Prakash, S Verma, MN Sumalatha, S Chattopadhyay. Oral manifestations of lipoid proteinosis: a case report and literature review.. Saudi Dent J. 2013;25:91-4", "MM Savage, DM Crockett, BF McCabe. Lipoid proteinosis of the larynx: a cause of voice change in the infant and young child.. Int J Pediatr Otorhinolaryngol. 1988;15:33-8", "M Siebert, HJ Markowitsch, P Bartel. Amygdala, affect and cognition: evidence from 10 patients with Urbach-Wiethe disease.. Brain. 2003;126:2627-37", "SS Steinhaeuser, E Morera, Z Budkova, A Schepsky, Q Wang, O Rolfsson, A Riedel, A Krueger, B Hilmarsdottir, GM Maelandsmo, B Valdimarsdottir. ECM1 secreted by HER2-overexpressing breast cancer cells promotes formation of a vascular niche accelerating cancer cell migration and invasion.. Lab Invest. 2020;100:928-44", "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", "HA Teive, E Ruschel, RP Munhoz. Spontaneous intracerebral hemorrhage in Urbach-Wiethe disease.. Neurology. 2013;80:1720-1", "HB Thornton, D Nel, D Thornton, J van Honk, GA Baker, DJ Stein. The neuropsychiatry and neuropsychology of lipoid proteinosis.. J Neuropsychiatry Clin Neurosci. 2008;20:86-92", "H Vahidnezhad, L Youssefian, A Tafakhori, Q Li, J Uitto, FV Rajabpour, M Pishnamazi, A Modabbernia, M Tabrizi. Lipoid proteinosis due to homozygous deletion mutation (c. 735delTG) in the ECM1 gene presents with seizures and hoarseness but no skin involvement.. Int J Dermatol Venereol. 2020;3:43-5", "W Van Hougenhouck-Tulleken, I Chan, T Hamada, H Thornton, T Jenkins, WH McLean, JA McGrath, M Ramsay. Clinical and molecular characterization of lipoid proteinosis in Namaqualand, South Africa.. Br J Dermatol. 2004;151:413-23", "L Wang, J Yu, J Ni, XM Xu, J Wang, H Ning, XF Pei, J Chen, S Yang, CB Underhill, L Liu, J Liekens, J Merregaert, L Zhang. Extracellular matrix protein 1 (ECM1) is over-expressed in malignant epithelial tumors.. Cancer Lett. 2003;200:57-67", "L Youssefian, H Vahidnezhad, M Daneshpazhooh, S Abdollahzadeh, H Talari, A Khoshnevisan, C Chams-Davatchi, R Mobasher, Q Li, J Uitto, S Akhondzadeh, M. Tabrizi. Lipoid proteinosis: phenotypic heterogeneity in Iranian families with c.507delT mutation in ECM1.. Exp Dermatol. 2015;24:220-2", "R Zhang, Y Liu, Y Xue, Y Wang, X Wang, S Shi. Cai T1, Wang Q. Treatment of lipoid proteinosis due to the p.C220G mutation in ECM1, a major allele in Chinese patients.. J Transl Med. 2014;12:85" ]	21/1/2016	22/7/2021		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
lms	lms	[ "Lehman Syndrome", "Lehman Syndrome", "Neurogenic locus notch homolog protein 3", "NOTCH3", "NOTCH3-Related Lateral Meningocele Syndrome" ]		Resham Ejaz, Melissa Carter, Karen Gripp	Summary The diagnosis of All probands reported to date with	## Diagnosis Formal diagnostic clinical criteria for 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 Typically, 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; however, to date, such variants have not been identified as a cause of this disorder. For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. ## Suggestive Findings ## 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 Typically, 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; however, to date, such variants have not been identified as a cause of this disorder. For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. ## Option 1 Typically, 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; however, to date, such variants have not been identified as a cause of this disorder. For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. ## Clinical Characteristics To date, 11 individuals have been identified with a pathogenic variant in A high nasal voice is noted in many individuals [ Many individuals have skeletal changes including scoliosis, kyphosis, vertebral fusion, scalloping of vertebrae, and wormian bones [ No genotype-phenotype correlations have been identified. Penetrance appears to be complete but data are limited. The title of this ## Clinical Description To date, 11 individuals have been identified with a pathogenic variant in A high nasal voice is noted in many individuals [ Many individuals have skeletal changes including scoliosis, kyphosis, vertebral fusion, scalloping of vertebrae, and wormian bones [ ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been identified. ## Penetrance Penetrance appears to be complete but data are limited. ## Nomenclature The title of this ## Prevalence ## Genetically Related (Allelic) Disorders See AD = autosomal dominant; CADASIL = ## Differential Diagnosis The differential diagnosis for Genes and Disorders of Interest in the Differential Diagnosis of AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance NS is most often inherited in an autosomal dominant manner. NS caused by pathogenic variants in ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with Spine MRI to assess for meningoceles Neurosurgical assessment to evaluate effect of lateral spinal meningocele size & location on neurologic function 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. GERD = gastroesophageal reflux disease; MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse The following medical issues are managed in a routine manner: cleft palate, cardiovascular issues, genitourinary abnormalities, ophthalmologic issues, hearing loss, feeding difficulties. Treatment of Manifestations in Individuals with There is no standard operative mgmt of lateral spinal meningoceles [ Symptomatic treatment of neurologic sequelæ (e.g., neurogenic bladder, paresthesias, back pain, &/or paraparesis) as needed Surgical intervention is generally avoided but may be necessary due to neurologic manifestations secondary to meningocele size & location [ 1 person benefited from CSF diversion w/a VP shunt for symptomatic relief of thoracolumbar meningocele [ When required, surgical approach is individualized & can incl laminectomy for smaller meningoceles, costotransversectomy for larger meningoceles. PT to ↓ risk for joint subluxation & dislocation Mgmt by specialists in chronic pain mgmt or rehab medicine as needed OT = occupational therapy; PT = physical therapy There are no established surveillance guidelines for lateral spinal meningoceles. Close clinical and radiographic monitoring is recommended for progressive neurologic symptoms and meningocele size enlargement [ Ongoing monitoring by the appropriate subspecialists for developmental, musculoskeletal, cardiovascular, genitourinary, gastrointestinal, ophthalmologic, and/or hearing issues is indicated. See Search • Spine MRI to assess for meningoceles • Neurosurgical assessment to evaluate effect of lateral spinal meningocele size & location on neurologic function • 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. • There is no standard operative mgmt of lateral spinal meningoceles [ • Symptomatic treatment of neurologic sequelæ (e.g., neurogenic bladder, paresthesias, back pain, &/or paraparesis) as needed • Surgical intervention is generally avoided but may be necessary due to neurologic manifestations secondary to meningocele size & location [ • 1 person benefited from CSF diversion w/a VP shunt for symptomatic relief of thoracolumbar meningocele [ • When required, surgical approach is individualized & can incl laminectomy for smaller meningoceles, costotransversectomy for larger meningoceles. • PT to ↓ risk for joint subluxation & dislocation • Mgmt by specialists in chronic pain mgmt or rehab medicine as needed ## 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 Spine MRI to assess for meningoceles Neurosurgical assessment to evaluate effect of lateral spinal meningocele size & location on neurologic function 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. GERD = gastroesophageal reflux disease; MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Spine MRI to assess for meningoceles • Neurosurgical assessment to evaluate effect of lateral spinal meningocele size & location on neurologic function • 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 The following medical issues are managed in a routine manner: cleft palate, cardiovascular issues, genitourinary abnormalities, ophthalmologic issues, hearing loss, feeding difficulties. Treatment of Manifestations in Individuals with There is no standard operative mgmt of lateral spinal meningoceles [ Symptomatic treatment of neurologic sequelæ (e.g., neurogenic bladder, paresthesias, back pain, &/or paraparesis) as needed Surgical intervention is generally avoided but may be necessary due to neurologic manifestations secondary to meningocele size & location [ 1 person benefited from CSF diversion w/a VP shunt for symptomatic relief of thoracolumbar meningocele [ When required, surgical approach is individualized & can incl laminectomy for smaller meningoceles, costotransversectomy for larger meningoceles. PT to ↓ risk for joint subluxation & dislocation Mgmt by specialists in chronic pain mgmt or rehab medicine as needed OT = occupational therapy; PT = physical therapy • There is no standard operative mgmt of lateral spinal meningoceles [ • Symptomatic treatment of neurologic sequelæ (e.g., neurogenic bladder, paresthesias, back pain, &/or paraparesis) as needed • Surgical intervention is generally avoided but may be necessary due to neurologic manifestations secondary to meningocele size & location [ • 1 person benefited from CSF diversion w/a VP shunt for symptomatic relief of thoracolumbar meningocele [ • When required, surgical approach is individualized & can incl laminectomy for smaller meningoceles, costotransversectomy for larger meningoceles. • PT to ↓ risk for joint subluxation & dislocation • Mgmt by specialists in chronic pain mgmt or rehab medicine as needed ## Surveillance There are no established surveillance guidelines for lateral spinal meningoceles. Close clinical and radiographic monitoring is recommended for progressive neurologic symptoms and meningocele size enlargement [ Ongoing monitoring by the appropriate subspecialists for developmental, musculoskeletal, cardiovascular, genitourinary, gastrointestinal, ophthalmologic, and/or hearing issues is indicated. ## 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 The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte 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 If the If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband is presumed to be low but slightly 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 the parents of affected individuals and young adults who are 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. • 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 • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If a parent of the proband has the • If the • If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband is presumed to be low but slightly 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 the parents of affected individuals and young adults who are affected. ## 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 The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte 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 If the If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband is presumed to be low but slightly greater than that of the general population because of the theoretic possibility of parental germline mosaicism. • 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 • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If a parent of the proband has the • If the • If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband is presumed to be low but slightly greater than that of the general population because of the theoretic 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 the parents of affected individuals and 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 the parents of affected individuals and 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. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • ## Molecular Genetics NOTCH3-Related Lateral Meningocele Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for NOTCH3-Related Lateral Meningocele Syndrome ( In In all individuals with ## Molecular Pathogenesis In In all individuals with ## Chapter Notes Web page: We thank the individuals with 5 May 2022 (ha) Comprehensive update posted live 23 June 2016 (bp) Review posted live 19 February 2016 (re) Original submission • 5 May 2022 (ha) Comprehensive update posted live • 23 June 2016 (bp) Review posted live • 19 February 2016 (re) Original submission ## Author Notes Web page: ## Acknowledgments We thank the individuals with ## Revision History 5 May 2022 (ha) Comprehensive update posted live 23 June 2016 (bp) Review posted live 19 February 2016 (re) Original submission • 5 May 2022 (ha) Comprehensive update posted live • 23 June 2016 (bp) Review posted live • 19 February 2016 (re) Original submission ## References ## Literature Cited Numerous lateral meningoceles (see arrows) protrude through the thoracic foramina in a sagittal view (a) and through the lumbar foramina in a sagittal (b) and axial (c) view. The curved arrow in (a) shows a meningocele protruding from the middle cranial fossa. Photographs of individuals with A-D. Patient 1 at age 24 years: Facial features with arched eyebrows, ptosis, flat midface, thin upper lip, low-set and posteriorly angulated ears, and low posterior hairline Hands with short and wide distal second and third fingers (pseudo-clubbing) E-G. Patient 20 at ages 13 years (E) and four years (F,G): Facial features at age 13 years similar to those at age four years with coarse and curly hair, tall forehead, high arched brows, ptosis, midfacial hypoplasia, long flat philtrum and thin upper lip, micrognathia, and low-set ears H-I. Patient 26 at age six years: Facial features showing a high forehead, shallow supraorbital ridges with arched eyebrows, ptosis, flat midface, thin and tented upper lip, low-set and posteriorly angulated ears, low posterior hairline, and a submandibular scar with keloid formation Reproduced with permission from	[]	23/6/2016	5/5/2022		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
lns	lns	[ "HGprt Deficiency", "HPRT Deficiency", "Hypoxanthine-Guanine Phosphoribosyltransferase Deficiency", "HGprt Deficiency", "HPRT Deficiency", "Hypoxanthine-Guanine Phosphoribosyltransferase Deficiency", "Lesch-Nyhan Disease (LND)", "HPRT1-Related Neurologic Dysfunction (HND)", "HPRT1-Related Hyperuricemia (HRH)", "Hypoxanthine-guanine phosphoribosyltransferase", "HPRT1", "HPRT1 Disorders" ]		Hyder A Jinnah	Summary The diagnosis of an	Lesch-Nyhan disease (LND) For synonyms and outdated names see • Lesch-Nyhan disease (LND) ## Diagnosis ID = intellectual disability; NA = not applicable; NDD = neurodevelopmental delay Hyperuricemia is often evident. Serum uric acid concentration greater than 8 mg/dL defines hyperuricemia in adults; however, the upper limit of normal, which varies by age, is lower in children. The urate:creatinine ratio, calculated from the concentration of uric acid and creatinine in a spot urine, provides a reliable measure of uric acid overproduction. A urate:creatinine ratio greater than two is characteristic for all Uric acid kidney stones or uric acid crystals present in the urine. Note: Absence of a known family history does not preclude the diagnosis of an Note: Identification of a hemizygous Molecular genetic testing can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. For an introduction to multigene panels click If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used for See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Individuals with Lesch-Nyhan disease tend to have residual enzyme levels lower than 2%. Individuals with Individuals with • Hyperuricemia is often evident. Serum uric acid concentration greater than 8 mg/dL defines hyperuricemia in adults; however, the upper limit of normal, which varies by age, is lower in children. • The urate:creatinine ratio, calculated from the concentration of uric acid and creatinine in a spot urine, provides a reliable measure of uric acid overproduction. A urate:creatinine ratio greater than two is characteristic for all • Uric acid kidney stones or uric acid crystals present in the urine. • If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. • For an introduction to multigene panels click • If exome sequencing is not diagnostic, • For an introduction to comprehensive genomic testing click • Individuals with Lesch-Nyhan disease tend to have residual enzyme levels lower than 2%. • Individuals with • Individuals with ## Suggestive Findings ID = intellectual disability; NA = not applicable; NDD = neurodevelopmental delay Hyperuricemia is often evident. Serum uric acid concentration greater than 8 mg/dL defines hyperuricemia in adults; however, the upper limit of normal, which varies by age, is lower in children. The urate:creatinine ratio, calculated from the concentration of uric acid and creatinine in a spot urine, provides a reliable measure of uric acid overproduction. A urate:creatinine ratio greater than two is characteristic for all Uric acid kidney stones or uric acid crystals present in the urine. Note: Absence of a known family history does not preclude the diagnosis of an • Hyperuricemia is often evident. Serum uric acid concentration greater than 8 mg/dL defines hyperuricemia in adults; however, the upper limit of normal, which varies by age, is lower in children. • The urate:creatinine ratio, calculated from the concentration of uric acid and creatinine in a spot urine, provides a reliable measure of uric acid overproduction. A urate:creatinine ratio greater than two is characteristic for all • Uric acid kidney stones or uric acid crystals present in the urine. ## Establishing the Diagnosis Note: Identification of a hemizygous Molecular genetic testing can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. For an introduction to multigene panels click If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used for See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Individuals with Lesch-Nyhan disease tend to have residual enzyme levels lower than 2%. Individuals with Individuals with • If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. • For an introduction to multigene panels click • If exome sequencing is not diagnostic, • For an introduction to comprehensive genomic testing click • Individuals with Lesch-Nyhan disease tend to have residual enzyme levels lower than 2%. • Individuals with • Individuals with ## Molecular Genetic Testing Molecular genetic testing can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. For an introduction to multigene panels click If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used for See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and 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. • If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. • For an introduction to multigene panels click • If exome sequencing is not diagnostic, • For an introduction to comprehensive genomic testing click ## Biochemical Testing Individuals with Lesch-Nyhan disease tend to have residual enzyme levels lower than 2%. Individuals with Individuals with • Individuals with Lesch-Nyhan disease tend to have residual enzyme levels lower than 2%. • Individuals with • Individuals with ## Clinical Characteristics Pathogenic variants in If untreated, overproduction of uric acid leads to precipitation of uric acid crystals in the urinary system. Crystals appear as an orange sandy material in the diapers. Larger stones may appear as "gravel" in diapers. Larger stones may be difficult to pass. Stones may cause hematuria and increase the risk for urinary tract infections. While crystals or gravel in the diaper may be an early feature, their significance is often not appreciated for years. Another potential consequence of untreated overproduction of uric acid is gouty arthritis caused by precipitation of uric acid in the joints. Complex precipitates mixed with proteins may form visible swellings known as tophi. Gout is uncommon in children and typically develops long after other manifestations are present. If overproduction of uric acid is not treated, renal failure is common. Some individuals develop renal failure even with treatment. LND is characterized by uric acid overproduction, motor dysfunction resembling severe cerebral palsy, intellectual disability, and self-injurious behavior. Within the first few years of life, abnormal movements emerge. The characteristic feature in all individuals is severe action dystonia [ The motor disability is sufficiently severe that children with LND do not walk and are usually confined to a wheelchair. Most need assistance with feeding and hygiene. In general, individuals with LND do not have severe intellectual disability. Formal psychological testing typically yields scores in the mild-to-moderate range of dysfunction. Self injury most often involves biting of the fingers, hands, lips, and cheeks [ In addition to self-injurious behavior, affected individuals often have other difficult behaviors including impulsiveness, aggressiveness, oppositional defiance, recurrent vomiting, spitting at others, and coprolalia. Testicular atrophy with delayed growth and puberty is very common. Macrocytic anemia unresponsive to vitamin supplements is very common, but does not usually require treatment [ Neuroimaging often reveals nonspecific changes of atrophy in the central nervous system with reduced cerebral volume and reduced caudate nucleus volume [ Approximately one third have seizures [ Approximately one third require gastrostomy because of dysphagia and/or recurrent aspiration [ Uncommon but particularly troublesome problems may include respiratory irregularities such as recurrent unexplained apnea [ The most common causes of death include pulmonary failure (from pneumonia or recurrent aspiration from dysphagia), renal failure, or sepsis from different causes. Sudden unexplained death in an otherwise well-tended individual may also occur [ HND is similar to LND, except the neurologic features are often less severe and self-injurious behavior does not occur. The spectrum of the severity of neurologic features in HND is broad. The most severely affected individuals are neurologically indistinguishable from those with LND; the least severely affected individuals may have only minor clumsiness with fine motor activity or relatively minor cognitive deficits [ The severity and spectrum of problems related to uric acid are indistinguishable from LND. Macrocytic anemia is common, but many of the other problems such as growth delay, dysphagia, seizures, and sudden death are less common. Life span is longer than in LND and may be normal for the least severely affected. HRH is similar to HND, except that clinically obvious neurologic deficits do not occur. While mild clumsiness may occur, clinically overt problems are not usually apparent and are only evident on detailed neurologic examination [ Mild cognitive deficits, especially problems with attention, are common but are not usually identified without formal neuropsychological testing [ The severity and spectrum of problems related to uric acid are indistinguishable from LND and HND. Life span is normal. Heterozygous females are virtually always clinically normal without evidence for motor or cognitive deficits. Production of uric acid may be slightly elevated, and some heterozygous females may develop gout when they are older [ Rarely the LND phenotype has been observed in heterozygous females as the result of skewed (nonrandom) X-chromosome inactivation of the chromosome bearing the normal Presence of biallelic Because the amount of residual HGprt enzyme activity correlates with the severity of the phenotype [ LND is associated with complete or near-complete loss of enzyme activity from the following types of Loss-of-function variants such as nonsense variants or frameshift variants due to small or large insertions or deletions Missense variants with absent or near-absent enzyme activity. These variants may reduce enzyme activity through different mechanisms including impaired kinetic properties, impaired dimerization of HGprt subunits required for functional activity, and poor protein stability. Most (but not all) splice site variants that result in major changes in the protein coding region HND is associated with Most HND-causing variants are missense variants. Occasionally variants affect splice sites, leaving a small proportion of correctly spliced transcripts. Rare variants are duplications, which may rarely revert to normal to varying degrees in different tissues, producing somatic mosaicism with varying residual HGprt enzyme activity [ HRH is associated with missense Most individuals with the same Splice site variants have been associated with variable phenotypes, sometimes in the same family, presumably due to differences in splicing fidelity. Some missense variants have been associated with variable phenotypes, sometimes in the same family, presumably due to differences in protein stability [ Although LND may also be referred to as Lesch-Nyhan syndrome, Lesch-Nyhan disease is the more accurate term because the cause of phenotypic elements that constitute the disorder is known. HRH may also be referred to as Kelley-Seegmiller syndrome. The prevalence of LND is approximately 1:380,000. The prevalence of the milder phenotypes (HND and HRH) is not well studied, but they appear to be less common than LND. • Testicular atrophy with delayed growth and puberty is very common. • Macrocytic anemia unresponsive to vitamin supplements is very common, but does not usually require treatment [ • Neuroimaging often reveals nonspecific changes of atrophy in the central nervous system with reduced cerebral volume and reduced caudate nucleus volume [ • Approximately one third have seizures [ • Approximately one third require gastrostomy because of dysphagia and/or recurrent aspiration [ • Uncommon but particularly troublesome problems may include respiratory irregularities such as recurrent unexplained apnea [ • Loss-of-function variants such as nonsense variants or frameshift variants due to small or large insertions or deletions • Missense variants with absent or near-absent enzyme activity. These variants may reduce enzyme activity through different mechanisms including impaired kinetic properties, impaired dimerization of HGprt subunits required for functional activity, and poor protein stability. • Most (but not all) splice site variants that result in major changes in the protein coding region • Most HND-causing variants are missense variants. • Occasionally variants affect splice sites, leaving a small proportion of correctly spliced transcripts. • Rare variants are duplications, which may rarely revert to normal to varying degrees in different tissues, producing somatic mosaicism with varying residual HGprt enzyme activity [ • Most individuals with the same • Splice site variants have been associated with variable phenotypes, sometimes in the same family, presumably due to differences in splicing fidelity. • Some missense variants have been associated with variable phenotypes, sometimes in the same family, presumably due to differences in protein stability [ ## Clinical Description Pathogenic variants in If untreated, overproduction of uric acid leads to precipitation of uric acid crystals in the urinary system. Crystals appear as an orange sandy material in the diapers. Larger stones may appear as "gravel" in diapers. Larger stones may be difficult to pass. Stones may cause hematuria and increase the risk for urinary tract infections. While crystals or gravel in the diaper may be an early feature, their significance is often not appreciated for years. Another potential consequence of untreated overproduction of uric acid is gouty arthritis caused by precipitation of uric acid in the joints. Complex precipitates mixed with proteins may form visible swellings known as tophi. Gout is uncommon in children and typically develops long after other manifestations are present. If overproduction of uric acid is not treated, renal failure is common. Some individuals develop renal failure even with treatment. LND is characterized by uric acid overproduction, motor dysfunction resembling severe cerebral palsy, intellectual disability, and self-injurious behavior. Within the first few years of life, abnormal movements emerge. The characteristic feature in all individuals is severe action dystonia [ The motor disability is sufficiently severe that children with LND do not walk and are usually confined to a wheelchair. Most need assistance with feeding and hygiene. In general, individuals with LND do not have severe intellectual disability. Formal psychological testing typically yields scores in the mild-to-moderate range of dysfunction. Self injury most often involves biting of the fingers, hands, lips, and cheeks [ In addition to self-injurious behavior, affected individuals often have other difficult behaviors including impulsiveness, aggressiveness, oppositional defiance, recurrent vomiting, spitting at others, and coprolalia. Testicular atrophy with delayed growth and puberty is very common. Macrocytic anemia unresponsive to vitamin supplements is very common, but does not usually require treatment [ Neuroimaging often reveals nonspecific changes of atrophy in the central nervous system with reduced cerebral volume and reduced caudate nucleus volume [ Approximately one third have seizures [ Approximately one third require gastrostomy because of dysphagia and/or recurrent aspiration [ Uncommon but particularly troublesome problems may include respiratory irregularities such as recurrent unexplained apnea [ The most common causes of death include pulmonary failure (from pneumonia or recurrent aspiration from dysphagia), renal failure, or sepsis from different causes. Sudden unexplained death in an otherwise well-tended individual may also occur [ HND is similar to LND, except the neurologic features are often less severe and self-injurious behavior does not occur. The spectrum of the severity of neurologic features in HND is broad. The most severely affected individuals are neurologically indistinguishable from those with LND; the least severely affected individuals may have only minor clumsiness with fine motor activity or relatively minor cognitive deficits [ The severity and spectrum of problems related to uric acid are indistinguishable from LND. Macrocytic anemia is common, but many of the other problems such as growth delay, dysphagia, seizures, and sudden death are less common. Life span is longer than in LND and may be normal for the least severely affected. HRH is similar to HND, except that clinically obvious neurologic deficits do not occur. While mild clumsiness may occur, clinically overt problems are not usually apparent and are only evident on detailed neurologic examination [ Mild cognitive deficits, especially problems with attention, are common but are not usually identified without formal neuropsychological testing [ The severity and spectrum of problems related to uric acid are indistinguishable from LND and HND. Life span is normal. Heterozygous females are virtually always clinically normal without evidence for motor or cognitive deficits. Production of uric acid may be slightly elevated, and some heterozygous females may develop gout when they are older [ Rarely the LND phenotype has been observed in heterozygous females as the result of skewed (nonrandom) X-chromosome inactivation of the chromosome bearing the normal Presence of biallelic • Testicular atrophy with delayed growth and puberty is very common. • Macrocytic anemia unresponsive to vitamin supplements is very common, but does not usually require treatment [ • Neuroimaging often reveals nonspecific changes of atrophy in the central nervous system with reduced cerebral volume and reduced caudate nucleus volume [ • Approximately one third have seizures [ • Approximately one third require gastrostomy because of dysphagia and/or recurrent aspiration [ • Uncommon but particularly troublesome problems may include respiratory irregularities such as recurrent unexplained apnea [ ## Affected Males Pathogenic variants in If untreated, overproduction of uric acid leads to precipitation of uric acid crystals in the urinary system. Crystals appear as an orange sandy material in the diapers. Larger stones may appear as "gravel" in diapers. Larger stones may be difficult to pass. Stones may cause hematuria and increase the risk for urinary tract infections. While crystals or gravel in the diaper may be an early feature, their significance is often not appreciated for years. Another potential consequence of untreated overproduction of uric acid is gouty arthritis caused by precipitation of uric acid in the joints. Complex precipitates mixed with proteins may form visible swellings known as tophi. Gout is uncommon in children and typically develops long after other manifestations are present. If overproduction of uric acid is not treated, renal failure is common. Some individuals develop renal failure even with treatment. ## Lesch-Nyhan Disease (LND) LND is characterized by uric acid overproduction, motor dysfunction resembling severe cerebral palsy, intellectual disability, and self-injurious behavior. Within the first few years of life, abnormal movements emerge. The characteristic feature in all individuals is severe action dystonia [ The motor disability is sufficiently severe that children with LND do not walk and are usually confined to a wheelchair. Most need assistance with feeding and hygiene. In general, individuals with LND do not have severe intellectual disability. Formal psychological testing typically yields scores in the mild-to-moderate range of dysfunction. Self injury most often involves biting of the fingers, hands, lips, and cheeks [ In addition to self-injurious behavior, affected individuals often have other difficult behaviors including impulsiveness, aggressiveness, oppositional defiance, recurrent vomiting, spitting at others, and coprolalia. Testicular atrophy with delayed growth and puberty is very common. Macrocytic anemia unresponsive to vitamin supplements is very common, but does not usually require treatment [ Neuroimaging often reveals nonspecific changes of atrophy in the central nervous system with reduced cerebral volume and reduced caudate nucleus volume [ Approximately one third have seizures [ Approximately one third require gastrostomy because of dysphagia and/or recurrent aspiration [ Uncommon but particularly troublesome problems may include respiratory irregularities such as recurrent unexplained apnea [ The most common causes of death include pulmonary failure (from pneumonia or recurrent aspiration from dysphagia), renal failure, or sepsis from different causes. Sudden unexplained death in an otherwise well-tended individual may also occur [ • Testicular atrophy with delayed growth and puberty is very common. • Macrocytic anemia unresponsive to vitamin supplements is very common, but does not usually require treatment [ • Neuroimaging often reveals nonspecific changes of atrophy in the central nervous system with reduced cerebral volume and reduced caudate nucleus volume [ • Approximately one third have seizures [ • Approximately one third require gastrostomy because of dysphagia and/or recurrent aspiration [ • Uncommon but particularly troublesome problems may include respiratory irregularities such as recurrent unexplained apnea [ HND is similar to LND, except the neurologic features are often less severe and self-injurious behavior does not occur. The spectrum of the severity of neurologic features in HND is broad. The most severely affected individuals are neurologically indistinguishable from those with LND; the least severely affected individuals may have only minor clumsiness with fine motor activity or relatively minor cognitive deficits [ The severity and spectrum of problems related to uric acid are indistinguishable from LND. Macrocytic anemia is common, but many of the other problems such as growth delay, dysphagia, seizures, and sudden death are less common. Life span is longer than in LND and may be normal for the least severely affected. HRH is similar to HND, except that clinically obvious neurologic deficits do not occur. While mild clumsiness may occur, clinically overt problems are not usually apparent and are only evident on detailed neurologic examination [ Mild cognitive deficits, especially problems with attention, are common but are not usually identified without formal neuropsychological testing [ The severity and spectrum of problems related to uric acid are indistinguishable from LND and HND. Life span is normal. ## Heterozygous Females Heterozygous females are virtually always clinically normal without evidence for motor or cognitive deficits. Production of uric acid may be slightly elevated, and some heterozygous females may develop gout when they are older [ Rarely the LND phenotype has been observed in heterozygous females as the result of skewed (nonrandom) X-chromosome inactivation of the chromosome bearing the normal Presence of biallelic ## Genotype-Phenotype Correlations Because the amount of residual HGprt enzyme activity correlates with the severity of the phenotype [ LND is associated with complete or near-complete loss of enzyme activity from the following types of Loss-of-function variants such as nonsense variants or frameshift variants due to small or large insertions or deletions Missense variants with absent or near-absent enzyme activity. These variants may reduce enzyme activity through different mechanisms including impaired kinetic properties, impaired dimerization of HGprt subunits required for functional activity, and poor protein stability. Most (but not all) splice site variants that result in major changes in the protein coding region HND is associated with Most HND-causing variants are missense variants. Occasionally variants affect splice sites, leaving a small proportion of correctly spliced transcripts. Rare variants are duplications, which may rarely revert to normal to varying degrees in different tissues, producing somatic mosaicism with varying residual HGprt enzyme activity [ HRH is associated with missense Most individuals with the same Splice site variants have been associated with variable phenotypes, sometimes in the same family, presumably due to differences in splicing fidelity. Some missense variants have been associated with variable phenotypes, sometimes in the same family, presumably due to differences in protein stability [ • Loss-of-function variants such as nonsense variants or frameshift variants due to small or large insertions or deletions • Missense variants with absent or near-absent enzyme activity. These variants may reduce enzyme activity through different mechanisms including impaired kinetic properties, impaired dimerization of HGprt subunits required for functional activity, and poor protein stability. • Most (but not all) splice site variants that result in major changes in the protein coding region • Most HND-causing variants are missense variants. • Occasionally variants affect splice sites, leaving a small proportion of correctly spliced transcripts. • Rare variants are duplications, which may rarely revert to normal to varying degrees in different tissues, producing somatic mosaicism with varying residual HGprt enzyme activity [ • Most individuals with the same • Splice site variants have been associated with variable phenotypes, sometimes in the same family, presumably due to differences in splicing fidelity. • Some missense variants have been associated with variable phenotypes, sometimes in the same family, presumably due to differences in protein stability [ ## Nomenclature Although LND may also be referred to as Lesch-Nyhan syndrome, Lesch-Nyhan disease is the more accurate term because the cause of phenotypic elements that constitute the disorder is known. HRH may also be referred to as Kelley-Seegmiller syndrome. ## Prevalence The prevalence of LND is approximately 1:380,000. The prevalence of the milder phenotypes (HND and HRH) is not well studied, but they appear to be less common than LND. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The index of suspicion is raised when developmental delay is associated with evidence of overproduction of uric acid, such as hyperuricemia, uric acid nephrolithiasis or crystals in the urine, or gouty arthritis. LND is first suspected when self-injurious behavior emerges. However, self-injurious behaviors occur in other conditions, including nonspecific intellectual disability, autism spectrum disorder, Tourette syndrome, ## Management To establish the extent of disease and the needs in an individual diagnosed with an Recommended Evaluations Following Initial Diagnosis in Individuals with Any renal stones. Note: Uric acid stones are radiolucent & may not appear on std x-rays. Any additional renal pathology (e.g., nephrocalcinosis, dystrophy). Gouty arthritis; Any tophaceous deposits. Info on nature, MOI, & implications of HRH to help make informed medical & personal decisions; Risk assessment & testing options to clarify genetic status of family members. BUN = blood urea nitrogen; HRH = Additional Recommended Evaluations Following Initial Diagnosis in Individuals with Neurologic eval Developmental eval PT/rehab eval PT/OT eval Motor disorder; Contractures (& if present, address); Dysarthria; History of seizures; ADL. Cognitive abilities & need for intervention; Any behavioral problems. Social worker interventions; Home nursing referral. ADL = activities of daily living; HND = Additional Recommended Evaluations Following Initial Diagnosis in Individuals with Poorly controlled self injury leads to multiple scars. Injuries may become infected or life threatening. Assess for oppositional defiant & other difficult behaviors. Provide counseling to therapists & teachers re mgmt of difficult behaviors. Assess for occult biting of oral mucosa & establish plan for tooth extraction when needed. >50% of all persons may need dental extraction because of self biting. LND = Lesch-Nyhan disease Following initial evaluations ( A multidisciplinary team may be needed. Depending on needs, this team may require specialists in medical genetics, neurology, behavioral management, developmental pediatrics, physical medicine and rehabilitation, physical therapy, occupational therapy, speech-language pathology, dentistry, and nephrology. Treatment of Manifestations in Individuals with Allopurinol most commonly used; febuxostat in case of allopurinol hypersensitivity Treatment required to ↓ risk for nephropathy, gouty arthritis, & tophi Titrate to maintain uric acid levels w/in normal limits. Avoid suppressing uric acid below normal limits because this ↑ risk of xanthine stones. Treatment ↓ risk of renal complications. Avoid dehydration, which concentrates purine metabolites in urinary system. Renal insufficiency or failure may occur despite medical therapy. When gouty arthritis occurs even w/treatment, consider compliance or insufficient hydration. May be painful when they erode overlying skin or underlying tissues; May become infected. Folate & B Treatment often is not needed because problem does not produce disability. HRH = Additional Treatments for Individuals with No medication reliably controls dystonia in HND. Antispasticity agents may be useful for spasticity. Cognitive problems may not be apparent w/o neuropsychological testing. Problems w/attention are common & create learning disability. HND = Additional Treatments for Individuals with Required by virtually all persons at some point; often required daily LND is exempt from laws that prevent use of restraints for extended periods. Negative reinforcement methods (punishment) worsen behavior & should not be used. Extinction methods work best, & require special expertise to implement. No medications reliably control self injury in LND. Benzodiazepines often used to ↓ anxiety Neuroleptics may worsen the dystonia. Tooth & mouth guards rarely reliable Dental extraction required in the majority LND = Lesch-Nyhan disease 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. Similarly, new or worsening neurologic problems are not expected over time [ The behavioral phenotype may wax and wane in severity over the years. Sudden worsening occurs with stress, for example relating to the pain of a kidney stone or change in social environment. In very young children with HND, self-injurious behavior may emerge, leading to reclassification of the diagnosis to LND. This behavior typically emerges between age two and four years but may be delayed until the teenage years. Recommended Surveillance for Individuals with Monitor 3-6x/yr during allopurinol titration. Annual assessments are sufficient after stable dose is achieved. Urinary system stones if clinically suspected; Evidence of worsening renal function. BUN = blood urea nitrogen; HRH = Additional Recommended Surveillance for Individuals with DD = developmental delay; HND = Additional Recommended Surveillance for Individuals with LND = Lesch-Nyhan disease Avoid the following: Probenecid and other drugs that reduce serum uric acid concentration by increasing renal excretion of uric acid; these drugs increase the risk of precipitation of uric acid in the urinary system and may cause acute renal failure. Certain chemotherapy agents, such as methotrexate, that block synthesis or use of purines. Individuals with all Periods of relative dehydration because they concentrate purine metabolites in the urinary system and increase the risk for renal stones or urate nephropathy It is appropriate to clarify the status of males at risk for See Numerous small-scale studies have reported benefits from a wide array of therapies including various types of mouth guards and dental appliances, deep brain stimulation, bone marrow transplantation, gabapentin, carbamazepine, S-adenosylmethionine, risperidone, and others. In all instances, follow-up experiences have not confirmed a significant long-term benefit. Because of their follow-on nature and frequent negative outcome, these attempts to confirm benefits often are not published. However, many families post their experience online using social media and, by searching these posts, the clinician can get a good feel for the likelihood that an experimental therapy will have a positive (or negative) impact on the affected individual and their family [ Search • Any renal stones. Note: Uric acid stones are radiolucent & may not appear on std x-rays. • Any additional renal pathology (e.g., nephrocalcinosis, dystrophy). • Gouty arthritis; • Any tophaceous deposits. • Info on nature, MOI, & implications of HRH to help make informed medical & personal decisions; • Risk assessment & testing options to clarify genetic status of family members. • Neurologic eval • Developmental eval • PT/rehab eval • PT/OT eval • Motor disorder; • Contractures (& if present, address); • Dysarthria; • History of seizures; • ADL. • Cognitive abilities & need for intervention; • Any behavioral problems. • Social worker interventions; • Home nursing referral. • Poorly controlled self injury leads to multiple scars. • Injuries may become infected or life threatening. • Assess for oppositional defiant & other difficult behaviors. • Provide counseling to therapists & teachers re mgmt of difficult behaviors. • Assess for occult biting of oral mucosa & establish plan for tooth extraction when needed. • >50% of all persons may need dental extraction because of self biting. • Allopurinol most commonly used; febuxostat in case of allopurinol hypersensitivity • Treatment required to ↓ risk for nephropathy, gouty arthritis, & tophi • Titrate to maintain uric acid levels w/in normal limits. • Avoid suppressing uric acid below normal limits because this ↑ risk of xanthine stones. • Treatment ↓ risk of renal complications. • Avoid dehydration, which concentrates purine metabolites in urinary system. • Renal insufficiency or failure may occur despite medical therapy. • When gouty arthritis occurs even w/treatment, consider compliance or insufficient hydration. • May be painful when they erode overlying skin or underlying tissues; • May become infected. • Folate & B • Treatment often is not needed because problem does not produce disability. • No medication reliably controls dystonia in HND. • Antispasticity agents may be useful for spasticity. • Cognitive problems may not be apparent w/o neuropsychological testing. • Problems w/attention are common & create learning disability. • Required by virtually all persons at some point; often required daily • LND is exempt from laws that prevent use of restraints for extended periods. • Negative reinforcement methods (punishment) worsen behavior & should not be used. • Extinction methods work best, & require special expertise to implement. • No medications reliably control self injury in LND. • Benzodiazepines often used to ↓ anxiety • Neuroleptics may worsen the dystonia. • Tooth & mouth guards rarely reliable • Dental extraction required in the majority • Monitor 3-6x/yr during allopurinol titration. • Annual assessments are sufficient after stable dose is achieved. • Urinary system stones if clinically suspected; • Evidence of worsening renal function. • Probenecid and other drugs that reduce serum uric acid concentration by increasing renal excretion of uric acid; these drugs increase the risk of precipitation of uric acid in the urinary system and may cause acute renal failure. • Certain chemotherapy agents, such as methotrexate, that block synthesis or use of purines. Individuals with all • Periods of relative dehydration because they concentrate purine metabolites in the urinary system and increase the risk for renal stones or urate nephropathy ## Evaluations Following Initial Diagnosis To establish the extent of disease and the needs in an individual diagnosed with an Recommended Evaluations Following Initial Diagnosis in Individuals with Any renal stones. Note: Uric acid stones are radiolucent & may not appear on std x-rays. Any additional renal pathology (e.g., nephrocalcinosis, dystrophy). Gouty arthritis; Any tophaceous deposits. Info on nature, MOI, & implications of HRH to help make informed medical & personal decisions; Risk assessment & testing options to clarify genetic status of family members. BUN = blood urea nitrogen; HRH = Additional Recommended Evaluations Following Initial Diagnosis in Individuals with Neurologic eval Developmental eval PT/rehab eval PT/OT eval Motor disorder; Contractures (& if present, address); Dysarthria; History of seizures; ADL. Cognitive abilities & need for intervention; Any behavioral problems. Social worker interventions; Home nursing referral. ADL = activities of daily living; HND = Additional Recommended Evaluations Following Initial Diagnosis in Individuals with Poorly controlled self injury leads to multiple scars. Injuries may become infected or life threatening. Assess for oppositional defiant & other difficult behaviors. Provide counseling to therapists & teachers re mgmt of difficult behaviors. Assess for occult biting of oral mucosa & establish plan for tooth extraction when needed. >50% of all persons may need dental extraction because of self biting. LND = Lesch-Nyhan disease • Any renal stones. Note: Uric acid stones are radiolucent & may not appear on std x-rays. • Any additional renal pathology (e.g., nephrocalcinosis, dystrophy). • Gouty arthritis; • Any tophaceous deposits. • Info on nature, MOI, & implications of HRH to help make informed medical & personal decisions; • Risk assessment & testing options to clarify genetic status of family members. • Neurologic eval • Developmental eval • PT/rehab eval • PT/OT eval • Motor disorder; • Contractures (& if present, address); • Dysarthria; • History of seizures; • ADL. • Cognitive abilities & need for intervention; • Any behavioral problems. • Social worker interventions; • Home nursing referral. • Poorly controlled self injury leads to multiple scars. • Injuries may become infected or life threatening. • Assess for oppositional defiant & other difficult behaviors. • Provide counseling to therapists & teachers re mgmt of difficult behaviors. • Assess for occult biting of oral mucosa & establish plan for tooth extraction when needed. • >50% of all persons may need dental extraction because of self biting. ## Treatment of Manifestations Following initial evaluations ( A multidisciplinary team may be needed. Depending on needs, this team may require specialists in medical genetics, neurology, behavioral management, developmental pediatrics, physical medicine and rehabilitation, physical therapy, occupational therapy, speech-language pathology, dentistry, and nephrology. Treatment of Manifestations in Individuals with Allopurinol most commonly used; febuxostat in case of allopurinol hypersensitivity Treatment required to ↓ risk for nephropathy, gouty arthritis, & tophi Titrate to maintain uric acid levels w/in normal limits. Avoid suppressing uric acid below normal limits because this ↑ risk of xanthine stones. Treatment ↓ risk of renal complications. Avoid dehydration, which concentrates purine metabolites in urinary system. Renal insufficiency or failure may occur despite medical therapy. When gouty arthritis occurs even w/treatment, consider compliance or insufficient hydration. May be painful when they erode overlying skin or underlying tissues; May become infected. Folate & B Treatment often is not needed because problem does not produce disability. HRH = Additional Treatments for Individuals with No medication reliably controls dystonia in HND. Antispasticity agents may be useful for spasticity. Cognitive problems may not be apparent w/o neuropsychological testing. Problems w/attention are common & create learning disability. HND = Additional Treatments for Individuals with Required by virtually all persons at some point; often required daily LND is exempt from laws that prevent use of restraints for extended periods. Negative reinforcement methods (punishment) worsen behavior & should not be used. Extinction methods work best, & require special expertise to implement. No medications reliably control self injury in LND. Benzodiazepines often used to ↓ anxiety Neuroleptics may worsen the dystonia. Tooth & mouth guards rarely reliable Dental extraction required in the majority LND = Lesch-Nyhan disease 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. • Allopurinol most commonly used; febuxostat in case of allopurinol hypersensitivity • Treatment required to ↓ risk for nephropathy, gouty arthritis, & tophi • Titrate to maintain uric acid levels w/in normal limits. • Avoid suppressing uric acid below normal limits because this ↑ risk of xanthine stones. • Treatment ↓ risk of renal complications. • Avoid dehydration, which concentrates purine metabolites in urinary system. • Renal insufficiency or failure may occur despite medical therapy. • When gouty arthritis occurs even w/treatment, consider compliance or insufficient hydration. • May be painful when they erode overlying skin or underlying tissues; • May become infected. • Folate & B • Treatment often is not needed because problem does not produce disability. • No medication reliably controls dystonia in HND. • Antispasticity agents may be useful for spasticity. • Cognitive problems may not be apparent w/o neuropsychological testing. • Problems w/attention are common & create learning disability. • Required by virtually all persons at some point; often required daily • LND is exempt from laws that prevent use of restraints for extended periods. • Negative reinforcement methods (punishment) worsen behavior & should not be used. • Extinction methods work best, & require special expertise to implement. • No medications reliably control self injury in LND. • Benzodiazepines often used to ↓ anxiety • Neuroleptics may worsen the dystonia. • Tooth & mouth guards rarely reliable • Dental extraction required in the majority ## 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. ## Surveillance Similarly, new or worsening neurologic problems are not expected over time [ The behavioral phenotype may wax and wane in severity over the years. Sudden worsening occurs with stress, for example relating to the pain of a kidney stone or change in social environment. In very young children with HND, self-injurious behavior may emerge, leading to reclassification of the diagnosis to LND. This behavior typically emerges between age two and four years but may be delayed until the teenage years. Recommended Surveillance for Individuals with Monitor 3-6x/yr during allopurinol titration. Annual assessments are sufficient after stable dose is achieved. Urinary system stones if clinically suspected; Evidence of worsening renal function. BUN = blood urea nitrogen; HRH = Additional Recommended Surveillance for Individuals with DD = developmental delay; HND = Additional Recommended Surveillance for Individuals with LND = Lesch-Nyhan disease • Monitor 3-6x/yr during allopurinol titration. • Annual assessments are sufficient after stable dose is achieved. • Urinary system stones if clinically suspected; • Evidence of worsening renal function. ## Agents/Circumstances to Avoid Avoid the following: Probenecid and other drugs that reduce serum uric acid concentration by increasing renal excretion of uric acid; these drugs increase the risk of precipitation of uric acid in the urinary system and may cause acute renal failure. Certain chemotherapy agents, such as methotrexate, that block synthesis or use of purines. Individuals with all Periods of relative dehydration because they concentrate purine metabolites in the urinary system and increase the risk for renal stones or urate nephropathy • Probenecid and other drugs that reduce serum uric acid concentration by increasing renal excretion of uric acid; these drugs increase the risk of precipitation of uric acid in the urinary system and may cause acute renal failure. • Certain chemotherapy agents, such as methotrexate, that block synthesis or use of purines. Individuals with all • Periods of relative dehydration because they concentrate purine metabolites in the urinary system and increase the risk for renal stones or urate nephropathy ## Evaluation of Relatives at Risk It is appropriate to clarify the status of males at risk for See ## Therapies Under Investigation Numerous small-scale studies have reported benefits from a wide array of therapies including various types of mouth guards and dental appliances, deep brain stimulation, bone marrow transplantation, gabapentin, carbamazepine, S-adenosylmethionine, risperidone, and others. In all instances, follow-up experiences have not confirmed a significant long-term benefit. Because of their follow-on nature and frequent negative outcome, these attempts to confirm benefits often are not published. However, many families post their experience online using social media and, by searching these posts, the clinician can get a good feel for the likelihood that an experimental therapy will have a positive (or negative) impact on the affected individual and their family [ Search ## Genetic Counseling The father of an affected male will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is likely to be heterozygous. If a woman has more than one affected child and no other affected relatives and if the proband has a known If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a If the mother of the proband has an Males who inherit a pathogenic Females who inherit the pathogenic variant will be heterozygotes and will virtually always be clinically normal. In rare instances, a heterozygous female may become symptomatic because of skewed (nonrandom) X-chromosome inactivation of the normal If the proband represents a simplex case (i.e., a single occurrence in a family) and if the proband has a known Males with LND or HND do not reproduce. Males with HRH transmit the All of their daughters, who will be heterozygotes and will virtually always be clinically normal (see Clinical Description, None of their sons. Molecular genetic testing may be able to identify the family member in whom a Note: (1) Females who are heterozygous will virtually always be clinically normal but may have increased uric acid excretion and some may develop hyperuricemia in later years. (2) Identification of female heterozygotes requires either (a) prior identification of the See Management, The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. Differences in perspective may exist among medical professionals and within families regarding the use 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 likely to be heterozygous. If a woman has more than one affected child and no other affected relatives and if the proband has a known • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a • If the mother of the proband has an • Males who inherit a pathogenic • Females who inherit the pathogenic variant will be heterozygotes and will virtually always be clinically normal. In rare instances, a heterozygous female may become symptomatic because of skewed (nonrandom) X-chromosome inactivation of the normal • Males who inherit a pathogenic • Females who inherit the pathogenic variant will be heterozygotes and will virtually always be clinically normal. In rare instances, a heterozygous female may become symptomatic because of skewed (nonrandom) X-chromosome inactivation of the normal • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the proband has a known • Males who inherit a pathogenic • Females who inherit the pathogenic variant will be heterozygotes and will virtually always be clinically normal. In rare instances, a heterozygous female may become symptomatic because of skewed (nonrandom) X-chromosome inactivation of the normal • Males with LND or HND do not reproduce. • Males with HRH transmit the • All of their daughters, who will be heterozygotes and will virtually always be clinically normal (see Clinical Description, • None of their sons. • All of their daughters, who will be heterozygotes and will virtually always be clinically normal (see Clinical Description, • None of their sons. • All of their daughters, who will be heterozygotes and will virtually always be clinically normal (see Clinical Description, • None of their sons. • The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. ## Mode of Inheritance ## Risk to Family Members The father of an affected male will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is likely to be heterozygous. If a woman has more than one affected child and no other affected relatives and if the proband has a known If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a If the mother of the proband has an Males who inherit a pathogenic Females who inherit the pathogenic variant will be heterozygotes and will virtually always be clinically normal. In rare instances, a heterozygous female may become symptomatic because of skewed (nonrandom) X-chromosome inactivation of the normal If the proband represents a simplex case (i.e., a single occurrence in a family) and if the proband has a known Males with LND or HND do not reproduce. Males with HRH transmit the All of their daughters, who will be heterozygotes and will virtually always be clinically normal (see Clinical Description, None of their sons. 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 likely to be heterozygous. If a woman has more than one affected child and no other affected relatives and if the proband has a known • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a • If the mother of the proband has an • Males who inherit a pathogenic • Females who inherit the pathogenic variant will be heterozygotes and will virtually always be clinically normal. In rare instances, a heterozygous female may become symptomatic because of skewed (nonrandom) X-chromosome inactivation of the normal • Males who inherit a pathogenic • Females who inherit the pathogenic variant will be heterozygotes and will virtually always be clinically normal. In rare instances, a heterozygous female may become symptomatic because of skewed (nonrandom) X-chromosome inactivation of the normal • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the proband has a known • Males who inherit a pathogenic • Females who inherit the pathogenic variant will be heterozygotes and will virtually always be clinically normal. In rare instances, a heterozygous female may become symptomatic because of skewed (nonrandom) X-chromosome inactivation of the normal • Males with LND or HND do not reproduce. • Males with HRH transmit the • All of their daughters, who will be heterozygotes and will virtually always be clinically normal (see Clinical Description, • None of their sons. • All of their daughters, who will be heterozygotes and will virtually always be clinically normal (see Clinical Description, • None of their sons. • All of their daughters, who will be heterozygotes and will virtually always be clinically normal (see Clinical Description, • None of their sons. ## Carrier Detection Note: (1) Females who are heterozygous will virtually always be clinically normal but may have increased uric acid excretion and some may develop hyperuricemia in later years. (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, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. • The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. ## 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 PO Box 5801 Bethesda MD 20824 • • • • PO Box 5801 • Bethesda MD 20824 • • • ## Molecular Genetics HPRT1 Disorders: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for HPRT1 Disorders ( The loss of HGprt-mediated purine recycling leads to secondary changes in purine synthesis, resulting in overproduction of uric acid as a purine waste product. Uric acid is not very soluble in body fluids, so its accumulation results in precipitation in the urinary system (nephrolithiasis) and joints (gouty arthritis). The mechanisms responsible for the neurobehavioral phenotype are not entirely understood, but are thought to relate to dysfunction of basal ganglia circuits [ Founder variants occurring in extended families are uncommon because males with LND do not reproduce. Males with HND rarely reproduce, but those with HRH may have families. Therefore, several families with multiple affected members have been reported [ For comprehensive information on Notable HND = Variants listed in the table have been provided by the author. ## Molecular Pathogenesis The loss of HGprt-mediated purine recycling leads to secondary changes in purine synthesis, resulting in overproduction of uric acid as a purine waste product. Uric acid is not very soluble in body fluids, so its accumulation results in precipitation in the urinary system (nephrolithiasis) and joints (gouty arthritis). The mechanisms responsible for the neurobehavioral phenotype are not entirely understood, but are thought to relate to dysfunction of basal ganglia circuits [ Founder variants occurring in extended families are uncommon because males with LND do not reproduce. Males with HND rarely reproduce, but those with HRH may have families. Therefore, several families with multiple affected members have been reported [ For comprehensive information on Notable HND = Variants listed in the table have been provided by the author. ## Chapter Notes Dr Jinnah is Professor of Neurology and Human Genetics with more than 20 years of experience in research on and clinical management of Lesch-Nyhan disease and its milder variants. He has an NIH-funded laboratory program devoted to developing a better understanding of the abnormalities in brain function that lead to the neurobehavioral aspects of the disease, and has conducted numerous experimental clinical trials. James C Harris, MD; Johns Hopkins University (2000-2020)Hyder A Jinnah, MD, PhD (2000-present)Janice A Nicklas, PhD; University of Vermont (2000-2007)William L Nyhan, MD, PhD; University of California, San Diego (2000-2020)J Patrick O'Neill, PhD; University of Vermont (2000-2020) 6 August 2020 (bp) Comprehensive update posted live 15 May 2014 (me) Comprehensive update posted live 10 June 2010 (me) Comprehensive update posted live 27 January 2009 (cd) Revision: deletion/duplication analysis available clinically 27 November 2007 (me) Comprehensive update posted live 8 February 2005 (me) Comprehensive update posted live 6 February 2003 (me) Comprehensive update posted live 25 September 2000 (me) Review posted live 20 March 2000 (jn) Original submission • 6 August 2020 (bp) Comprehensive update posted live • 15 May 2014 (me) Comprehensive update posted live • 10 June 2010 (me) Comprehensive update posted live • 27 January 2009 (cd) Revision: deletion/duplication analysis available clinically • 27 November 2007 (me) Comprehensive update posted live • 8 February 2005 (me) Comprehensive update posted live • 6 February 2003 (me) Comprehensive update posted live • 25 September 2000 (me) Review posted live • 20 March 2000 (jn) Original submission ## Author Notes Dr Jinnah is Professor of Neurology and Human Genetics with more than 20 years of experience in research on and clinical management of Lesch-Nyhan disease and its milder variants. He has an NIH-funded laboratory program devoted to developing a better understanding of the abnormalities in brain function that lead to the neurobehavioral aspects of the disease, and has conducted numerous experimental clinical trials. ## Author History James C Harris, MD; Johns Hopkins University (2000-2020)Hyder A Jinnah, MD, PhD (2000-present)Janice A Nicklas, PhD; University of Vermont (2000-2007)William L Nyhan, MD, PhD; University of California, San Diego (2000-2020)J Patrick O'Neill, PhD; University of Vermont (2000-2020) ## Revision History 6 August 2020 (bp) Comprehensive update posted live 15 May 2014 (me) Comprehensive update posted live 10 June 2010 (me) Comprehensive update posted live 27 January 2009 (cd) Revision: deletion/duplication analysis available clinically 27 November 2007 (me) Comprehensive update posted live 8 February 2005 (me) Comprehensive update posted live 6 February 2003 (me) Comprehensive update posted live 25 September 2000 (me) Review posted live 20 March 2000 (jn) Original submission • 6 August 2020 (bp) Comprehensive update posted live • 15 May 2014 (me) Comprehensive update posted live • 10 June 2010 (me) Comprehensive update posted live • 27 January 2009 (cd) Revision: deletion/duplication analysis available clinically • 27 November 2007 (me) Comprehensive update posted live • 8 February 2005 (me) Comprehensive update posted live • 6 February 2003 (me) Comprehensive update posted live • 25 September 2000 (me) Review posted live • 20 March 2000 (jn) Original submission ## References ## Literature Cited	[ "HF Cakmakli, RJ Torres, A Menendez, G Yalcin-Cakmakli, CC Porter, JG Puig, HA Jinnah. Macrocytic anemia in Lesch-Nyhan disease and its variants.. Genet Med. 2019;21:353-60", "I Ceballos-Picot, F Auge, R Fu, A Olivier-Bandini, J Cahu, B Chabrol, B Aral, B de Martinville, JP Lecain, HA Jinnah. Phenotypic variation among seven members of one family with deficiency of hypoxanthine-guanine phosphoribosyltransferase.. Mol Genet Metab. 2013;110:268-74", "AC Cotton, RB Bell, HA Jinnah. Expert opinion vs patient perspective in treatment of rare disorders: tooth extraction in Lesch-Nyhan disease as an example.. JIMD Rep. 2018;41:25-7", "L De Gregorio, HA Jinnah, JC Harris, WL Nyhan, DJ Schretlen, LM Trombley, JP O'Neill. Lesch-Nyhan disease in a female with a clinically normal monozygotic twin.. Mol Genet Metab. 2005;85:70-7", "R Fu, I Ceballos-Picot, RJ Torres, LE Larovere, Y Yamada, KV Nguyen, M Hegde, JE Visser, DJ Schretlen, WL Nyhan, JG Puig, PJ O'Neill, HA Jinnah. Genotype-phenotype correlations in neurogenetics: Lesch-Nyhan disease as a model disorder.. Brain. 2014;137:1282-303", "R Fu, D Sutcliffe, H Zhao, X Huang, DJ Schretlen, S Benkovic, HA Jinnah. Clinical severity in Lesch-Nyhan disease: the role of residual enzyme and compensatory pathways.. Mol Genet Metab. 2015;114:55-61", "M Göttle, CN Prudente, R Fu, D Sutcliffe, H Pang, D Cooper, E Veledar, JD Glass, M Gearing, JE Visser, HA Jinnah. Loss of neurotransmitter phenotype among midbrain dopamine neurons in Lesch-Nyhan disease.. Ann Neurol. 2014;76:95-107", "HA Jinnah, I Ceballos-Picot, RJ Torres, JE Visser, DJ Schretlen, A Verdu, LE Laróvere, C-J Chen, A Cossu, Ch-H Wu, R Sampat, S-J Chang, RD de Kremer, W Nyhan, JC Harris, SG Reich, JG Puig. Attenuated variants of Lesch-Nyhan disease.. Brain. 2010;133:671-89", "HA Jinnah, JE Visser, JC Harris, A Verdu, L Larovere, I Ceballos-Picot, P Gonzalez-Alegre, V Neychev, RJ Torres, O Dulac, I Desguerre, DJ Schretlen, KL Robey, G Barabas, BR Bloem, W Nyhan, R De Kremer, GE Eddey, JG Puig, SG Reich. Delineation of the motor disorder of Lesch-Nyhan disease.. Brain. 2006;129:1201-17", "A Madeo, M Di Rocco, A Brassier, N Bahi-Buisson, P De Lonlay, I Ceballos-Picot. Clinical, biochemical and genetic characteristics of a cohort of 101 French and Italian patients with HPRT deficiency.. Mol Genet Metab. 2019;127:147-57", "VK Neychev, HA Jinnah. Sudden death in Lesch-Nyhan disease.. Dev Med Child Neurol. 2006;48:923-6", "WL Nyhan, LU Vuong, R Broock. Prenatal diagnosis of Lesch-Nyhan disease.. Prenat Diagn. 2003;23:807-9", "L Olson, D. Houlihan. A review of behavioral treatments used for Lesch-Nyhan syndrome.. Behav Modif. 2000;24:202-22", "JG Puig, FA Mateos, RJ Torres, AS Buno. Purine metabolism in female heterozygotes for hypoxanthine-guanine phosphoribosyltransferase deficiency.. Eur J Clin Invest. 1998;28:950-7", "KL Robey, JF Reck, KD Giacomini, G Barabas, GE Eddey. Modes and patterns of self-mutilation in persons with Lesch-Nyhan disease.. Dev Med Child Neurol. 2003;45:167-71", "R Sampat, R Fu, LE Larovere, RJ Torres, I Ceballos-Picot, M Fischbach, R de Kremer, DJ Schretlen, JG Puig, HA Jinnah. Mechanisms for phenotypic variation in Lesch-Nyhan disease and its variants.. Hum Genet. 2011;129:71-8", "DJ Schretlen, JC Harris, KS Park, HA Jinnah, NO del Pozo. Neurocognitive functioning in Lesch-Nyhan disease and partial hypoxanthine-guanine phosphoribosyltransferase deficiency.. J Int Neuropsychol Soc. 2001;7:805-12", "DJ Schretlen, M Varvaris, TE Ho, TD Vannorsdall, B Gordon, JC Harris, HA Jinnah. Regional brain abnormalities in Lesch-Nyhan disease and its variants: a cross-sectional analysis.. Lancet Neurol. 2013;12:1151-8", "DJ Schretlen, J Ward, SM Meyer, J Yun, JG Puig, WL Nyhan, HA Jinnah, JC Harris. Behavioral aspects of Lesch-Nyhan disease and its variants.. Dev Med Child Neurol. 2005;47:673-7", "JE Visser, PR Baer, HA Jinnah. Lesch-Nyhan syndrome and the basal ganglia.. Brain Res Rev. 2000;32:449-75", "I. Willers. Germline mosaicism complicates molecular diagnosis of Lesch-Nyhan syndrome.. Prenat Diagn. 2004;24:737-40" ]	25/9/2000	6/8/2020	27/1/2009	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
loeys-dietz	loeys-dietz	[ "Loeys-Dietz Aortic Aneurysm Syndrome", "Loeys-Dietz Aortic Aneurysm Syndrome", "Importin-8", "Mothers against decapentaplegic homolog 2", "Mothers against decapentaplegic homolog 3", "TGF-beta receptor type-1", "TGF-beta receptor type-2", "Transforming growth factor beta-2 proprotein", "Transforming growth factor beta-3 proprotein", "IPO8", "SMAD2", "SMAD3", "TGFB2", "TGFB3", "TGFBR1", "TGFBR2", "Loeys-Dietz Syndrome" ]	Loeys-Dietz Syndrome	Bart L Loeys, Harry C Dietz	Summary Loeys-Dietz syndrome (LDS) is characterized by vascular findings (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections), skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus, and cervical spine malformation and/or instability), craniofacial features (hypertelorism, strabismus, bifid uvula / cleft palate, and craniosynostosis that can involve any sutures), and cutaneous findings (velvety and translucent skin, easy bruising, and dystrophic scars). Individuals with LDS are predisposed to widespread and aggressive arterial aneurysms and pregnancy-related complications including uterine rupture and death. Individuals with LDS can show a strong predisposition for allergic/inflammatory disease including asthma, eczema, and reactions to food or environmental allergens. There is also an increased incidence of gastrointestinal inflammation including eosinophilic esophagitis and gastritis or inflammatory bowel disease. Wide variation in the distribution and severity of clinical features can be seen in individuals with LDS, even among affected individuals within a family who have the same pathogenic variant. The diagnosis of LDS is established in (1) a proband with characteristic clinical findings or (2) by the identification of a heterozygous pathogenic variant in LDS caused by a pathogenic variant in If the LDS-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.	## Diagnosis No consensus clinical diagnostic criteria for Loeys-Dietz syndrome (LDS) have been published. LDS Evaluation is best done with magnetic resonance angiography (MRA) or CT angiogram (CTA) with 3D reconstruction from head to pelvis to identify arterial aneurysms or dissections and arterial tortuosity throughout the arterial tree. Tortuosity is often most prominent in head and neck vessels. Approximately 50% of individuals with LDS studied had an aneurysm distant from the aortic root that would not have been detected by echocardiography. Pectus excavatum or pectus carinatum Scoliosis Joint laxity or contracture (typically involving the fingers) Arachnodactyly Talipes equinovarus Cervical spine malformation and/or instability Osteoarthritis Hypertelorism Bifid uvula / cleft palate Craniosynostosis, in which any sutures can be involved Soft and velvety skin Translucent skin with easily visible underlying veins Easy bruising Dystrophic scars Milia, predominantly on the face Food allergies Seasonal allergies Asthma / chronic sinusitis Eczema Eosinophilic esophagitis/gastritis Inflammatory bowel disease Aortic root enlargement (defined as an aortic root z score ≥2 standard deviations above the mean) or type A dissection Other characteristic clinical features of LDS: craniofacial, skeletal, cutaneous, and/or vascular manifestations (especially arterial tortuosity, prominently including the head and neck vessels, and aneurysms or dissections involving medium-to-large muscular arteries throughout the arterial tree) Family history of established diagnosis of LDS Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ For an introduction to multigene panels click When the phenotype is indistinguishable from other inherited disorders with features observed in LDS, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Loeys-Dietz Syndrome LDS = Loeys-Dietz syndrome; MOI = mode of inheritance 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. Data derived from the subscription-based professional view of Human Gene Mutation Database [ Deletion of Whole-gene deletion of Based on rare individuals with discriminating features of LDS who show no pathogenic variants in the known genes, additional LDS-associated genes remain to be identified [BL Loeys & HC Dietz, personal observations]. • • Evaluation is best done with magnetic resonance angiography (MRA) or CT angiogram (CTA) with 3D reconstruction from head to pelvis to identify arterial aneurysms or dissections and arterial tortuosity throughout the arterial tree. • Tortuosity is often most prominent in head and neck vessels. • Approximately 50% of individuals with LDS studied had an aneurysm distant from the aortic root that would not have been detected by echocardiography. • Evaluation is best done with magnetic resonance angiography (MRA) or CT angiogram (CTA) with 3D reconstruction from head to pelvis to identify arterial aneurysms or dissections and arterial tortuosity throughout the arterial tree. • Tortuosity is often most prominent in head and neck vessels. • Approximately 50% of individuals with LDS studied had an aneurysm distant from the aortic root that would not have been detected by echocardiography. • Evaluation is best done with magnetic resonance angiography (MRA) or CT angiogram (CTA) with 3D reconstruction from head to pelvis to identify arterial aneurysms or dissections and arterial tortuosity throughout the arterial tree. • Tortuosity is often most prominent in head and neck vessels. • Approximately 50% of individuals with LDS studied had an aneurysm distant from the aortic root that would not have been detected by echocardiography. • Pectus excavatum or pectus carinatum • Scoliosis • Joint laxity or contracture (typically involving the fingers) • Arachnodactyly • Talipes equinovarus • Cervical spine malformation and/or instability • Osteoarthritis • Hypertelorism • Bifid uvula / cleft palate • Craniosynostosis, in which any sutures can be involved • Soft and velvety skin • Translucent skin with easily visible underlying veins • Easy bruising • Dystrophic scars • Milia, predominantly on the face • Food allergies • Seasonal allergies • Asthma / chronic sinusitis • Eczema • Eosinophilic esophagitis/gastritis • Inflammatory bowel disease • Aortic root enlargement (defined as an aortic root z score ≥2 standard deviations above the mean) or type A dissection • Other characteristic clinical features of LDS: craniofacial, skeletal, cutaneous, and/or vascular manifestations (especially arterial tortuosity, prominently including the head and neck vessels, and aneurysms or dissections involving medium-to-large muscular arteries throughout the arterial tree) • Family history of established diagnosis of LDS ## Suggestive Findings LDS Evaluation is best done with magnetic resonance angiography (MRA) or CT angiogram (CTA) with 3D reconstruction from head to pelvis to identify arterial aneurysms or dissections and arterial tortuosity throughout the arterial tree. Tortuosity is often most prominent in head and neck vessels. Approximately 50% of individuals with LDS studied had an aneurysm distant from the aortic root that would not have been detected by echocardiography. Pectus excavatum or pectus carinatum Scoliosis Joint laxity or contracture (typically involving the fingers) Arachnodactyly Talipes equinovarus Cervical spine malformation and/or instability Osteoarthritis Hypertelorism Bifid uvula / cleft palate Craniosynostosis, in which any sutures can be involved Soft and velvety skin Translucent skin with easily visible underlying veins Easy bruising Dystrophic scars Milia, predominantly on the face Food allergies Seasonal allergies Asthma / chronic sinusitis Eczema Eosinophilic esophagitis/gastritis Inflammatory bowel disease • • Evaluation is best done with magnetic resonance angiography (MRA) or CT angiogram (CTA) with 3D reconstruction from head to pelvis to identify arterial aneurysms or dissections and arterial tortuosity throughout the arterial tree. • Tortuosity is often most prominent in head and neck vessels. • Approximately 50% of individuals with LDS studied had an aneurysm distant from the aortic root that would not have been detected by echocardiography. • Evaluation is best done with magnetic resonance angiography (MRA) or CT angiogram (CTA) with 3D reconstruction from head to pelvis to identify arterial aneurysms or dissections and arterial tortuosity throughout the arterial tree. • Tortuosity is often most prominent in head and neck vessels. • Approximately 50% of individuals with LDS studied had an aneurysm distant from the aortic root that would not have been detected by echocardiography. • Evaluation is best done with magnetic resonance angiography (MRA) or CT angiogram (CTA) with 3D reconstruction from head to pelvis to identify arterial aneurysms or dissections and arterial tortuosity throughout the arterial tree. • Tortuosity is often most prominent in head and neck vessels. • Approximately 50% of individuals with LDS studied had an aneurysm distant from the aortic root that would not have been detected by echocardiography. • Pectus excavatum or pectus carinatum • Scoliosis • Joint laxity or contracture (typically involving the fingers) • Arachnodactyly • Talipes equinovarus • Cervical spine malformation and/or instability • Osteoarthritis • Hypertelorism • Bifid uvula / cleft palate • Craniosynostosis, in which any sutures can be involved • Soft and velvety skin • Translucent skin with easily visible underlying veins • Easy bruising • Dystrophic scars • Milia, predominantly on the face • Food allergies • Seasonal allergies • Asthma / chronic sinusitis • Eczema • Eosinophilic esophagitis/gastritis • Inflammatory bowel disease ## Establishing the Diagnosis Aortic root enlargement (defined as an aortic root z score ≥2 standard deviations above the mean) or type A dissection Other characteristic clinical features of LDS: craniofacial, skeletal, cutaneous, and/or vascular manifestations (especially arterial tortuosity, prominently including the head and neck vessels, and aneurysms or dissections involving medium-to-large muscular arteries throughout the arterial tree) Family history of established diagnosis of LDS Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ For an introduction to multigene panels click When the phenotype is indistinguishable from other inherited disorders with features observed in LDS, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Loeys-Dietz Syndrome LDS = Loeys-Dietz syndrome; MOI = mode of inheritance 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. Data derived from the subscription-based professional view of Human Gene Mutation Database [ Deletion of Whole-gene deletion of Based on rare individuals with discriminating features of LDS who show no pathogenic variants in the known genes, additional LDS-associated genes remain to be identified [BL Loeys & HC Dietz, personal observations]. • Aortic root enlargement (defined as an aortic root z score ≥2 standard deviations above the mean) or type A dissection • Other characteristic clinical features of LDS: craniofacial, skeletal, cutaneous, and/or vascular manifestations (especially arterial tortuosity, prominently including the head and neck vessels, and aneurysms or dissections involving medium-to-large muscular arteries throughout the arterial tree) • Family history of established diagnosis of LDS ## Option 1 For an introduction to multigene panels click ## Option 2 When the phenotype is indistinguishable from other inherited disorders with features observed in LDS, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Loeys-Dietz Syndrome LDS = Loeys-Dietz syndrome; MOI = mode of inheritance 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. Data derived from the subscription-based professional view of Human Gene Mutation Database [ Deletion of Whole-gene deletion of Based on rare individuals with discriminating features of LDS who show no pathogenic variants in the known genes, additional LDS-associated genes remain to be identified [BL Loeys & HC Dietz, personal observations]. ## Clinical Characteristics Loeys-Dietz syndrome (LDS) represents a wide phenotypic spectrum in which affected individuals may have various combinations of clinical features ranging from a severe syndromic presentation with significant extravascular systemic findings in young children to predominantly thoracic aortic aneurysm/dissection occurring in adults. Clinical variability is also observed among individuals in the same family who have the same pathogenic variant. The most common findings involve the vascular, skeletal, craniofacial, cutaneous, allergic/inflammatory, and ocular systems [ The major sources of morbidity and early mortality in LDS are dilatation of the aorta at the level of the sinuses of Valsalva, a predisposition for aortic dissection and rupture, mitral valve prolapse (MVP) with or without regurgitation, and enlargement of the proximal pulmonary artery. Individuals with LDS have more severe vascular disease (with frequent involvement of vascular segments distant from the aortic root) than that observed in The arterial involvement is widespread, and arterial tortuosity is present in a majority of affected individuals. Most affected individuals have multiple arterial anomalies. Vertebral and carotid artery dissection and cerebral bleeding have been described; rarely, isolated carotid artery dissection in the absence of aortic root involvement has been observed [ Aortic samples from individuals with LDS had significantly more diffuse medial degeneration than did samples from individuals with Marfan syndrome or control individuals. The changes are not entirely specific for LDS, but in the appropriate clinicopathologic setting help differentiate it from other vascular diseases [ The skeletal findings are characterized by Marfan syndrome-like skeletal features and joint laxity or contractures [ Combined thumb and wrist signs were present in one third of individuals with LDS. Note: (1) The Walker-Murdoch wrist sign is the overlapping of the complete distal phalanx of the thumb and fifth finger when wrapped around the opposite wrist. (2) The "thumb sign" (Steinberg) is an extension of the entire distal phalanx of the thumb beyond the ulnar border of the hand when apposed across the palm. Dolichostenomelia (leading to an increase in the arm span-to-height ratio and a decrease in the upper-to-lower segment ratio) is less common in LDS than in Marfan syndrome. Overgrowth of the ribs can push the sternum in (pectus excavatum) or out (pectus carinatum). Preliminary data suggest that approximately 15% (or more) of affected individuals have structural cervical spine anomalies and at least 25% have cervical spine instability. Spondylolisthesis and scoliosis can be mild or severe and progressive. Acetabular protrusion, present in one third of individuals, is usually mild but can be associated with pain or functional limitations. Pes planus, often associated with inward rotation at the ankle, contributes to difficulty with ambulation, leg fatigue, and muscle cramps. Preliminary evidence suggests that individuals with LDS have an increased incidence of osteoporosis with increased fracture incidence and delayed bone healing [ Note: Musculoskeletal findings, including hypotonia, have been observed in neonates with LDS [ In their most severe presentation, craniofacial anomalies in individuals with LDS are characterized by hypertelorism and craniosynostosis. Craniosynostosis most commonly involves premature fusion of the sagittal suture (resulting in dolichocephaly). Coronal suture synostosis (resulting in brachycephaly) and metopic suture synostosis (resulting in trigonocephaly) have also been described. Bifid uvula is considered the mildest expression of a cleft palate. Sometimes the uvula has an unusual broad appearance with or without a midline raphe. Other craniofacial characteristics include malar flattening and retrognathia. The skin findings, similar to those seen in vascular Ehlers-Danlos syndrome (see Individuals with LDS are predisposed to developing allergic disease including asthma, food allergy, eczema, allergic rhinitis, and eosinophilic gastrointestinal disease. Some affected individuals have exhibited elevated immunoglobulin E levels, eosinophil counts, and T helper 2 (TH2) cytokines in plasma [ Myopia is less frequent and less severe than that seen in Marfan syndrome. Significant refractive errors can lead to amblyopia. Other common ocular features include strabismus and blue sclerae. Retinal detachment has been reported rarely. Ectopia lentis is not observed except in exceedingly rare case reports of unclear significance. As in other connective tissue disorders, Life-threatening manifestations include The two most common neuroradiologic findings are dural ectasia (the precise incidence of which is unknown, as only a minority of affected individuals have undergone appropriate examination) and Arnold-Chiari type I malformation, which may be relatively rare. A minority of affected individuals have Less common associated findings requiring further exploration include submandibular branchial cysts and defective tooth enamel. Genes are listed in Loeys-Dietz Syndrome (LDS): Associated Genes and Subtypes LDS = Loeys-Dietz syndrome Several individuals with While the implicated gene can correlate broadly with disease severity (see Rare examples of non-penetrance in LDS have been documented. In some instances, non-penetrance is explained by mosaicism [ While various clinical presentations have in the past been labeled as LDS type I (craniofacial features present), LDS type II (minimal to absent craniofacial features), and LDS type III (presence of osteoarthritis), it is now recognized that LDS caused by a heterozygous pathogenic variant in any of the seven known genes (see Marfan syndrome type 2 was a designation initially applied by The exact prevalence of LDS is unknown but estimated to be 1:50,000. More than 1,000 families with LDS have been described in the literature. No phenotypes other than those discussed in this Other phenotypes associated with germline pathogenic variants in Allelic Disorders • The arterial involvement is widespread, and arterial tortuosity is present in a majority of affected individuals. • Most affected individuals have multiple arterial anomalies. • Vertebral and carotid artery dissection and cerebral bleeding have been described; rarely, isolated carotid artery dissection in the absence of aortic root involvement has been observed [ • Spondylolisthesis and scoliosis can be mild or severe and progressive. • Acetabular protrusion, present in one third of individuals, is usually mild but can be associated with pain or functional limitations. • Pes planus, often associated with inward rotation at the ankle, contributes to difficulty with ambulation, leg fatigue, and muscle cramps. • Preliminary evidence suggests that individuals with LDS have an increased incidence of osteoporosis with increased fracture incidence and delayed bone healing [ ## Clinical Description Loeys-Dietz syndrome (LDS) represents a wide phenotypic spectrum in which affected individuals may have various combinations of clinical features ranging from a severe syndromic presentation with significant extravascular systemic findings in young children to predominantly thoracic aortic aneurysm/dissection occurring in adults. Clinical variability is also observed among individuals in the same family who have the same pathogenic variant. The most common findings involve the vascular, skeletal, craniofacial, cutaneous, allergic/inflammatory, and ocular systems [ The major sources of morbidity and early mortality in LDS are dilatation of the aorta at the level of the sinuses of Valsalva, a predisposition for aortic dissection and rupture, mitral valve prolapse (MVP) with or without regurgitation, and enlargement of the proximal pulmonary artery. Individuals with LDS have more severe vascular disease (with frequent involvement of vascular segments distant from the aortic root) than that observed in The arterial involvement is widespread, and arterial tortuosity is present in a majority of affected individuals. Most affected individuals have multiple arterial anomalies. Vertebral and carotid artery dissection and cerebral bleeding have been described; rarely, isolated carotid artery dissection in the absence of aortic root involvement has been observed [ Aortic samples from individuals with LDS had significantly more diffuse medial degeneration than did samples from individuals with Marfan syndrome or control individuals. The changes are not entirely specific for LDS, but in the appropriate clinicopathologic setting help differentiate it from other vascular diseases [ The skeletal findings are characterized by Marfan syndrome-like skeletal features and joint laxity or contractures [ Combined thumb and wrist signs were present in one third of individuals with LDS. Note: (1) The Walker-Murdoch wrist sign is the overlapping of the complete distal phalanx of the thumb and fifth finger when wrapped around the opposite wrist. (2) The "thumb sign" (Steinberg) is an extension of the entire distal phalanx of the thumb beyond the ulnar border of the hand when apposed across the palm. Dolichostenomelia (leading to an increase in the arm span-to-height ratio and a decrease in the upper-to-lower segment ratio) is less common in LDS than in Marfan syndrome. Overgrowth of the ribs can push the sternum in (pectus excavatum) or out (pectus carinatum). Preliminary data suggest that approximately 15% (or more) of affected individuals have structural cervical spine anomalies and at least 25% have cervical spine instability. Spondylolisthesis and scoliosis can be mild or severe and progressive. Acetabular protrusion, present in one third of individuals, is usually mild but can be associated with pain or functional limitations. Pes planus, often associated with inward rotation at the ankle, contributes to difficulty with ambulation, leg fatigue, and muscle cramps. Preliminary evidence suggests that individuals with LDS have an increased incidence of osteoporosis with increased fracture incidence and delayed bone healing [ Note: Musculoskeletal findings, including hypotonia, have been observed in neonates with LDS [ In their most severe presentation, craniofacial anomalies in individuals with LDS are characterized by hypertelorism and craniosynostosis. Craniosynostosis most commonly involves premature fusion of the sagittal suture (resulting in dolichocephaly). Coronal suture synostosis (resulting in brachycephaly) and metopic suture synostosis (resulting in trigonocephaly) have also been described. Bifid uvula is considered the mildest expression of a cleft palate. Sometimes the uvula has an unusual broad appearance with or without a midline raphe. Other craniofacial characteristics include malar flattening and retrognathia. The skin findings, similar to those seen in vascular Ehlers-Danlos syndrome (see Individuals with LDS are predisposed to developing allergic disease including asthma, food allergy, eczema, allergic rhinitis, and eosinophilic gastrointestinal disease. Some affected individuals have exhibited elevated immunoglobulin E levels, eosinophil counts, and T helper 2 (TH2) cytokines in plasma [ Myopia is less frequent and less severe than that seen in Marfan syndrome. Significant refractive errors can lead to amblyopia. Other common ocular features include strabismus and blue sclerae. Retinal detachment has been reported rarely. Ectopia lentis is not observed except in exceedingly rare case reports of unclear significance. As in other connective tissue disorders, Life-threatening manifestations include The two most common neuroradiologic findings are dural ectasia (the precise incidence of which is unknown, as only a minority of affected individuals have undergone appropriate examination) and Arnold-Chiari type I malformation, which may be relatively rare. A minority of affected individuals have Less common associated findings requiring further exploration include submandibular branchial cysts and defective tooth enamel. • The arterial involvement is widespread, and arterial tortuosity is present in a majority of affected individuals. • Most affected individuals have multiple arterial anomalies. • Vertebral and carotid artery dissection and cerebral bleeding have been described; rarely, isolated carotid artery dissection in the absence of aortic root involvement has been observed [ • Spondylolisthesis and scoliosis can be mild or severe and progressive. • Acetabular protrusion, present in one third of individuals, is usually mild but can be associated with pain or functional limitations. • Pes planus, often associated with inward rotation at the ankle, contributes to difficulty with ambulation, leg fatigue, and muscle cramps. • Preliminary evidence suggests that individuals with LDS have an increased incidence of osteoporosis with increased fracture incidence and delayed bone healing [ ## Cardiovascular The major sources of morbidity and early mortality in LDS are dilatation of the aorta at the level of the sinuses of Valsalva, a predisposition for aortic dissection and rupture, mitral valve prolapse (MVP) with or without regurgitation, and enlargement of the proximal pulmonary artery. Individuals with LDS have more severe vascular disease (with frequent involvement of vascular segments distant from the aortic root) than that observed in The arterial involvement is widespread, and arterial tortuosity is present in a majority of affected individuals. Most affected individuals have multiple arterial anomalies. Vertebral and carotid artery dissection and cerebral bleeding have been described; rarely, isolated carotid artery dissection in the absence of aortic root involvement has been observed [ Aortic samples from individuals with LDS had significantly more diffuse medial degeneration than did samples from individuals with Marfan syndrome or control individuals. The changes are not entirely specific for LDS, but in the appropriate clinicopathologic setting help differentiate it from other vascular diseases [ • The arterial involvement is widespread, and arterial tortuosity is present in a majority of affected individuals. • Most affected individuals have multiple arterial anomalies. • Vertebral and carotid artery dissection and cerebral bleeding have been described; rarely, isolated carotid artery dissection in the absence of aortic root involvement has been observed [ ## Skeletal The skeletal findings are characterized by Marfan syndrome-like skeletal features and joint laxity or contractures [ Combined thumb and wrist signs were present in one third of individuals with LDS. Note: (1) The Walker-Murdoch wrist sign is the overlapping of the complete distal phalanx of the thumb and fifth finger when wrapped around the opposite wrist. (2) The "thumb sign" (Steinberg) is an extension of the entire distal phalanx of the thumb beyond the ulnar border of the hand when apposed across the palm. Dolichostenomelia (leading to an increase in the arm span-to-height ratio and a decrease in the upper-to-lower segment ratio) is less common in LDS than in Marfan syndrome. Overgrowth of the ribs can push the sternum in (pectus excavatum) or out (pectus carinatum). Preliminary data suggest that approximately 15% (or more) of affected individuals have structural cervical spine anomalies and at least 25% have cervical spine instability. Spondylolisthesis and scoliosis can be mild or severe and progressive. Acetabular protrusion, present in one third of individuals, is usually mild but can be associated with pain or functional limitations. Pes planus, often associated with inward rotation at the ankle, contributes to difficulty with ambulation, leg fatigue, and muscle cramps. Preliminary evidence suggests that individuals with LDS have an increased incidence of osteoporosis with increased fracture incidence and delayed bone healing [ Note: Musculoskeletal findings, including hypotonia, have been observed in neonates with LDS [ • Spondylolisthesis and scoliosis can be mild or severe and progressive. • Acetabular protrusion, present in one third of individuals, is usually mild but can be associated with pain or functional limitations. • Pes planus, often associated with inward rotation at the ankle, contributes to difficulty with ambulation, leg fatigue, and muscle cramps. • Preliminary evidence suggests that individuals with LDS have an increased incidence of osteoporosis with increased fracture incidence and delayed bone healing [ ## Craniofacial In their most severe presentation, craniofacial anomalies in individuals with LDS are characterized by hypertelorism and craniosynostosis. Craniosynostosis most commonly involves premature fusion of the sagittal suture (resulting in dolichocephaly). Coronal suture synostosis (resulting in brachycephaly) and metopic suture synostosis (resulting in trigonocephaly) have also been described. Bifid uvula is considered the mildest expression of a cleft palate. Sometimes the uvula has an unusual broad appearance with or without a midline raphe. Other craniofacial characteristics include malar flattening and retrognathia. ## Cutaneous The skin findings, similar to those seen in vascular Ehlers-Danlos syndrome (see ## Allergy and Gastrointestinal Disease Individuals with LDS are predisposed to developing allergic disease including asthma, food allergy, eczema, allergic rhinitis, and eosinophilic gastrointestinal disease. Some affected individuals have exhibited elevated immunoglobulin E levels, eosinophil counts, and T helper 2 (TH2) cytokines in plasma [ ## Ocular Myopia is less frequent and less severe than that seen in Marfan syndrome. Significant refractive errors can lead to amblyopia. Other common ocular features include strabismus and blue sclerae. Retinal detachment has been reported rarely. Ectopia lentis is not observed except in exceedingly rare case reports of unclear significance. ## Other As in other connective tissue disorders, Life-threatening manifestations include The two most common neuroradiologic findings are dural ectasia (the precise incidence of which is unknown, as only a minority of affected individuals have undergone appropriate examination) and Arnold-Chiari type I malformation, which may be relatively rare. A minority of affected individuals have Less common associated findings requiring further exploration include submandibular branchial cysts and defective tooth enamel. ## Phenotype Correlations by Gene Genes are listed in Loeys-Dietz Syndrome (LDS): Associated Genes and Subtypes LDS = Loeys-Dietz syndrome Several individuals with ## Genotype-Phenotype Correlations While the implicated gene can correlate broadly with disease severity (see ## Penetrance Rare examples of non-penetrance in LDS have been documented. In some instances, non-penetrance is explained by mosaicism [ ## Nomenclature While various clinical presentations have in the past been labeled as LDS type I (craniofacial features present), LDS type II (minimal to absent craniofacial features), and LDS type III (presence of osteoarthritis), it is now recognized that LDS caused by a heterozygous pathogenic variant in any of the seven known genes (see Marfan syndrome type 2 was a designation initially applied by ## Prevalence The exact prevalence of LDS is unknown but estimated to be 1:50,000. More than 1,000 families with LDS have been described in the literature. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this Other phenotypes associated with germline pathogenic variants in Allelic Disorders ## Differential Diagnosis Comparison of Clinical Features in Loeys-Dietz Syndrome, Marfan Syndrome, and Shprintzen-Goldberg Syndrome + = feature is present (presence of more than one "+" indicates that a feature is more common, with "+++" indicating most common); − = feature is absent; ? = unknown if clinical feature is associated with Developmental delays are primarily motor delays. Genes of Interest in the Differential Diagnosis of Loeys-Dietz Syndrome AD = autosomal dominant; AR = autosomal recessive; LDS = Loeys-Dietz syndrome; MOI = mode of inheritance; XL = X-linked Arginine-to-cysteine pathogenic variants in Vascular EDS is almost always inherited in an autosomal dominant manner, but rare examples of biallelic inheritance have been reported. Pathogenic variants in Greene et al [2023] Noonan syndrome is most often inherited in an autosomal dominant manner. Noonan syndrome caused by pathogenic variants in Heterozygous Listed genes are reported to have a definitive or strong HTAD association by the Clinical Genome Resource (ClinGen) HTAD Gene Curation Expert Panel (see Heritable Thoracic Aortic Disease Overview, ## Marfan Syndrome and Shprintzen-Goldberg Syndrome Comparison of Clinical Features in Loeys-Dietz Syndrome, Marfan Syndrome, and Shprintzen-Goldberg Syndrome + = feature is present (presence of more than one "+" indicates that a feature is more common, with "+++" indicating most common); − = feature is absent; ? = unknown if clinical feature is associated with Developmental delays are primarily motor delays. ## Genes of Interest in the Differential Diagnosis of Loeys-Dietz Syndrome Genes of Interest in the Differential Diagnosis of Loeys-Dietz Syndrome AD = autosomal dominant; AR = autosomal recessive; LDS = Loeys-Dietz syndrome; MOI = mode of inheritance; XL = X-linked Arginine-to-cysteine pathogenic variants in Vascular EDS is almost always inherited in an autosomal dominant manner, but rare examples of biallelic inheritance have been reported. Pathogenic variants in Greene et al [2023] Noonan syndrome is most often inherited in an autosomal dominant manner. Noonan syndrome caused by pathogenic variants in Heterozygous Listed genes are reported to have a definitive or strong HTAD association by the Clinical Genome Resource (ClinGen) HTAD Gene Curation Expert Panel (see Heritable Thoracic Aortic Disease Overview, ## Other Considerations ## Management An extensive review of management guidelines for Loeys-Dietz syndrome (LDS) has been published [ To establish the extent of disease and needs in an individual diagnosed with LDS, the evaluations summarized in Loeys-Dietz Syndrome: Recommended Evaluations Following Initial Diagnosis Echocardiography MRA or CT w/3D reconstruction from head to pelvis to identify arterial aneurysms & arterial tortuosity throughout the arterial tree Select findings (e.g., severe aortic dilatation) may require immediate attention of cardiologist or cardiothoracic surgeon. Clinical assessment for pectus deformity, clubfoot, scoliosis, pes planus Assessment for congenital hip dislocation & abnormal joint mobility Spine radiographs (incl flexion & extension views of cervical spine) to detect skeletal manifestations that may require attention by an orthopedist (e.g., severe scoliosis, cervical spine instability) Assessment for refractive errors Specific assessment for retinal detachment LDS = Loeys-Dietz syndrome; MOI = mode of inheritance; MRA = magnetic resonance angiography Medical geneticist, certified genetic counselor, certified advanced genetic nurse Management of LDS is most effective through the coordinated input of a multidisciplinary team of specialists including a clinical geneticist, cardiologist, cardiothoracic surgeon, orthopedist, and ophthalmologist (see Loeys-Dietz Syndrome: Treatment of Manifestations Aortic dissection occurs at smaller aortic diameters in LDS than in Severe craniofacial manifestations are often assoc w/& can be used to predict severe cardiovascular manifestations. Vascular disease is not limited to the aortic root. Imaging of the complete arterial tree from head to pelvis by MRA or CTA is necessary. Many persons can undergo a valve-sparing procedure that precludes the need for chronic anticoagulation. Surgical repair may not eliminate risk of dissection & death, & earlier intervention based on family history or affected person's personal assessment of risk vs benefit may be indicated. Standard treatment for allergic complications such as seasonal allergies, food allergies, asthma, & eczema Consider referral to allergist/immunologist in those w/severe disease. Inflammatory or allergic gastrointestinal findings are treated in standard fashion w/guidance of gastroenterologist. Mgmt by ophthalmologist w/expertise in connective tissue disorders Careful & aggressive refraction & visual correction is mandatory in young children at risk for amblyopia. CTA = CT angiogram; MRA = magnetic resonance angiography To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Loeys-Dietz Syndrome: Recommended Surveillance At least every other year, or more frequently per cardiologist More frequent imaging may be indicated based on genotype, family history, absolute vessel size or growth rate, or vascular pathology. Assessment for refractive error Specific assessment for retinal detachment CTA = computerized tomography angiography; MRA = magnetic resonance angiography The following should be avoided: Contact sports, competitive sports, and isometric exercise. Note: Individuals can and should remain active with aerobic activities performed in moderation. Agents that stimulate the cardiovascular system, including routine use of decongestants or triptan medications for migraine headache management Activities that cause joint injury or pain For individuals at risk for recurrent pneumothorax, breathing against a resistance (e.g., playing a brass instrument) or positive pressure ventilation (e.g., scuba diving) It is recommended that the genetic status of relatives of any age at risk for LDS be clarified either by molecular genetic testing or by clinical examination so that affected individuals can undergo regular cardiovascular screening to detect aortic aneurysms and initiate appropriate medical or surgical intervention (see Molecular genetic testing if the LDS-related pathogenic variant(s) in the family is known Examination for manifestations of LDS if the pathogenic variant(s) in the family is not known. Echocardiography and extensive vascular imaging of relatives is indicated upon identification of any suggestive findings of LDS, and even in apparently unaffected individuals if findings are subtle in the index case. See Pregnancy can be dangerous for women with LDS. Complications include aortic dissection/rupture or uterine rupture during pregnancy or delivery, or aortic dissection/rupture in the immediate postpartum period. Increased frequency of aortic imaging is recommended, both during pregnancy and in the weeks following delivery. However, with appropriate supervision and high-risk obstetric management, women with LDS can tolerate pregnancy and delivery [ Search • Echocardiography • MRA or CT w/3D reconstruction from head to pelvis to identify arterial aneurysms & arterial tortuosity throughout the arterial tree • Select findings (e.g., severe aortic dilatation) may require immediate attention of cardiologist or cardiothoracic surgeon. • Clinical assessment for pectus deformity, clubfoot, scoliosis, pes planus • Assessment for congenital hip dislocation & abnormal joint mobility • Spine radiographs (incl flexion & extension views of cervical spine) to detect skeletal manifestations that may require attention by an orthopedist (e.g., severe scoliosis, cervical spine instability) • Assessment for refractive errors • Specific assessment for retinal detachment • Aortic dissection occurs at smaller aortic diameters in LDS than in • Severe craniofacial manifestations are often assoc w/& can be used to predict severe cardiovascular manifestations. • Vascular disease is not limited to the aortic root. Imaging of the complete arterial tree from head to pelvis by MRA or CTA is necessary. • Many persons can undergo a valve-sparing procedure that precludes the need for chronic anticoagulation. • Surgical repair may not eliminate risk of dissection & death, & earlier intervention based on family history or affected person's personal assessment of risk vs benefit may be indicated. • Standard treatment for allergic complications such as seasonal allergies, food allergies, asthma, & eczema • Consider referral to allergist/immunologist in those w/severe disease. • Inflammatory or allergic gastrointestinal findings are treated in standard fashion w/guidance of gastroenterologist. • Mgmt by ophthalmologist w/expertise in connective tissue disorders • Careful & aggressive refraction & visual correction is mandatory in young children at risk for amblyopia. • At least every other year, or more frequently per cardiologist • More frequent imaging may be indicated based on genotype, family history, absolute vessel size or growth rate, or vascular pathology. • Assessment for refractive error • Specific assessment for retinal detachment • Contact sports, competitive sports, and isometric exercise. Note: Individuals can and should remain active with aerobic activities performed in moderation. • Agents that stimulate the cardiovascular system, including routine use of decongestants or triptan medications for migraine headache management • Activities that cause joint injury or pain • For individuals at risk for recurrent pneumothorax, breathing against a resistance (e.g., playing a brass instrument) or positive pressure ventilation (e.g., scuba diving) • Molecular genetic testing if the LDS-related pathogenic variant(s) in the family is known • Examination for manifestations of LDS if the pathogenic variant(s) in the family is not known. Echocardiography and extensive vascular imaging of relatives is indicated upon identification of any suggestive findings of LDS, and even in apparently unaffected individuals if findings are subtle in the index case. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with LDS, the evaluations summarized in Loeys-Dietz Syndrome: Recommended Evaluations Following Initial Diagnosis Echocardiography MRA or CT w/3D reconstruction from head to pelvis to identify arterial aneurysms & arterial tortuosity throughout the arterial tree Select findings (e.g., severe aortic dilatation) may require immediate attention of cardiologist or cardiothoracic surgeon. Clinical assessment for pectus deformity, clubfoot, scoliosis, pes planus Assessment for congenital hip dislocation & abnormal joint mobility Spine radiographs (incl flexion & extension views of cervical spine) to detect skeletal manifestations that may require attention by an orthopedist (e.g., severe scoliosis, cervical spine instability) Assessment for refractive errors Specific assessment for retinal detachment LDS = Loeys-Dietz syndrome; MOI = mode of inheritance; MRA = magnetic resonance angiography Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Echocardiography • MRA or CT w/3D reconstruction from head to pelvis to identify arterial aneurysms & arterial tortuosity throughout the arterial tree • Select findings (e.g., severe aortic dilatation) may require immediate attention of cardiologist or cardiothoracic surgeon. • Clinical assessment for pectus deformity, clubfoot, scoliosis, pes planus • Assessment for congenital hip dislocation & abnormal joint mobility • Spine radiographs (incl flexion & extension views of cervical spine) to detect skeletal manifestations that may require attention by an orthopedist (e.g., severe scoliosis, cervical spine instability) • Assessment for refractive errors • Specific assessment for retinal detachment ## Treatment of Manifestations Management of LDS is most effective through the coordinated input of a multidisciplinary team of specialists including a clinical geneticist, cardiologist, cardiothoracic surgeon, orthopedist, and ophthalmologist (see Loeys-Dietz Syndrome: Treatment of Manifestations Aortic dissection occurs at smaller aortic diameters in LDS than in Severe craniofacial manifestations are often assoc w/& can be used to predict severe cardiovascular manifestations. Vascular disease is not limited to the aortic root. Imaging of the complete arterial tree from head to pelvis by MRA or CTA is necessary. Many persons can undergo a valve-sparing procedure that precludes the need for chronic anticoagulation. Surgical repair may not eliminate risk of dissection & death, & earlier intervention based on family history or affected person's personal assessment of risk vs benefit may be indicated. Standard treatment for allergic complications such as seasonal allergies, food allergies, asthma, & eczema Consider referral to allergist/immunologist in those w/severe disease. Inflammatory or allergic gastrointestinal findings are treated in standard fashion w/guidance of gastroenterologist. Mgmt by ophthalmologist w/expertise in connective tissue disorders Careful & aggressive refraction & visual correction is mandatory in young children at risk for amblyopia. CTA = CT angiogram; MRA = magnetic resonance angiography • Aortic dissection occurs at smaller aortic diameters in LDS than in • Severe craniofacial manifestations are often assoc w/& can be used to predict severe cardiovascular manifestations. • Vascular disease is not limited to the aortic root. Imaging of the complete arterial tree from head to pelvis by MRA or CTA is necessary. • Many persons can undergo a valve-sparing procedure that precludes the need for chronic anticoagulation. • Surgical repair may not eliminate risk of dissection & death, & earlier intervention based on family history or affected person's personal assessment of risk vs benefit may be indicated. • Standard treatment for allergic complications such as seasonal allergies, food allergies, asthma, & eczema • Consider referral to allergist/immunologist in those w/severe disease. • Inflammatory or allergic gastrointestinal findings are treated in standard fashion w/guidance of gastroenterologist. • Mgmt by ophthalmologist w/expertise in connective tissue disorders • Careful & aggressive refraction & visual correction is mandatory in young children at risk for amblyopia. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Loeys-Dietz Syndrome: Recommended Surveillance At least every other year, or more frequently per cardiologist More frequent imaging may be indicated based on genotype, family history, absolute vessel size or growth rate, or vascular pathology. Assessment for refractive error Specific assessment for retinal detachment CTA = computerized tomography angiography; MRA = magnetic resonance angiography • At least every other year, or more frequently per cardiologist • More frequent imaging may be indicated based on genotype, family history, absolute vessel size or growth rate, or vascular pathology. • Assessment for refractive error • Specific assessment for retinal detachment ## Agents/Circumstances to Avoid The following should be avoided: Contact sports, competitive sports, and isometric exercise. Note: Individuals can and should remain active with aerobic activities performed in moderation. Agents that stimulate the cardiovascular system, including routine use of decongestants or triptan medications for migraine headache management Activities that cause joint injury or pain For individuals at risk for recurrent pneumothorax, breathing against a resistance (e.g., playing a brass instrument) or positive pressure ventilation (e.g., scuba diving) • Contact sports, competitive sports, and isometric exercise. Note: Individuals can and should remain active with aerobic activities performed in moderation. • Agents that stimulate the cardiovascular system, including routine use of decongestants or triptan medications for migraine headache management • Activities that cause joint injury or pain • For individuals at risk for recurrent pneumothorax, breathing against a resistance (e.g., playing a brass instrument) or positive pressure ventilation (e.g., scuba diving) ## Evaluation of Relatives at Risk It is recommended that the genetic status of relatives of any age at risk for LDS be clarified either by molecular genetic testing or by clinical examination so that affected individuals can undergo regular cardiovascular screening to detect aortic aneurysms and initiate appropriate medical or surgical intervention (see Molecular genetic testing if the LDS-related pathogenic variant(s) in the family is known Examination for manifestations of LDS if the pathogenic variant(s) in the family is not known. Echocardiography and extensive vascular imaging of relatives is indicated upon identification of any suggestive findings of LDS, and even in apparently unaffected individuals if findings are subtle in the index case. See • Molecular genetic testing if the LDS-related pathogenic variant(s) in the family is known • Examination for manifestations of LDS if the pathogenic variant(s) in the family is not known. Echocardiography and extensive vascular imaging of relatives is indicated upon identification of any suggestive findings of LDS, and even in apparently unaffected individuals if findings are subtle in the index case. ## Pregnancy Management Pregnancy can be dangerous for women with LDS. Complications include aortic dissection/rupture or uterine rupture during pregnancy or delivery, or aortic dissection/rupture in the immediate postpartum period. Increased frequency of aortic imaging is recommended, both during pregnancy and in the weeks following delivery. However, with appropriate supervision and high-risk obstetric management, women with LDS can tolerate pregnancy and delivery [ ## Therapies Under Investigation Search ## Genetic Counseling Loeys-Dietz syndrome (LDS) caused by a pathogenic variant in Approximately 75% of individuals diagnosed with LDS have the disorder as the result of a Approximately 25% of individuals diagnosed with LDS have an affected parent. Familial recurrence is more common in less severe presentations of LDS. 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 both parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and determine their need for If a molecular diagnosis has been established in the proband, the pathogenic variant identified in the proband is not identified in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism * (parental somatic and gonadal mosaicism have been reported in rare families [ * Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. A proband may appear to be the only family member with LDS 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, If a parent of the proband is affected and/or is known to have the LDS-related pathogenic variant identified in the proband, the risk to the sibs is 50%. Clinical variability may be observed among individuals in the same family who have the same pathogenic variant. If the proband has a known LDS-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 gonadal mosaicism [ If both 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 reduced penetrance in a heterozygous parent or parental gonadal mosaicism. Each child of an individual with LDS has a 50% chance of inheriting the pathogenic variant. The penetrance of 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. 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 can be dangerous for women with LDS; appropriate supervision and high-risk obstetric management is recommended (see 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 75% of individuals diagnosed with LDS have the disorder as the result of a • Approximately 25% of individuals diagnosed with LDS have an affected parent. Familial recurrence is more common in less severe presentations of LDS. • 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 both parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and determine their need for • If a molecular diagnosis has been established in the proband, the pathogenic variant identified in the proband is not identified in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism * (parental somatic and gonadal mosaicism have been reported in rare families [ • * Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism * (parental somatic and gonadal mosaicism have been reported in rare families [ • * Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. • A proband may appear to be the only family member with LDS 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, • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism * (parental somatic and gonadal mosaicism have been reported in rare families [ • * Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. • If a parent of the proband is affected and/or is known to have the LDS-related pathogenic variant identified in the proband, the risk to the sibs is 50%. • Clinical variability may be observed among individuals in the same family who have the same pathogenic variant. • If the proband has a known LDS-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 gonadal mosaicism [ • If both 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 reduced penetrance in a heterozygous parent or parental gonadal mosaicism. • Each child of an individual with LDS has a 50% chance of inheriting the pathogenic variant. • The penetrance of • 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 or at risk. • Pregnancy can be dangerous for women with LDS; appropriate supervision and high-risk obstetric management is recommended (see ## Mode of Inheritance Loeys-Dietz syndrome (LDS) caused by a pathogenic variant in ## Autosomal Dominant Inheritance – Risk to Family Members Approximately 75% of individuals diagnosed with LDS have the disorder as the result of a Approximately 25% of individuals diagnosed with LDS have an affected parent. Familial recurrence is more common in less severe presentations of LDS. 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 both parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and determine their need for If a molecular diagnosis has been established in the proband, the pathogenic variant identified in the proband is not identified in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism * (parental somatic and gonadal mosaicism have been reported in rare families [ * Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. A proband may appear to be the only family member with LDS 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, If a parent of the proband is affected and/or is known to have the LDS-related pathogenic variant identified in the proband, the risk to the sibs is 50%. Clinical variability may be observed among individuals in the same family who have the same pathogenic variant. If the proband has a known LDS-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 gonadal mosaicism [ If both 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 reduced penetrance in a heterozygous parent or parental gonadal mosaicism. Each child of an individual with LDS has a 50% chance of inheriting the pathogenic variant. The penetrance of • Approximately 75% of individuals diagnosed with LDS have the disorder as the result of a • Approximately 25% of individuals diagnosed with LDS have an affected parent. Familial recurrence is more common in less severe presentations of LDS. • 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 both parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and determine their need for • If a molecular diagnosis has been established in the proband, the pathogenic variant identified in the proband is not identified in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism * (parental somatic and gonadal mosaicism have been reported in rare families [ • * Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism * (parental somatic and gonadal mosaicism have been reported in rare families [ • * Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. • A proband may appear to be the only family member with LDS 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, • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism * (parental somatic and gonadal mosaicism have been reported in rare families [ • * Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. • If a parent of the proband is affected and/or is known to have the LDS-related pathogenic variant identified in the proband, the risk to the sibs is 50%. • Clinical variability may be observed among individuals in the same family who have the same pathogenic variant. • If the proband has a known LDS-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 gonadal mosaicism [ • If both 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 reduced penetrance in a heterozygous parent or parental gonadal mosaicism. • Each child of an individual with LDS has a 50% chance of inheriting the pathogenic variant. • The penetrance of ## Autosomal Recessive 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. ## 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 can be dangerous for women with LDS; appropriate supervision and high-risk obstetric management is recommended (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. • Pregnancy can be dangerous for women with LDS; appropriate supervision and high-risk obstetric management is recommended (see ## Prenatal Testing and Preimplantation Genetic Testing Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources Canada • • Canada • • • • • • • • • ## Molecular Genetics Loeys-Dietz Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Loeys-Dietz Syndrome ( In the initial description of In keeping with this hypothesis, one of the original individuals with a Marfan syndrome-like phenotype was shown to contain a translocation breakpoint within Experiments exploring TGF-β signaling in cells that only express mutated receptors may not be informative for the situation in vivo when affected individuals are heterozygous for these pathogenic variants. Diminished but not absent function of TGF-β receptors may initiate chronic and dysregulated compensatory mechanisms that result in too much TGF-β signaling. Indeed, the study of fibroblasts derived from heterozygous individuals with LDS failed to reveal any defect in the acute phase response to administered ligand and showed an apparent increase in TGF-β signaling after 24 hours of ligand deprivation and a slower decline in the TGF-β signal after restoration of ligand. An even more informative result was the observation of increased nuclear accumulation of phosphorylated mothers against decapentaplegic homolog 2 (the protein encoded by Loeys-Dietz Syndrome: Gene-Specific Laboratory Considerations Variation in Ala repeat length ( Missense variants in the extracellular cytokine-binding domain & variants leading to haploinsufficiency do not cause LDS. Variants that do not escape nonsense-mediated decay are considered non-pathogenic. Missense variants in the serine-threonine kinase domain have a higher likelihood of being pathogenic. Genes from • Variation in Ala repeat length ( • Missense variants in the extracellular cytokine-binding domain & variants leading to haploinsufficiency do not cause LDS. • Variants that do not escape nonsense-mediated decay are considered non-pathogenic. • Missense variants in the serine-threonine kinase domain have a higher likelihood of being pathogenic. ## Molecular Pathogenesis In the initial description of In keeping with this hypothesis, one of the original individuals with a Marfan syndrome-like phenotype was shown to contain a translocation breakpoint within Experiments exploring TGF-β signaling in cells that only express mutated receptors may not be informative for the situation in vivo when affected individuals are heterozygous for these pathogenic variants. Diminished but not absent function of TGF-β receptors may initiate chronic and dysregulated compensatory mechanisms that result in too much TGF-β signaling. Indeed, the study of fibroblasts derived from heterozygous individuals with LDS failed to reveal any defect in the acute phase response to administered ligand and showed an apparent increase in TGF-β signaling after 24 hours of ligand deprivation and a slower decline in the TGF-β signal after restoration of ligand. An even more informative result was the observation of increased nuclear accumulation of phosphorylated mothers against decapentaplegic homolog 2 (the protein encoded by Loeys-Dietz Syndrome: Gene-Specific Laboratory Considerations Variation in Ala repeat length ( Missense variants in the extracellular cytokine-binding domain & variants leading to haploinsufficiency do not cause LDS. Variants that do not escape nonsense-mediated decay are considered non-pathogenic. Missense variants in the serine-threonine kinase domain have a higher likelihood of being pathogenic. Genes from • Variation in Ala repeat length ( • Missense variants in the extracellular cytokine-binding domain & variants leading to haploinsufficiency do not cause LDS. • Variants that do not escape nonsense-mediated decay are considered non-pathogenic. • Missense variants in the serine-threonine kinase domain have a higher likelihood of being pathogenic. ## Chapter Notes Gretchen Oswald ( Prof Harry C Dietz ( Contact Prof Dietz and Prof Loeys to inquire about review of variants of uncertain significance in genes associated with LDS. HD would like to acknowledge funding support from the Howard Hughes Medical Institute, the National Institutes of Health, the Bloomberg Fund of the Marfan Foundation, the Smilow Center for Marfan Syndrome Research, the Loeys-Dietz Syndrome Foundation, the Feather Foundation, the DEFY Foundation, the Ehlers-Danlos Syndrome Foundation, and the Kasper, Aldredge, Coles and Daskal Family Foundations for generous research support. BL would like to acknowledge funding support from the European Research Council (ERC), Research Foundation Flanders (FWO), the F101G Foundation, and the Methusalem fund from the University of Antwerp. Both HD and BL thank their colleagues, trainees, and patients for essential contributions, inspiration, and insights. 12 September 2024 (sw) Comprehensive update posted live 1 March 2018 (ma) Comprehensive update posted live 11 July 2013 (me) Comprehensive update posted live 28 February 2008 (me) Review posted live 2 July 2007 (bl) Original submission • 12 September 2024 (sw) Comprehensive update posted live • 1 March 2018 (ma) Comprehensive update posted live • 11 July 2013 (me) Comprehensive update posted live • 28 February 2008 (me) Review posted live • 2 July 2007 (bl) Original submission ## Author Notes Gretchen Oswald ( Prof Harry C Dietz ( Contact Prof Dietz and Prof Loeys to inquire about review of variants of uncertain significance in genes associated with LDS. ## Acknowledgments HD would like to acknowledge funding support from the Howard Hughes Medical Institute, the National Institutes of Health, the Bloomberg Fund of the Marfan Foundation, the Smilow Center for Marfan Syndrome Research, the Loeys-Dietz Syndrome Foundation, the Feather Foundation, the DEFY Foundation, the Ehlers-Danlos Syndrome Foundation, and the Kasper, Aldredge, Coles and Daskal Family Foundations for generous research support. BL would like to acknowledge funding support from the European Research Council (ERC), Research Foundation Flanders (FWO), the F101G Foundation, and the Methusalem fund from the University of Antwerp. Both HD and BL thank their colleagues, trainees, and patients for essential contributions, inspiration, and insights. ## Revision History 12 September 2024 (sw) Comprehensive update posted live 1 March 2018 (ma) Comprehensive update posted live 11 July 2013 (me) Comprehensive update posted live 28 February 2008 (me) Review posted live 2 July 2007 (bl) Original submission • 12 September 2024 (sw) Comprehensive update posted live • 1 March 2018 (ma) Comprehensive update posted live • 11 July 2013 (me) Comprehensive update posted live • 28 February 2008 (me) Review posted live • 2 July 2007 (bl) Original submission ## References ## Literature Cited	[]	28/2/2008	12/9/2024	29/4/2008	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
lowe	lowe	[ "Oculocerebrorenal Syndrome", "Oculocerebrorenal Syndrome of Lowe", "Oculocerebrorenal Syndrome", "Oculocerebrorenal Syndrome of Lowe", "Inositol polyphosphate 5-phosphatase OCRL", "OCRL", "Lowe Syndrome" ]	Lowe Syndrome	Richard Alan Lewis, Robert L Nussbaum, Eileen D Brewer	Summary Lowe syndrome (oculocerebrorenal syndrome) is characterized by involvement of the eyes, central nervous system, and kidneys. Dense congenital cataracts are found in all affected boys and infantile glaucoma in approximately 50%. All boys have impaired vision; corrected acuity is rarely better than 20/100. Generalized hypotonia is noted at birth and is of central (brain) origin. Deep tendon reflexes are usually absent. Hypotonia may slowly improve with age, but normal motor tone and strength are never achieved. Motor milestones are delayed. Almost all affected males have some degree of intellectual disability; 10%-25% function in the low-normal or borderline range, approximately 25% in the mild-to-moderate range, and 50%-65% in the severe-to-profound range of intellectual disability. Affected males have varying degrees of proximal renal tubular dysfunction of the Fanconi type, including low molecular-weight (LMW) proteinuria, aminoaciduria, bicarbonate wasting and renal tubular acidosis, phosphaturia with hypophosphatemia and renal rickets, hypercalciuria, sodium and potassium wasting, and polyuria. The features of symptomatic Fanconi syndrome do not usually become manifest until after the first few months of life, except for LMW proteinuria. Glomerulosclerosis associated with chronic tubular injury usually results in slowly progressive chronic renal failure and end-stage renal disease between the second and fourth decades of life. The diagnosis of Lowe syndrome is established in a male proband with typical clinical and laboratory findings and a hemizygous pathogenic variant in Early removal of cataracts with postoperative glasses; management of glaucoma; early infant therapy, preschool intervention program and individualized education program throughout schooling; behavior modification plan; anticonvulsant therapy if seizures are present. Treatment of renal tubular dysfunction includes oral supplements of sodium and potassium bicarbonate or citrate to correct acidosis and hypokalemia, and oral phosphate and oral calcitriol (1,25-dihydroxyvitamin D Consider human growth hormone therapy to improve growth velocity; tube feedings may be needed to treat infant feeding problems associated with hypotonia; standard treatment for gastroesophageal reflux if present. Bracing or surgery for severe or progressive scoliosis or joint hypermobility; resection of fibromas and cutaneous cysts if painful or impairing function. Lowe syndrome is inherited in an X-linked manner.	## Diagnosis Lowe syndrome Bilateral dense congenital cataracts Infantile congenital hypotonia Delayed development Proximal renal tubular transport dysfunction of the Fanconi type characterized by low molecular-weight (LMW) proteinuria (including retinol binding protein, N-acetyl glucosaminidase, and albumin), aminoaciduria and varying degrees of bicarbonaturia and acidosis, phosphaturia and hypophosphatemia, and hypercalciuria. Note: LMW proteinuria, characterized by the excretion of proteins such as retinal binding protein and N-acetyl glucosaminidase, is seen in Lowe syndrome, the allelic disorder Dent disease (see Note: If a variant of unknown significance or no pathogenic variant is identified in a male with a clinical diagnosis consistent with Lowe syndrome, testing of inositol polyphosphate 5-phosphatase OCRL-1 activity in cultured skin fibroblasts is a possible option. Affected males have less than 10% normal activity of the enzyme. Such testing is abnormal in more than 99% of affected males and was shown to have high negative predictive value for Lowe syndrome in individuals referred with only partial overlap with Lowe syndrome phenotype who had no pathogenic variant found in 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 Lowe syndrome is broad, individuals with the distinctive findings described in For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see 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 Lowe 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. Translocations between an autosome and an X chromosome with a breakpoint through • Bilateral dense congenital cataracts • Infantile congenital hypotonia • Delayed development • Proximal renal tubular transport dysfunction of the Fanconi type characterized by low molecular-weight (LMW) proteinuria (including retinol binding protein, N-acetyl glucosaminidase, and albumin), aminoaciduria and varying degrees of bicarbonaturia and acidosis, phosphaturia and hypophosphatemia, and hypercalciuria. • For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see • For an introduction to multigene panels click ## Suggestive Findings Lowe syndrome Bilateral dense congenital cataracts Infantile congenital hypotonia Delayed development Proximal renal tubular transport dysfunction of the Fanconi type characterized by low molecular-weight (LMW) proteinuria (including retinol binding protein, N-acetyl glucosaminidase, and albumin), aminoaciduria and varying degrees of bicarbonaturia and acidosis, phosphaturia and hypophosphatemia, and hypercalciuria. Note: LMW proteinuria, characterized by the excretion of proteins such as retinal binding protein and N-acetyl glucosaminidase, is seen in Lowe syndrome, the allelic disorder Dent disease (see • Bilateral dense congenital cataracts • Infantile congenital hypotonia • Delayed development • Proximal renal tubular transport dysfunction of the Fanconi type characterized by low molecular-weight (LMW) proteinuria (including retinol binding protein, N-acetyl glucosaminidase, and albumin), aminoaciduria and varying degrees of bicarbonaturia and acidosis, phosphaturia and hypophosphatemia, and hypercalciuria. ## Establishing the Diagnosis Note: If a variant of unknown significance or no pathogenic variant is identified in a male with a clinical diagnosis consistent with Lowe syndrome, testing of inositol polyphosphate 5-phosphatase OCRL-1 activity in cultured skin fibroblasts is a possible option. Affected males have less than 10% normal activity of the enzyme. Such testing is abnormal in more than 99% of affected males and was shown to have high negative predictive value for Lowe syndrome in individuals referred with only partial overlap with Lowe syndrome phenotype who had no pathogenic variant found in 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 Lowe syndrome is broad, individuals with the distinctive findings described in For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see 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 Lowe 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. Translocations between an autosome and an X chromosome with a breakpoint through • For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see • For an introduction to multigene panels click ## 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 Lowe syndrome is broad, individuals with the distinctive findings described in For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see 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 Lowe 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. Translocations between an autosome and an X chromosome with a breakpoint through • For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see • For an introduction to multigene panels click ## Clinical Characteristics Usually only males have the disorder. A few affected females with the clinical manifestations of Lowe syndrome have been reported [ The major clinical manifestations found in males with Lowe syndrome involve the eyes, central nervous system, and kidneys. Nearly all post-pubertal heterozygous females have lens opacities; a few will have additional findings. With the wide availability of molecular genetic testing, phenotypic heterogeneity appears to be substantially greater than previously suspected, such that individuals who lack certain features of Lowe syndrome can still have pathogenic variants in Microphthalmos and enophthalmos, related to the lens abnormality, are noted occasionally. Infantile glaucoma, present in approximately 50% of affected males, is difficult to control and often results in buphthalmos (enlarged eyes) and progressive visual loss [ Strabismus, retinal dystrophy, secondary corneal scarring, and calcific band keratopathy with keloid formation [ All boys have impaired vision; corrected acuity is rarely better than 20/100 [ Feeding difficulties in infancy associated with poor head control, sucking, or swallowing may be a consequence of the hypotonia. Decreased motor tone also results in delayed motor milestones. Independent ambulation occurs in approximately 25% of boys between age three and six years and in 75% by age six to 13 years. Some never walk, requiring the use of a wheelchair for mobility [ Approximately 50% of affected boys have seizure disorders, most often of the generalized type and usually starting before age six years [ Behavior problems (i.e., self-stimulation or stereotypic and obsessive-compulsive behaviors) are frequent and include many problems common to visually and intellectually handicapped individuals. Occasionally, violent tantrums or aggressive and self-abusive behaviors occur [ Almost all affected males have some degree of intellectual impairment. Between 10% and 25% of affected males function in the low-normal or borderline range, approximately 25% function in the mild-to-moderate range, and 50%-65% function in the severe-to-profound range of intellectual disability [ As adults, most affected men reside with their families. A few are functional enough to live in a group home or even independently with appropriate assistance and guidance. LMW proteins are normally filtered by the glomerulus, then reabsorbed in the proximal tubule through endocytosis and metabolized in lysosomes in proximal tubular cells. When reabsorption and/or metabolism are dysfunctional, LMW proteins, including retinol-binding protein, beta-2-microglobulin, and the lysosmal enzyme N-acetyl glucosaminidase, are lost in the urine. LMW proteinuria has been identified as early as just after birth [ The molecular size of albumin is at the upper end of the size range for LMW proteins, so the small percentage of albumin that is normally filtered by the glomerulus is also reabsorbed and metabolized by the proximal tubule via the LMW protein transport process. In Lowe syndrome, proximal renal tubular dysfunction often leads to clinically apparent albuminuria (urine dipstick albumin 1-4+; nephrotic range proteinuria >1 g/m All boys have LMW proteinuria and albuminuria, likely due to downstream disordered endocytosis and postendocytic membrane trafficking in the proximal tubular cell [ Progressive glomerulosclerosis likely results from progressive renal tubular injury, which eventually may lead to chronic kidney disease (CKD) and end-stage renal disease (ESRD) between the second and fourth decades of life [ Slow weight gain may occur because of insufficient caloric intake. Gastroesophageal reflux, most common in infancy, may be seen at any age. Aspiration of food along with a decreased ability to cough effectively to clear lung fields may lead to atelectasis, pneumonia, or chronic lung disease. Poor abdominal muscle tone increases the risk for chronic constipation and the development of (predominantly inguinal) hernias. However, even in the presence of well-corrected Fanconi syndrome and no findings of rickets, some boys have repeat pathologic bone fractures with poor healing and bone demineralization on radiographs or bone densitometry [E Brewer, personal observation]. Whether some of the bone disease is related to inactivity resulting from muscle hypotonia and immobilization in severely affected boys or to a primary defect in bone mineralization/molecular transport requires further study. Decreased truncal motor tone increases the risk of developing scoliosis, present in approximately 50% of affected boys [ Hypermobile joints may result in joint dislocation, especially of the hips and knees. In affected teenagers and adults, joint swelling, arthritis, tenosynovitis, and subcutaneous benign fibromas, often on the hands and feet and most especially in areas of repeated trauma, are noted frequently [ Elevated serum creatine kinase (CK), AST, and LDH are typical in Lowe syndrome and likely due to abnormal muscle metabolism [ Undescended testes (cryptorchidism) are noted in approximately one third of affected boys [ Puberty may be delayed in onset; otherwise, male secondary sexual development is normal. Superficial cysts may occur in the mouth and on the skin, especially the scalp, lower back and buttocks.The skin cysts may become painful and occasionally infected. Histologic examination revealed epidermal cysts in which the dermis was lined by several layers of stratified squamous epithelium with a granular layer and filled with keratin flakes [ Approximately 95% of postpubertal heterozygous females have characteristic findings in the lens of each eye on slit lamp examination through a dilated pupil by an experienced ophthalmologist. The lens findings have correlated with the results of molecular genetic studies in predicting heterozygosity for the pathogenic variant in Most heterozygous females show numerous irregular, punctate, smooth, off-white (white to gray) opacities, present in the lens cortex, more in the anterior cortex than the posterior cortex, and distributed in radial bands that wrap around the lens equator. Classically, the nucleus is spared. On retroillumination, the opacities are distributed in a radial, spoke-like pattern and can be relatively dense in a wedge shape comparable to an hour or two on the face of a clock, alternating with a similar-sized wedge with few to no opacities. A few heterozygous females (~10%) have a dense central precapsular dead-white cataract at the posterior pole of the lens that may be visually significant if it is large. Similarly, the cataracts in some heterozygous females may become visually significant by the fourth decade and require surgery without the diagnostic importance being recognized. The manifestations of Lowe syndrome besides those seen in the lens are not observed in heterozygous females unless there is either rare X;autosome translocation with the X chromosome breakpoint at To date, correlation of genotype with phenotype has not been established. Differing clinical courses have been noted in unrelated individuals with the same Penetrance is complete, with variability in severity of phenotype in affected males within any given family. Oculocerebrorenal syndrome, the formal term for this disorder, is synonymous with Lowe syndrome, and may be preferred to avoid eponymous syndrome nomenclature. Lowe syndrome is an uncommon, pan ethnic disorder with an estimated prevalence of 1:500,000 in the general population, based on observations of the American Lowe Syndrome Association and the Italian Association of Lowe syndrome [ The disorder has been seen in America, Europe, Australia, Japan, and India and is believed to occur worldwide. • Microphthalmos and enophthalmos, related to the lens abnormality, are noted occasionally. • Infantile glaucoma, present in approximately 50% of affected males, is difficult to control and often results in buphthalmos (enlarged eyes) and progressive visual loss [ • Strabismus, retinal dystrophy, secondary corneal scarring, and calcific band keratopathy with keloid formation [ • Feeding difficulties in infancy associated with poor head control, sucking, or swallowing may be a consequence of the hypotonia. • Decreased motor tone also results in delayed motor milestones. Independent ambulation occurs in approximately 25% of boys between age three and six years and in 75% by age six to 13 years. Some never walk, requiring the use of a wheelchair for mobility [ • LMW proteins are normally filtered by the glomerulus, then reabsorbed in the proximal tubule through endocytosis and metabolized in lysosomes in proximal tubular cells. • When reabsorption and/or metabolism are dysfunctional, LMW proteins, including retinol-binding protein, beta-2-microglobulin, and the lysosmal enzyme N-acetyl glucosaminidase, are lost in the urine. LMW proteinuria has been identified as early as just after birth [ • Slow weight gain may occur because of insufficient caloric intake. • Gastroesophageal reflux, most common in infancy, may be seen at any age. • Aspiration of food along with a decreased ability to cough effectively to clear lung fields may lead to atelectasis, pneumonia, or chronic lung disease. • Poor abdominal muscle tone increases the risk for chronic constipation and the development of (predominantly inguinal) hernias. • Decreased truncal motor tone increases the risk of developing scoliosis, present in approximately 50% of affected boys [ • Hypermobile joints may result in joint dislocation, especially of the hips and knees. • In affected teenagers and adults, joint swelling, arthritis, tenosynovitis, and subcutaneous benign fibromas, often on the hands and feet and most especially in areas of repeated trauma, are noted frequently [ • Elevated serum creatine kinase (CK), AST, and LDH are typical in Lowe syndrome and likely due to abnormal muscle metabolism [ • Undescended testes (cryptorchidism) are noted in approximately one third of affected boys [ • Puberty may be delayed in onset; otherwise, male secondary sexual development is normal. ## Clinical Description Usually only males have the disorder. A few affected females with the clinical manifestations of Lowe syndrome have been reported [ The major clinical manifestations found in males with Lowe syndrome involve the eyes, central nervous system, and kidneys. Nearly all post-pubertal heterozygous females have lens opacities; a few will have additional findings. With the wide availability of molecular genetic testing, phenotypic heterogeneity appears to be substantially greater than previously suspected, such that individuals who lack certain features of Lowe syndrome can still have pathogenic variants in Microphthalmos and enophthalmos, related to the lens abnormality, are noted occasionally. Infantile glaucoma, present in approximately 50% of affected males, is difficult to control and often results in buphthalmos (enlarged eyes) and progressive visual loss [ Strabismus, retinal dystrophy, secondary corneal scarring, and calcific band keratopathy with keloid formation [ All boys have impaired vision; corrected acuity is rarely better than 20/100 [ Feeding difficulties in infancy associated with poor head control, sucking, or swallowing may be a consequence of the hypotonia. Decreased motor tone also results in delayed motor milestones. Independent ambulation occurs in approximately 25% of boys between age three and six years and in 75% by age six to 13 years. Some never walk, requiring the use of a wheelchair for mobility [ Approximately 50% of affected boys have seizure disorders, most often of the generalized type and usually starting before age six years [ Behavior problems (i.e., self-stimulation or stereotypic and obsessive-compulsive behaviors) are frequent and include many problems common to visually and intellectually handicapped individuals. Occasionally, violent tantrums or aggressive and self-abusive behaviors occur [ Almost all affected males have some degree of intellectual impairment. Between 10% and 25% of affected males function in the low-normal or borderline range, approximately 25% function in the mild-to-moderate range, and 50%-65% function in the severe-to-profound range of intellectual disability [ As adults, most affected men reside with their families. A few are functional enough to live in a group home or even independently with appropriate assistance and guidance. LMW proteins are normally filtered by the glomerulus, then reabsorbed in the proximal tubule through endocytosis and metabolized in lysosomes in proximal tubular cells. When reabsorption and/or metabolism are dysfunctional, LMW proteins, including retinol-binding protein, beta-2-microglobulin, and the lysosmal enzyme N-acetyl glucosaminidase, are lost in the urine. LMW proteinuria has been identified as early as just after birth [ The molecular size of albumin is at the upper end of the size range for LMW proteins, so the small percentage of albumin that is normally filtered by the glomerulus is also reabsorbed and metabolized by the proximal tubule via the LMW protein transport process. In Lowe syndrome, proximal renal tubular dysfunction often leads to clinically apparent albuminuria (urine dipstick albumin 1-4+; nephrotic range proteinuria >1 g/m All boys have LMW proteinuria and albuminuria, likely due to downstream disordered endocytosis and postendocytic membrane trafficking in the proximal tubular cell [ Progressive glomerulosclerosis likely results from progressive renal tubular injury, which eventually may lead to chronic kidney disease (CKD) and end-stage renal disease (ESRD) between the second and fourth decades of life [ Slow weight gain may occur because of insufficient caloric intake. Gastroesophageal reflux, most common in infancy, may be seen at any age. Aspiration of food along with a decreased ability to cough effectively to clear lung fields may lead to atelectasis, pneumonia, or chronic lung disease. Poor abdominal muscle tone increases the risk for chronic constipation and the development of (predominantly inguinal) hernias. However, even in the presence of well-corrected Fanconi syndrome and no findings of rickets, some boys have repeat pathologic bone fractures with poor healing and bone demineralization on radiographs or bone densitometry [E Brewer, personal observation]. Whether some of the bone disease is related to inactivity resulting from muscle hypotonia and immobilization in severely affected boys or to a primary defect in bone mineralization/molecular transport requires further study. Decreased truncal motor tone increases the risk of developing scoliosis, present in approximately 50% of affected boys [ Hypermobile joints may result in joint dislocation, especially of the hips and knees. In affected teenagers and adults, joint swelling, arthritis, tenosynovitis, and subcutaneous benign fibromas, often on the hands and feet and most especially in areas of repeated trauma, are noted frequently [ Elevated serum creatine kinase (CK), AST, and LDH are typical in Lowe syndrome and likely due to abnormal muscle metabolism [ Undescended testes (cryptorchidism) are noted in approximately one third of affected boys [ Puberty may be delayed in onset; otherwise, male secondary sexual development is normal. Superficial cysts may occur in the mouth and on the skin, especially the scalp, lower back and buttocks.The skin cysts may become painful and occasionally infected. Histologic examination revealed epidermal cysts in which the dermis was lined by several layers of stratified squamous epithelium with a granular layer and filled with keratin flakes [ Approximately 95% of postpubertal heterozygous females have characteristic findings in the lens of each eye on slit lamp examination through a dilated pupil by an experienced ophthalmologist. The lens findings have correlated with the results of molecular genetic studies in predicting heterozygosity for the pathogenic variant in Most heterozygous females show numerous irregular, punctate, smooth, off-white (white to gray) opacities, present in the lens cortex, more in the anterior cortex than the posterior cortex, and distributed in radial bands that wrap around the lens equator. Classically, the nucleus is spared. On retroillumination, the opacities are distributed in a radial, spoke-like pattern and can be relatively dense in a wedge shape comparable to an hour or two on the face of a clock, alternating with a similar-sized wedge with few to no opacities. A few heterozygous females (~10%) have a dense central precapsular dead-white cataract at the posterior pole of the lens that may be visually significant if it is large. Similarly, the cataracts in some heterozygous females may become visually significant by the fourth decade and require surgery without the diagnostic importance being recognized. The manifestations of Lowe syndrome besides those seen in the lens are not observed in heterozygous females unless there is either rare X;autosome translocation with the X chromosome breakpoint at • Microphthalmos and enophthalmos, related to the lens abnormality, are noted occasionally. • Infantile glaucoma, present in approximately 50% of affected males, is difficult to control and often results in buphthalmos (enlarged eyes) and progressive visual loss [ • Strabismus, retinal dystrophy, secondary corneal scarring, and calcific band keratopathy with keloid formation [ • Feeding difficulties in infancy associated with poor head control, sucking, or swallowing may be a consequence of the hypotonia. • Decreased motor tone also results in delayed motor milestones. Independent ambulation occurs in approximately 25% of boys between age three and six years and in 75% by age six to 13 years. Some never walk, requiring the use of a wheelchair for mobility [ • LMW proteins are normally filtered by the glomerulus, then reabsorbed in the proximal tubule through endocytosis and metabolized in lysosomes in proximal tubular cells. • When reabsorption and/or metabolism are dysfunctional, LMW proteins, including retinol-binding protein, beta-2-microglobulin, and the lysosmal enzyme N-acetyl glucosaminidase, are lost in the urine. LMW proteinuria has been identified as early as just after birth [ • Slow weight gain may occur because of insufficient caloric intake. • Gastroesophageal reflux, most common in infancy, may be seen at any age. • Aspiration of food along with a decreased ability to cough effectively to clear lung fields may lead to atelectasis, pneumonia, or chronic lung disease. • Poor abdominal muscle tone increases the risk for chronic constipation and the development of (predominantly inguinal) hernias. • Decreased truncal motor tone increases the risk of developing scoliosis, present in approximately 50% of affected boys [ • Hypermobile joints may result in joint dislocation, especially of the hips and knees. • In affected teenagers and adults, joint swelling, arthritis, tenosynovitis, and subcutaneous benign fibromas, often on the hands and feet and most especially in areas of repeated trauma, are noted frequently [ • Elevated serum creatine kinase (CK), AST, and LDH are typical in Lowe syndrome and likely due to abnormal muscle metabolism [ • Undescended testes (cryptorchidism) are noted in approximately one third of affected boys [ • Puberty may be delayed in onset; otherwise, male secondary sexual development is normal. ## Males Microphthalmos and enophthalmos, related to the lens abnormality, are noted occasionally. Infantile glaucoma, present in approximately 50% of affected males, is difficult to control and often results in buphthalmos (enlarged eyes) and progressive visual loss [ Strabismus, retinal dystrophy, secondary corneal scarring, and calcific band keratopathy with keloid formation [ All boys have impaired vision; corrected acuity is rarely better than 20/100 [ Feeding difficulties in infancy associated with poor head control, sucking, or swallowing may be a consequence of the hypotonia. Decreased motor tone also results in delayed motor milestones. Independent ambulation occurs in approximately 25% of boys between age three and six years and in 75% by age six to 13 years. Some never walk, requiring the use of a wheelchair for mobility [ Approximately 50% of affected boys have seizure disorders, most often of the generalized type and usually starting before age six years [ Behavior problems (i.e., self-stimulation or stereotypic and obsessive-compulsive behaviors) are frequent and include many problems common to visually and intellectually handicapped individuals. Occasionally, violent tantrums or aggressive and self-abusive behaviors occur [ Almost all affected males have some degree of intellectual impairment. Between 10% and 25% of affected males function in the low-normal or borderline range, approximately 25% function in the mild-to-moderate range, and 50%-65% function in the severe-to-profound range of intellectual disability [ As adults, most affected men reside with their families. A few are functional enough to live in a group home or even independently with appropriate assistance and guidance. LMW proteins are normally filtered by the glomerulus, then reabsorbed in the proximal tubule through endocytosis and metabolized in lysosomes in proximal tubular cells. When reabsorption and/or metabolism are dysfunctional, LMW proteins, including retinol-binding protein, beta-2-microglobulin, and the lysosmal enzyme N-acetyl glucosaminidase, are lost in the urine. LMW proteinuria has been identified as early as just after birth [ The molecular size of albumin is at the upper end of the size range for LMW proteins, so the small percentage of albumin that is normally filtered by the glomerulus is also reabsorbed and metabolized by the proximal tubule via the LMW protein transport process. In Lowe syndrome, proximal renal tubular dysfunction often leads to clinically apparent albuminuria (urine dipstick albumin 1-4+; nephrotic range proteinuria >1 g/m All boys have LMW proteinuria and albuminuria, likely due to downstream disordered endocytosis and postendocytic membrane trafficking in the proximal tubular cell [ Progressive glomerulosclerosis likely results from progressive renal tubular injury, which eventually may lead to chronic kidney disease (CKD) and end-stage renal disease (ESRD) between the second and fourth decades of life [ Slow weight gain may occur because of insufficient caloric intake. Gastroesophageal reflux, most common in infancy, may be seen at any age. Aspiration of food along with a decreased ability to cough effectively to clear lung fields may lead to atelectasis, pneumonia, or chronic lung disease. Poor abdominal muscle tone increases the risk for chronic constipation and the development of (predominantly inguinal) hernias. However, even in the presence of well-corrected Fanconi syndrome and no findings of rickets, some boys have repeat pathologic bone fractures with poor healing and bone demineralization on radiographs or bone densitometry [E Brewer, personal observation]. Whether some of the bone disease is related to inactivity resulting from muscle hypotonia and immobilization in severely affected boys or to a primary defect in bone mineralization/molecular transport requires further study. Decreased truncal motor tone increases the risk of developing scoliosis, present in approximately 50% of affected boys [ Hypermobile joints may result in joint dislocation, especially of the hips and knees. In affected teenagers and adults, joint swelling, arthritis, tenosynovitis, and subcutaneous benign fibromas, often on the hands and feet and most especially in areas of repeated trauma, are noted frequently [ Elevated serum creatine kinase (CK), AST, and LDH are typical in Lowe syndrome and likely due to abnormal muscle metabolism [ Undescended testes (cryptorchidism) are noted in approximately one third of affected boys [ Puberty may be delayed in onset; otherwise, male secondary sexual development is normal. Superficial cysts may occur in the mouth and on the skin, especially the scalp, lower back and buttocks.The skin cysts may become painful and occasionally infected. Histologic examination revealed epidermal cysts in which the dermis was lined by several layers of stratified squamous epithelium with a granular layer and filled with keratin flakes [ • Microphthalmos and enophthalmos, related to the lens abnormality, are noted occasionally. • Infantile glaucoma, present in approximately 50% of affected males, is difficult to control and often results in buphthalmos (enlarged eyes) and progressive visual loss [ • Strabismus, retinal dystrophy, secondary corneal scarring, and calcific band keratopathy with keloid formation [ • Feeding difficulties in infancy associated with poor head control, sucking, or swallowing may be a consequence of the hypotonia. • Decreased motor tone also results in delayed motor milestones. Independent ambulation occurs in approximately 25% of boys between age three and six years and in 75% by age six to 13 years. Some never walk, requiring the use of a wheelchair for mobility [ • LMW proteins are normally filtered by the glomerulus, then reabsorbed in the proximal tubule through endocytosis and metabolized in lysosomes in proximal tubular cells. • When reabsorption and/or metabolism are dysfunctional, LMW proteins, including retinol-binding protein, beta-2-microglobulin, and the lysosmal enzyme N-acetyl glucosaminidase, are lost in the urine. LMW proteinuria has been identified as early as just after birth [ • Slow weight gain may occur because of insufficient caloric intake. • Gastroesophageal reflux, most common in infancy, may be seen at any age. • Aspiration of food along with a decreased ability to cough effectively to clear lung fields may lead to atelectasis, pneumonia, or chronic lung disease. • Poor abdominal muscle tone increases the risk for chronic constipation and the development of (predominantly inguinal) hernias. • Decreased truncal motor tone increases the risk of developing scoliosis, present in approximately 50% of affected boys [ • Hypermobile joints may result in joint dislocation, especially of the hips and knees. • In affected teenagers and adults, joint swelling, arthritis, tenosynovitis, and subcutaneous benign fibromas, often on the hands and feet and most especially in areas of repeated trauma, are noted frequently [ • Elevated serum creatine kinase (CK), AST, and LDH are typical in Lowe syndrome and likely due to abnormal muscle metabolism [ • Undescended testes (cryptorchidism) are noted in approximately one third of affected boys [ • Puberty may be delayed in onset; otherwise, male secondary sexual development is normal. ## Females Approximately 95% of postpubertal heterozygous females have characteristic findings in the lens of each eye on slit lamp examination through a dilated pupil by an experienced ophthalmologist. The lens findings have correlated with the results of molecular genetic studies in predicting heterozygosity for the pathogenic variant in Most heterozygous females show numerous irregular, punctate, smooth, off-white (white to gray) opacities, present in the lens cortex, more in the anterior cortex than the posterior cortex, and distributed in radial bands that wrap around the lens equator. Classically, the nucleus is spared. On retroillumination, the opacities are distributed in a radial, spoke-like pattern and can be relatively dense in a wedge shape comparable to an hour or two on the face of a clock, alternating with a similar-sized wedge with few to no opacities. A few heterozygous females (~10%) have a dense central precapsular dead-white cataract at the posterior pole of the lens that may be visually significant if it is large. Similarly, the cataracts in some heterozygous females may become visually significant by the fourth decade and require surgery without the diagnostic importance being recognized. The manifestations of Lowe syndrome besides those seen in the lens are not observed in heterozygous females unless there is either rare X;autosome translocation with the X chromosome breakpoint at ## Genotype-Phenotype Correlations To date, correlation of genotype with phenotype has not been established. Differing clinical courses have been noted in unrelated individuals with the same ## Penetrance Penetrance is complete, with variability in severity of phenotype in affected males within any given family. ## Nomenclature Oculocerebrorenal syndrome, the formal term for this disorder, is synonymous with Lowe syndrome, and may be preferred to avoid eponymous syndrome nomenclature. ## Prevalence Lowe syndrome is an uncommon, pan ethnic disorder with an estimated prevalence of 1:500,000 in the general population, based on observations of the American Lowe Syndrome Association and the Italian Association of Lowe syndrome [ The disorder has been seen in America, Europe, Australia, Japan, and India and is believed to occur worldwide. ## Genetically Related (Allelic) Disorders Pathogenic variants in Although the renal tubulopathy in Lowe syndrome (which is mainly characterized by altered low molecular-weight protein and albumin 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 domains [ • 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 domains [ ## Differential Diagnosis Low molecular-weight (LMW) proteinuria is a feature of Fanconi syndrome and can also be seen in other conditions including Like Lowe syndrome, generalized congenital infections (e.g., rubella) are associated with a combination of congenital or neonatal-onset cataracts, hypotonia, proximal renal tubular dysfunction, and/or delayed development and should be considered in the differential diagnosis of Lowe syndrome. Genetic disorders that may be associated with these features are summarized in Disorders to Consider in the Differential Diagnosis of Lowe Syndrome Hypotonia May have congenital cataracts Retinal dystrophy Renal cysts DD Poor feeding Neonatal seizures common Distinctive craniofacial features (e.g., flat face, broad nasal bridge, large anterior fontanelle, widely split sutures) SNHL Liver dysfunction Bony stippling (chondrodysplasia punctata) of patella(e) & other long bones may occur. Congenital cataracts Hypotonia ID Dental anomalies (e.g., cone-shaped incisors & supernumerary teeth) Heterozygous females have Y-shaped sutural cataracts & may have dental anomalies. Microcornea No renal abnormalities Facial dysmorphisms (e.g., anteverted pinnae) Absence of characteristic facial appearance seen in Lowe syndrome (i.e., sunken orbits & bitemporal hollowing) Congenital cataracts Hypotonia Renal anomalies (most commonly renal hypoplasia or agenesis, renal cortical cysts, hydronephrosis, & structural anomalies of collecting system) Moderate-to-severe ID Prenatal & postnatal growth restriction Microcephaly Distinctive facial features Cleft palate Cardiac defects Underdeveloped external genitalia in males Postaxial polydactyly 2-3 toe syndactyly Cataracts ID Infantile hypotonia; severe generalized weakness at birth Respiratory insufficiency at birth No significant renal disease Seizures Hypotonia at birth or developing in early infancy Renal findings incl Fanconi syndrome, RTA, & renal failure are frequent (esp in Kearns-Sayre syndrome, mt encephalomyopathy & mt depletion syndrome) Common features of mt disease incl: ptosis, external ophthalmoplegia, proximal myopathy, exercise intolerance, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, diabetes mellitus CNS findings (often fluctuating): encephalopathy, dementia, migraine, stroke-like episodes, ataxia Note: Congenital cataract is seen in Renal Fanconi syndrome Poor growth; in untreated persons, failure to grow is generally noticed at age 6-9 mos. Retinal disease Typical cystine crystals on slit lamp exam of cornea No cataracts Intellectual abilities low-normal No hypotonia LMW proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, CKD Cataract may be seen in juveniles w/Donnai-Barrow syndrome. High myopia No congenital cataracts SNHL Hypertelorism Large anterior fontanelles Hypotonia not typical; motor milestones only slightly delayed AD = autosomal dominant; AR = autosomal recessive; CKD = chronic kidney disease; CNS = central nervous system; DD = developmental delay; DiffDx = differential diagnosis; ID = intellectual disability; LMW = low molecular-weight; MOI = mode of inheritance; mt = mitochondrial; RTA = renal tubular acidosis; SNHL = sensorineural hearing loss; XL = X-linked Mitochondrial disorders may be caused by defects of nuclear DNA or mtDNA: nuclear gene defects may be inherited in an autosomal recessive, autosomal dominant, or X-linked manner, mitochondrial DNA defects are transmitted by maternal inheritance. Cystine-depleting therapy begun just after birth can attenuate the Fanconi syndrome. • Hypotonia • May have congenital cataracts • Retinal dystrophy • Renal cysts • DD • Poor feeding • Neonatal seizures common • Distinctive craniofacial features (e.g., flat face, broad nasal bridge, large anterior fontanelle, widely split sutures) • SNHL • Liver dysfunction • Bony stippling (chondrodysplasia punctata) of patella(e) & other long bones may occur. • Congenital cataracts • Hypotonia • ID • Dental anomalies (e.g., cone-shaped incisors & supernumerary teeth) • Heterozygous females have Y-shaped sutural cataracts & may have dental anomalies. • Microcornea • No renal abnormalities • Facial dysmorphisms (e.g., anteverted pinnae) • Absence of characteristic facial appearance seen in Lowe syndrome (i.e., sunken orbits & bitemporal hollowing) • Congenital cataracts • Hypotonia • Renal anomalies (most commonly renal hypoplasia or agenesis, renal cortical cysts, hydronephrosis, & structural anomalies of collecting system) • Moderate-to-severe ID • Prenatal & postnatal growth restriction • Microcephaly • Distinctive facial features • Cleft palate • Cardiac defects • Underdeveloped external genitalia in males • Postaxial polydactyly • 2-3 toe syndactyly • Cataracts • ID • Infantile hypotonia; severe generalized weakness at birth • Respiratory insufficiency at birth • No significant renal disease • Seizures • Hypotonia at birth or developing in early infancy • Renal findings incl Fanconi syndrome, RTA, & renal failure are frequent (esp in Kearns-Sayre syndrome, mt encephalomyopathy & mt depletion syndrome) • Common features of mt disease incl: ptosis, external ophthalmoplegia, proximal myopathy, exercise intolerance, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, diabetes mellitus • CNS findings (often fluctuating): encephalopathy, dementia, migraine, stroke-like episodes, ataxia • Note: Congenital cataract is seen in • Renal Fanconi syndrome • Poor growth; in untreated persons, failure to grow is generally noticed at age 6-9 mos. • Retinal disease • Typical cystine crystals on slit lamp exam of cornea • No cataracts • Intellectual abilities low-normal • No hypotonia • LMW proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, CKD • Cataract may be seen in juveniles w/Donnai-Barrow syndrome. • High myopia • No congenital cataracts • SNHL • Hypertelorism • Large anterior fontanelles • Hypotonia not typical; motor milestones only slightly delayed ## Management To establish the extent of disease in an individual diagnosed with Lowe syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Lowe Syndrome Developmental & behavior assessments EEG if seizures present to optimize therapy Serum electrolytes, glucose, calcium, phosphorus, creatinine Simultaneous urinalysis, urine pH, sodium, potassium, chloride, calcium, phosphorus, creatinine, amino acids, protein & retinol-binding protein, &/or N-acetyl glucosaminidase (if available) Growth parameters Infants assessed for feeding problems & gastroesophageal reflux, incl a pH probe study Interpretation of these results allows diagnosis of type 2 renal tubular acidosis, hypokalemia, phosphate wasting with decreased tubular reabsorption of phosphate (TRP), hypercalciuria (urine calcium/creatinine ratio >0.02), amino aciduria, albuminuria (urine dipstick-positive albumin and urine protein/creatinine ratio >0.2), LMW proteinuria, and CKD (serum creatinine). Management of the varying clinical problems usually requires more than one medical specialist; experts in pediatric ophthalmology, nephrology, clinical biochemical genetics, metabolism, nutrition, endocrinology, neurology, child development, behavior, rehabilitation, general surgery, orthopedics, or dentistry may be involved. Treatment of Manifestations in Individuals with Lowe Syndrome Early removal to promote proper visual stimulation & development Postoperative glasses to improve vision & replace the crystalline lens power Surgical implantation of artificial lenses (due to high prevalence of infantile glaucoma) Contact lenses (due to risk for corneal keloids) NG tube feedings or feeding gastrostomy w/or w/o fundoplication may be necessary to treat infant feeding & nutrition problems related to hypotonia. Standard treatment for gastroesophageal reflux, if present CKD = chronic kidney disease; ESRD = end-stage renal disease; IEP = individualized education program; NG = nasogastric Recommended Surveillance for Individuals with Lowe Syndrome As determined by specialist based on type & severity of eye abnormality Promptly w/any signs of ↑ intraocular pressure (e.g., excessive tearing, eye rubbing, change in clarity/transparency of cornea) If on supplemental bicarbonate or citrate, phosphorus or calcitriol or other vitamin D analog, need kidney function assessment May need serum vitamin D-25 hydroxy to assess for parent vitamin D deficiency Every 1-2 mos in infants Every 3-6 mos in older children & adolescents Every 3 mos if on growth hormone Testing includes measurement of (a) serum concentrations of electrolyte, blood urea nitrogen (BUN), creatinine, calcium, phosphorus, albumin, intact parathyroid hormone, and 1,25-dihydroxyvitamin D and (b) urinalysis and random urine protein, calcium, and creatinine. See Search • Developmental & behavior assessments • EEG if seizures present to optimize therapy • Serum electrolytes, glucose, calcium, phosphorus, creatinine • Simultaneous urinalysis, urine pH, sodium, potassium, chloride, calcium, phosphorus, creatinine, amino acids, protein & retinol-binding protein, &/or N-acetyl glucosaminidase (if available) • Growth parameters • Infants assessed for feeding problems & gastroesophageal reflux, incl a pH probe study • Early removal to promote proper visual stimulation & development • Postoperative glasses to improve vision & replace the crystalline lens power • Surgical implantation of artificial lenses (due to high prevalence of infantile glaucoma) • Contact lenses (due to risk for corneal keloids) • NG tube feedings or feeding gastrostomy w/or w/o fundoplication may be necessary to treat infant feeding & nutrition problems related to hypotonia. • Standard treatment for gastroesophageal reflux, if present • As determined by specialist based on type & severity of eye abnormality • Promptly w/any signs of ↑ intraocular pressure (e.g., excessive tearing, eye rubbing, change in clarity/transparency of cornea) • If on supplemental bicarbonate or citrate, phosphorus or calcitriol or other vitamin D analog, need kidney function assessment • May need serum vitamin D-25 hydroxy to assess for parent vitamin D deficiency • Every 1-2 mos in infants • Every 3-6 mos in older children & adolescents • Every 3 mos if on growth hormone ## Evaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with Lowe syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Lowe Syndrome Developmental & behavior assessments EEG if seizures present to optimize therapy Serum electrolytes, glucose, calcium, phosphorus, creatinine Simultaneous urinalysis, urine pH, sodium, potassium, chloride, calcium, phosphorus, creatinine, amino acids, protein & retinol-binding protein, &/or N-acetyl glucosaminidase (if available) Growth parameters Infants assessed for feeding problems & gastroesophageal reflux, incl a pH probe study Interpretation of these results allows diagnosis of type 2 renal tubular acidosis, hypokalemia, phosphate wasting with decreased tubular reabsorption of phosphate (TRP), hypercalciuria (urine calcium/creatinine ratio >0.02), amino aciduria, albuminuria (urine dipstick-positive albumin and urine protein/creatinine ratio >0.2), LMW proteinuria, and CKD (serum creatinine). • Developmental & behavior assessments • EEG if seizures present to optimize therapy • Serum electrolytes, glucose, calcium, phosphorus, creatinine • Simultaneous urinalysis, urine pH, sodium, potassium, chloride, calcium, phosphorus, creatinine, amino acids, protein & retinol-binding protein, &/or N-acetyl glucosaminidase (if available) • Growth parameters • Infants assessed for feeding problems & gastroesophageal reflux, incl a pH probe study ## Treatment of Manifestations Management of the varying clinical problems usually requires more than one medical specialist; experts in pediatric ophthalmology, nephrology, clinical biochemical genetics, metabolism, nutrition, endocrinology, neurology, child development, behavior, rehabilitation, general surgery, orthopedics, or dentistry may be involved. Treatment of Manifestations in Individuals with Lowe Syndrome Early removal to promote proper visual stimulation & development Postoperative glasses to improve vision & replace the crystalline lens power Surgical implantation of artificial lenses (due to high prevalence of infantile glaucoma) Contact lenses (due to risk for corneal keloids) NG tube feedings or feeding gastrostomy w/or w/o fundoplication may be necessary to treat infant feeding & nutrition problems related to hypotonia. Standard treatment for gastroesophageal reflux, if present CKD = chronic kidney disease; ESRD = end-stage renal disease; IEP = individualized education program; NG = nasogastric • Early removal to promote proper visual stimulation & development • Postoperative glasses to improve vision & replace the crystalline lens power • Surgical implantation of artificial lenses (due to high prevalence of infantile glaucoma) • Contact lenses (due to risk for corneal keloids) • NG tube feedings or feeding gastrostomy w/or w/o fundoplication may be necessary to treat infant feeding & nutrition problems related to hypotonia. • Standard treatment for gastroesophageal reflux, if present ## Surveillance Recommended Surveillance for Individuals with Lowe Syndrome As determined by specialist based on type & severity of eye abnormality Promptly w/any signs of ↑ intraocular pressure (e.g., excessive tearing, eye rubbing, change in clarity/transparency of cornea) If on supplemental bicarbonate or citrate, phosphorus or calcitriol or other vitamin D analog, need kidney function assessment May need serum vitamin D-25 hydroxy to assess for parent vitamin D deficiency Every 1-2 mos in infants Every 3-6 mos in older children & adolescents Every 3 mos if on growth hormone Testing includes measurement of (a) serum concentrations of electrolyte, blood urea nitrogen (BUN), creatinine, calcium, phosphorus, albumin, intact parathyroid hormone, and 1,25-dihydroxyvitamin D and (b) urinalysis and random urine protein, calcium, and creatinine. • As determined by specialist based on type & severity of eye abnormality • Promptly w/any signs of ↑ intraocular pressure (e.g., excessive tearing, eye rubbing, change in clarity/transparency of cornea) • If on supplemental bicarbonate or citrate, phosphorus or calcitriol or other vitamin D analog, need kidney function assessment • May need serum vitamin D-25 hydroxy to assess for parent vitamin D deficiency • Every 1-2 mos in infants • Every 3-6 mos in older children & adolescents • Every 3 mos if on growth hormone ## Agents/Circumstances to Avoid ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Lowe 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 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, the mother may be a heterozygote or have germline mosaicism, or the affected male may have a The mother of a child with Lowe syndrome who represents a simplex case (i.e., a single occurrence in a family) should be thoroughly evaluated by an experienced ophthalmologist for the characteristic punctate anterior radial lens opacities seen in female heterozygotes. If the mother of the proband is heterozygous for an If the proband represents a simplex case (i.e., a single occurrence in a family) and if the Note: Molecular genetic testing may be able to identify the family member in whom a Biochemical enzymatic assays for inositol polyphosphate 5-phosphatase OCRL-1 activity are The optimal time for determination of genetic risk, clarification of heterozygote 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 adult females who are heterozygotes, or are at risk of being heterozygotes. Once the Because of the relatively high rate (4.5%) of germline mosaicism, Differences in perspective may exist among medical professionals and within families regarding the use 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, the mother may be a heterozygote or have germline mosaicism, or the affected male may have a • The mother of a child with Lowe syndrome who represents a simplex case (i.e., a single occurrence in a family) should be thoroughly evaluated by an experienced ophthalmologist for the characteristic punctate anterior radial lens opacities seen in female heterozygotes. • If the mother of the proband is heterozygous for an • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the • The optimal time for determination of genetic risk, clarification of heterozygote 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 adult females who are heterozygotes, or are at risk of being heterozygotes. ## Mode of Inheritance Lowe 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 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, the mother may be a heterozygote or have germline mosaicism, or the affected male may have a The mother of a child with Lowe syndrome who represents a simplex case (i.e., a single occurrence in a family) should be thoroughly evaluated by an experienced ophthalmologist for the characteristic punctate anterior radial lens opacities seen in female heterozygotes. If the mother of the proband is heterozygous for an If the proband represents a simplex case (i.e., a single occurrence in a family) and if the Note: Molecular genetic testing may be able to identify the family member in whom a • The father of an affected male will not have the disorder, nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. • Note: If a woman has more than one affected child and no other affected relatives and if the • If a male is the only affected family member, the mother may be a heterozygote or have germline mosaicism, or the affected male may have a • The mother of a child with Lowe syndrome who represents a simplex case (i.e., a single occurrence in a family) should be thoroughly evaluated by an experienced ophthalmologist for the characteristic punctate anterior radial lens opacities seen in female heterozygotes. • If the mother of the proband is heterozygous for an • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the ## Heterozygote Detection Biochemical enzymatic assays for inositol polyphosphate 5-phosphatase OCRL-1 activity are ## Related Genetic Counseling Issues The optimal time for determination of genetic risk, clarification of heterozygote 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 adult females who are heterozygotes, or are at risk of being heterozygotes. • The optimal time for determination of genetic risk, clarification of heterozygote 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 adult females who are heterozygotes, or are at risk of being heterozygotes. ## Prenatal Testing and Preimplantation Genetic Testing Once the Because of the relatively high rate (4.5%) of germline mosaicism, Differences in perspective may exist among medical professionals and within families regarding the use 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 864346 Plano TX 75086-4346 77 West Heath Road London NW3 7TH United Kingdom • • PO Box 864346 • Plano TX 75086-4346 • • • 77 West Heath Road • London NW3 7TH • United Kingdom • • • ## Molecular Genetics Lowe Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Lowe Syndrome ( Lowe syndrome results from loss of inositol polyphosphate 5-phosphatase OCRL-1 (phosphatidylinositol polyphosphate 5-phosphatase OCRL-1) activity. Although the exact mechanisms are unclear, the absence of the protein and elevated PtdIns (4,5) P Cell membrane composition Actin cytoskeletal organization Endocytosis Lysosomal-autophagic pathway Primary ciliary synthesis and function Loss of OCRL-1 ultimately leads to abnormal differentiation, cell migration, and function in certain cell types (i.e., renal tubule or lens epithelium). Such changes could result in the birth defects and other clinical manifestations of Lowe syndrome [ The enzyme is present in the trans-Golgi network and the endosomal and lysosomal compartment of a variety of cell types, including brain, skeletal muscle, heart, kidney (cultured proximal renal tubular cells), lung, ovary, testis, cultured fibroblasts, placenta, chorionic villi samples, and cultured amniocytes. Of the identified pathogenic variants, 93% have been located in exons 10-18 and exons 19-23 of • Cell membrane composition • Actin cytoskeletal organization • Endocytosis • Lysosomal-autophagic pathway • Primary ciliary synthesis and function ## Molecular Pathogenesis Lowe syndrome results from loss of inositol polyphosphate 5-phosphatase OCRL-1 (phosphatidylinositol polyphosphate 5-phosphatase OCRL-1) activity. Although the exact mechanisms are unclear, the absence of the protein and elevated PtdIns (4,5) P Cell membrane composition Actin cytoskeletal organization Endocytosis Lysosomal-autophagic pathway Primary ciliary synthesis and function Loss of OCRL-1 ultimately leads to abnormal differentiation, cell migration, and function in certain cell types (i.e., renal tubule or lens epithelium). Such changes could result in the birth defects and other clinical manifestations of Lowe syndrome [ The enzyme is present in the trans-Golgi network and the endosomal and lysosomal compartment of a variety of cell types, including brain, skeletal muscle, heart, kidney (cultured proximal renal tubular cells), lung, ovary, testis, cultured fibroblasts, placenta, chorionic villi samples, and cultured amniocytes. Of the identified pathogenic variants, 93% have been located in exons 10-18 and exons 19-23 of • Cell membrane composition • Actin cytoskeletal organization • Endocytosis • Lysosomal-autophagic pathway • Primary ciliary synthesis and function ## References ## Literature Cited ## Chapter Notes Eileen D Brewer, MD (2007-present) Richard A Lewis, MD, MS (2007-present) Robert L Nussbaum, MD (2007-present) Rebecca S Wappner, MD, FAAP, FACMG; Indiana University School of Medicine (2001-2007) 18 April 2019 (ha) Comprehensive update posted live 23 February 2012 (me) Comprehensive update posted live 12 March 2008 (cd) Revision: FISH analysis available on a clinical basis 16 November 2007 (cd) Revision: mutation scanning no longer available on a clinical basis 5 January 2007 (me) Comprehensive update posted live 19 September 2003 (me) Comprehensive update posted live 24 July 2001 (me) Review posted live 13 April 2001 (rw) Original submission • 18 April 2019 (ha) Comprehensive update posted live • 23 February 2012 (me) Comprehensive update posted live • 12 March 2008 (cd) Revision: FISH analysis available on a clinical basis • 16 November 2007 (cd) Revision: mutation scanning no longer available on a clinical basis • 5 January 2007 (me) Comprehensive update posted live • 19 September 2003 (me) Comprehensive update posted live • 24 July 2001 (me) Review posted live • 13 April 2001 (rw) Original submission ## Author History Eileen D Brewer, MD (2007-present) Richard A Lewis, MD, MS (2007-present) Robert L Nussbaum, MD (2007-present) Rebecca S Wappner, MD, FAAP, FACMG; Indiana University School of Medicine (2001-2007) ## Revision History 18 April 2019 (ha) Comprehensive update posted live 23 February 2012 (me) Comprehensive update posted live 12 March 2008 (cd) Revision: FISH analysis available on a clinical basis 16 November 2007 (cd) Revision: mutation scanning no longer available on a clinical basis 5 January 2007 (me) Comprehensive update posted live 19 September 2003 (me) Comprehensive update posted live 24 July 2001 (me) Review posted live 13 April 2001 (rw) Original submission • 18 April 2019 (ha) Comprehensive update posted live • 23 February 2012 (me) Comprehensive update posted live • 12 March 2008 (cd) Revision: FISH analysis available on a clinical basis • 16 November 2007 (cd) Revision: mutation scanning no longer available on a clinical basis • 5 January 2007 (me) Comprehensive update posted live • 19 September 2003 (me) Comprehensive update posted live • 24 July 2001 (me) Review posted live • 13 April 2001 (rw) Original submission	[ "F Anglani, L Terrin, M Brugnara, M Battista, V Cantaluppi, M Ceol, L Bertoldi, G Valle, MP Joy, BR Pober, M Longoni. Hypercalciuria and nephrolithiasis: Expanding the renal phenotype of Donnai-Barrow syndrome.. Clin Genet 2018;94:187-8", "BH Athreya, HR Schumacher, HD Getz, ME Norman, S Borden, CL Witzleben. Arthropathy of Lowe's (oculocerebrorenal) syndrome.. Arthritis Rheum 1983;26:728-35", "D Bockenhauer, A Bökenkamp, W van't Hoff, E Levtchenko, JE Kist-van Holthe, V Tasic, M Ludwig. Renal phenotype in Lowe Syndrome: a selective proximal tubular dysfunction.. Clin J Am Soc Nephrol. 2008;3:1430-6", "A Bökenkamp, D Böckenhauer, HI Cheong, B Hoppe, V Tasic, R Unwin, M Ludwig. Dent-2 disease: a mild variant of Lowe syndrome.. J Pediatr. 2009;155:94-9", "A Bökenkamp, M Ludwig. The oculocerebrorenal syndrome of Lowe: an update.. Pediatr Nephrol 2016;31:2201-12", "M Cau, M Addis, R Congiu, C Meloni, A Cao, S Santaniello, M Loi, F Emma, O Zuffardi, R Ciccone, G Sole, MA Melis. A locus for familial skewed X chromosome inactivation maps to chromosome Xq25 in a family with a female manifesting Lowe syndrome.. J Hum Genet. 2006;51:1030-6", "LR Charnas, WA Gahl. The oculocerebrorenal syndrome of Lowe.. Adv Pediatr 1991;38:75-107", "LR Charnas, I Bernardini, D Rader, JM Hoeg, WA Gahl. Clinical and laboratory findings in the oculocerebrorenal syndrome of Low, with special reference to growth and renal function.. N Engl J Med 1991;324:1318-25", "GW Cibis, RC Tripathi, BJ Tripathi, DJ Harris. Corneal keloid in Lowe's syndrome.. Arch Ophthalmol 1982;100:1795-9", "S Cui, CJ Guerriero, CM Szalinski, CL Kinlough, RP Hughey, OA Weisz. OCRL1 function in renal epithelial membrane traffic.. Am J Physiol Renal Physiol. 2010;298:F335-45", "MA De Matteis, L Staiano, F Emma, O Devuyst. The 5-phosphatase OCRL in Lowe syndrome and Dent disease 2.. Nature Reviews Nephrology 2017;13:455-70", "D Elliman, A Woodley. Tenosynovitis in Lowe syndrome.. J Pediatr 1983;103:1011", "BP Festa, M Berquez, A Gassama, I Amrein, HM Ismail, M Samardzija, L Staiano, A Luciani, C Grimm, RL Nussbaum, MA De Matteis, OM Dorchies, L Scapozza, DP Wolfer, O Devuyst. OCRL deficiency impairs endolysosomal function in a humanized mouse model for Lowe syndrome and dent disease.. Hum Mol Genet. 2019;28:1931-46", "J Finsterer, FA Scorza. Renal manifestations of primary mitochondrial disorders.. Biomed Rep. 2017;6:487-94", "M Harrison, EW Odell, EC Sheehy. Dental findings in Lowe syndrome. .. Pediatr Dent. 1999;21:425-8", "H Hichri, J Rendu, N Monnier, C Coutton, O Dorseuil, RV Poussou, G Baujat, A Blanchard, F Nobili, B Ranchin, M Remesy, R Salomon, V Satre, J Lunardi. From Lowe syndrome to Dent disease: correlations between mutations of the OCRL1 gene and clinical and biochemical phenotypes.. Hum Mutat. 2011;32:379-88", "SV Hodgson, JZ Heckmatt, E Hughes, JA Crolla, V Dubowitz, M Bobrow. A balanced de novo X/autosome translocation in a girl with manifestations of Lowe syndrome.. Am J Med Genet 1986;23:837-47", "RR Hoopes, AE Shrimpton, SJ Knohl, P Hueber, B Hoppe, J Matyus, A Simckes, V Tasic, B Toenshoff, SF Suchy, RL Nussbaum, SJ Scheinman. Dent Disease with mutations in OCRL1.. Am J Hum Genet 2005;76:260-7", "S Ikehara, A Utani. Multiple protrusive epidermal cysts on the scalp of a Lowe syndrome patient.. J Dermatol. 2017;44:105-7", "L Kenworthy, T Park, LR Charnas. Cognitive and behavioral profile of the oculocerebrorenal syndrome of Lowe.. Am J Med Genet 1993;46:297-303", "HK Kim, JH Kim, YM Kim, G-H Kim, BH Lee, J-H Choi. Lowe syndrome: a single center’s experience in Korea.. Korean J Pediatr 2014;57:140-8", "D Lasne, G Baujat, T Mirault, J Lunardi, F Grelac, M Egot, R Salomon, C Bachelot-Loza. Bleeding disorders in Lowe syndrome patients: evidence for a link between OCRL mutations and primary haemostasis disorders.. Br J Haematol. 2010;150:685-8", "GF Laube, IM Russell-Eggitt, WG van't Hoff. Early proximal tubular dysfunction in Lowe's syndrome.. Arch Dis Child 2004;89:479-80", "AM Leahey, LR Charnas, RL Nussbaum. Nonsense mutations in the OCRL-1 gene in patients with the oculocerebrorenal syndrome of Lowe.. Hum Mol Genet 1993;2:461-3", "T Lin, RA Lewis, RL Nussbaum. Molecular confirmation of carriers for Lowe syndrome.. Ophthalmology 1999;106:119-22", "N Luo, A Kumar, M Conwell, RN Weinreb, R Anderson, Y Sun. Compensatory Role of Inositol 5-Phosphatase INPP5B to OCRL in Primary Cilia Formation in Oculocerebrorenal Syndrome of Lowe.. PLoS One. 2013;8", "N Monnier, V Satre, E Lerouge, F Berthoin, J Lunardi. OCRL1 mutation analysis in French Lowe syndrome patients: implications for molecular diagnosis strategy and genetic counseling.. Hum Mutat 2000;16:157-65", "OT Mueller, JK Hartsfield, LA Gallardo, YP Essig, KL Miller, PR Papenhausen, TA Tedesco. Lowe oculocerebrorenal syndrome in a female with a balanced X;20 translocation: mapping of the X chromosome breakpoint.. Am J Hum Genet 1991;49:804-10", "Y Murakami, M Wataya-Kaneda, Y Iwatani, T Kubota, H Nakano, I Katayama. Novel mutation of. J Dermatol 2018;45:372-3", "F Recker, M Zaniew, D Bockenhauer, N Miglietti, A Bökenkamp, A Moczulska, A Rogowska-Kalisz, G Laube, V Said-Conti, B Kasap-Demir, A Niemirska, M Litwin, G Siten, KH Chrzanowska, A Krajewska-Walasek, M Szczepanska, K Pawlaczyk, P Sikora, M Ludwig. Characterization of 28 novel patients expands the mutational and phenotypic spectrum of Lowe syndrome.. Pediatr Nephrol 2015;30:931-43", "DS Reilly, RA Lewis, DH Ledbetter, RL Nussbaum. Tightly linked flanking markers for the Lowe oculocerebrorenal syndrome, with application to carrier assessment.. Am J Hum Genet 1988;42:748-55", "W Röschinger, AC Muntau, G Rudolph, AA Roscher, S Kammerer. Carrier assessment in families with lowe oculocerebrorenal syndrome: novel mutations in the OCRL1 gene and correlation of direct DNA diagnosis with ocular examination.. Mol Genet Metab 2000;69:213-22", "V Satre, N Monnier, F Berthoin, C Ayuso, A Joannard, PS Jouk, I Lopez-Pajares, A Megabarne, HJ Philippe, H Plauchu, ML Torres, J Lunardi. Characterization of a germline mosaicism in families with Lowe syndrome, and identification of seven novel mutations in the OCRL1 gene.. Am J Hum Genet 1999;65:68-76", "AE Shrimpton, RR Hoopes, SJ Knohl, P Hueber, AA Reed, PT Christie, T Igarashi, P Lee, A Lehman, C White, DV Milford, MR Sanchez, R Unwin, OM Wrong, RV Thakker, SJ Scheinman. OCRL1 mutations in Dent 2 patients suggest a mechanism for phenotypic variability.. Nephron Physiol. 2009;112:27-36", "SF Suchy, RL Nussbaum. The deficiency of PIP2 5-phosphatase in Lowe syndrome affects actin polymerization.. Am J Hum Genet 2002;71:1420-7", "E Tosetto, M Addis, G Caridi, C Meloni, F Emma, G Vergine, G Stringini, T Papalia, G Barbano, GM Ghiggeri, L Ruggeri, N Miglietti, A D'Angelo, MA Melis, F Anglani. Locus heterogeneity of Dent's disease: OCRL1 and TMEM27 genes in patients with no CLCN5 mutations.. Pediatr Nephrol. 2009;24:1967-73", "A Ungewickell, ME Ward, E Ungewickell, PW Majerus. The inositol polyphosphate 5-phosphatase Ocrl associates with endosomes that are partially coated with clathrin.. Proc Natl Acad Sci U S A 2004;101:13501-6", "M Vicinanza, A Di Campli, E Polishchuk, M Santoro, G Di Tullio, A Godi, E Levtchenko, MG De Leo, R Polishchuk, L Sandoval, MP Marzolo, MA De Matteis. OCRL controls trafficking through early endosomes via PtdIns4,5P. EMBO J. 2011;30:4970-85", "BE Warner, CD Inward, CP Burren. Gonadotrophin abnormalities in an infant with Lowe syndrome.. Endocrinol Diabetes Metab Case Rep. 2017:2017", "M Zaniew, A Bökenkamp, M Kolbuc, C La Scola, F Baronio, A Niemirska, M Szczepanska, J Burger, A La Manna, M Miklaszewska, A Rogowsha-Kalisz, J Gellermann, A Zampetoglou, A Wasilewska, M Roszak, J Moczko, A Krzemien, D Runowski, G Siten, I Zaluska-Lesniewska, P Fonduli, F Zurrida, F Paglialonga, Z Gucev, D Paripovic, R Rus, V Said-Conti, L Sartz, WY Chung, SJ Park, JW Lee, YH Park, YH Ahn, P Sikora, CJ Stefanidis, V Tasic, M Konrad, F Anglani, M Addis, HI Cheong, M Ludwig, D Bockehauer. Long-term renal outcome in children with. Nephrol Dial Transplant 2018;33:85-94", "X Zhang, PA Hartz, E Philip, LC Racusen, PW Majerus. Cell lines from kidney proximal tubules of a patient with Lowe syndrome lack OCRL inositol polyphosphate 5-phosphatase and accumulate phosphatidylinositol 4,5-bisphosphate.. J Biol Chem 1998;273:1574-82", "X Zhang, AB Jefferson, V Auethavekiat, PW Majerus. The protein deficient in Lowe syndrome is a phosphatidylinositol-4,5- bisphosphate 5-phosphatase.. Proc Natl Acad Sci U S A 1995;92:4853-6" ]	24/7/2001	18/4/2019	4/1/2019	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]

Subsets and Splits

No community queries yet

The top public SQL queries from the community will appear here once available.