Fabry disease is the most common of the lysosomal storage disorders and results from deficient activity of the enzyme alpha-galactosidase A (a-Gal A), leading to progressive lysosomal deposition of globotriaosylceramide and its derivatives in cells throughout the body. The classic form, occurring in males with less than 1% a-Gal A enzyme activity, usually has its onset in childhood or adolescence with periodic crises of severe pain in the extremities (acroparesthesia), the appearance of vascular cutaneous lesions (angiokeratomas), sweating abnormalities (anhidrosis, hypohidrosis, and rarely hyperhidrosis), characteristic corneal and lenticular opacities, and proteinuria. Gradual deterioration of renal function to end-stage renal disease (ESRD) usually occurs in men in the third to fifth decade. In middle age, most males successfully treated for ESRD develop cardiac and/or cerebrovascular disease, a major cause of morbidity and mortality. Heterozygous females typically have milder symptoms at a later age of onset than males. Rarely, females may be relatively asymptomatic throughout a normal life span or may have symptoms as severe as those observed in males with the classic phenotype. In contrast, late-onset forms occur in males with greater than 1% a-Gal A activity. Clinical manifestations include cardiac disease, which usually presents in the sixth to eighth decade with left ventricular hypertrophy, cardiomyopathy, arrhythmia, and proteinuria; renal failure, associated with ESRD but without the skin lesions or pain; or cerebrovascular disease presenting as stroke or transient ischemic attack.

The dystrophinopathies cover a spectrum of X-linked muscle disease ranging from mild to severe that includes Duchenne muscular dystrophy, Becker muscular dystrophy, and DMD-associated dilated cardiomyopathy (DCM). The mild end of the spectrum includes the phenotypes of asymptomatic increase in serum concentration of creatine phosphokinase (CK) and muscle cramps with myoglobinuria. The severe end of the spectrum includes progressive muscle diseases that are classified as Duchenne/Becker muscular dystrophy when skeletal muscle is primarily affected and as DMD-associated DCM when the heart is primarily affected. Duchenne muscular dystrophy (DMD) usually presents in early childhood with delayed motor milestones including delays in walking independently and standing up from a supine position. Proximal weakness causes a waddling gait and difficulty climbing stairs, running, jumping, and standing up from a squatting position. DMD is rapidly progressive, with affected children being wheelchair dependent by age 12 years. Cardiomyopathy occurs in almost all individuals with DMD after age 18 years. Few survive beyond the third decade, with respiratory complications and progressive cardiomyopathy being common causes of death. Becker muscular dystrophy (BMD) is characterized by later-onset skeletal muscle weakness. With improved diagnostic techniques, it has been recognized that the mild end of the spectrum includes men with onset of symptoms after age 30 years who remain ambulatory even into their 60s. Despite the milder skeletal muscle involvement, heart failure from DCM is a common cause of morbidity and the most common cause of death in BMD. Mean age of death is in the mid-40s. DMD-associated DCM is characterized by left ventricular dilation and congestive heart failure. Females heterozygous for a DMD pathogenic variant are at increased risk for DCM.

FBN1-related Marfan syndrome (Marfan syndrome), a systemic disorder of connective tissue with a high degree of clinical variability, comprises a broad phenotypic continuum ranging from mild (features of Marfan syndrome in one or a few systems) to severe and rapidly progressive neonatal multiorgan disease. Cardinal manifestations involve the ocular, skeletal, and cardiovascular systems. Ocular findings include myopia (>50% of affected individuals); ectopia lentis (seen in approximately 60% of affected individuals); and an increased risk for retinal detachment, glaucoma, and early cataracts. Skeletal system manifestations include bone overgrowth and joint laxity; disproportionately long extremities for the size of the trunk (dolichostenomelia); overgrowth of the ribs that can push the sternum in (pectus excavatum) or out (pectus carinatum); and scoliosis that ranges from mild to severe and progressive. The major morbidity and early mortality in Marfan syndrome relate to the cardiovascular system and include dilatation of the aorta at the level of the sinuses of Valsalva (predisposing to aortic tear and rupture), mitral valve prolapse with or without regurgitation, tricuspid valve prolapse, and enlargement of the proximal pulmonary artery. Severe and prolonged regurgitation of the mitral and/or aortic valve can predispose to left ventricular dysfunction and occasionally heart failure. With proper management, the life expectancy of someone with Marfan syndrome approximates that of the general population.

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 early progressive disease, CNS involvement (manifest primarily by progressive cognitive deterioration), progressive airway disease, and cardiac disease usually result in death in the first or second decade of life. In those with slowly progressive disease, the CNS is not (or is minimally) affected, although the effect of GAG accumulation on other organ systems may be early progressive to the same degree as in those who have progressive cognitive decline. Survival into the early adult years with normal intelligence is common in the slowly progressing form of the disease. 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.

Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are characterized by paragangliomas (tumors that arise from neuroendocrine tissues distributed along the paravertebral axis from the base of the skull to the pelvis) and pheochromocytomas (paragangliomas that are confined to the adrenal medulla). Sympathetic paragangliomas cause catecholamine excess; parasympathetic paragangliomas are most often nonsecretory. Extra-adrenal parasympathetic paragangliomas are located predominantly in the skull base and neck (referred to as head and neck PGL [HNPGL]) and sometimes in the upper mediastinum; approximately 95% of such tumors are nonsecretory. In contrast, sympathetic extra-adrenal paragangliomas are generally confined to the lower mediastinum, abdomen, and pelvis, and are typically secretory. Pheochromocytomas, which arise from the adrenal medulla, typically lead to catecholamine excess. Symptoms of PGL/PCC result from either mass effects or catecholamine hypersecretion (e.g., sustained or paroxysmal elevations in blood pressure, headache, episodic profuse sweating, forceful palpitations, pallor, and apprehension or anxiety). The risk for developing metastatic disease is greater for extra-adrenal sympathetic paragangliomas than for pheochromocytomas.

Hutchinson-Gilford progeria syndrome (HGPS) is characterized by clinical features that typically develop in childhood and resemble some features of accelerated aging. Children with HGPS usually appear normal at birth. Profound failure to thrive occurs during the first year. Characteristic facial features include head that is disproportionately large for the face, narrow nasal ridge, narrow nasal tip, thin vermilion of the upper and lower lips, small mouth, and retro- and micrognathia. Common features include loss of subcutaneous fat, delayed eruption and loss of primary teeth, abnormal skin with small outpouchings over the abdomen and upper thighs, alopecia, nail dystrophy, coxa valga, and progressive joint contractures. Later findings include low-frequency conductive hearing loss, dental crowding, and partial lack of secondary tooth eruption. Motor and mental development is normal. Death occurs as a result of complications of severe atherosclerosis, either cardiac disease (myocardial infarction or heart failure) or cerebrovascular disease (stroke), generally between ages six and 20 years. Average life span is approximately 14.5 years.

Adult Refsum disease (ARD is associated with elevated plasma phytanic acid levels, late childhood-onset (or later) retinitis pigmentosa, and variable combinations of anosmia, polyneuropathy, deafness, ataxia, and ichthyosis. Onset of symptoms ranges from age seven months to older than age 50 years. Cardiac arrhythmia and heart failure caused by cardiomyopathy are potentially severe health problems that develop later in life.

MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) is a multisystem disorder with protean manifestations. The vast majority of affected individuals develop signs and symptoms of MELAS between ages two and 40 years. Common clinical manifestations include stroke-like episodes, encephalopathy with seizures and/or dementia, muscle weakness and exercise intolerance, normal early psychomotor development, recurrent headaches, recurrent vomiting, hearing impairment, peripheral neuropathy, learning disability, and short stature. During the stroke-like episodes neuroimaging shows increased T2-weighted signal areas that do not correspond to the classic vascular distribution (hence the term "stroke-like"). Lactic acidemia is very common and muscle biopsies typically show ragged red fibers.

FLNA deficiency is associated with a phenotypic spectrum that includes FLNA-related periventricular nodular heterotopia (Huttenlocher syndrome), congenital heart disease (patent ductus arteriosus, atrial and ventricular septal defects), valvular dystrophy, dilation and rupture of the thoracic aortic, pulmonary disease (pulmonary hypertension, alveolar hypoplasia, emphysema, asthma, chronic bronchitis), gastrointestinal dysmotility and obstruction, joint hypermobility, and macrothrombocytopenia.

GLB1-related disorders comprise two phenotypically distinct lysosomal storage disorders: GM1 gangliosidosis and mucopolysaccharidosis type IVB (MPS IVB). The phenotype of GM1 gangliosidosis constitutes a spectrum ranging from severe (infantile) to intermediate (late-infantile and juvenile) to mild (chronic/adult). Type I (infantile) GM1 gangliosidosis begins before age 12 months. Prenatal manifestations may include nonimmune hydrops fetalis, intrauterine growth restriction, and placental vacuolization; congenital dermal melanocytosis (Mongolian spots) may be observed. Macular cherry-red spot is detected on eye exam. Progressive central nervous system dysfunction leads to spasticity and rapid regression; blindness, deafness, decerebrate rigidity, seizures, feeding difficulties, and oral secretions are observed. Life expectancy is two to three years. Type II can be subdivided into the late-infantile (onset age 1-3 years) and juvenile (onset age 3-10 years) phenotypes. Central nervous system dysfunction manifests as progressive cognitive, motor, and speech decline as measured by psychometric testing. There may be mild corneal clouding, hepatosplenomegaly, and/or cardiomyopathy; the typical course is characterized by progressive neurologic decline, progressive skeletal disease in some individuals (including kyphosis and avascular necrosis of the femoral heads), and progressive feeding difficulties leading to aspiration risk. Type III begins in late childhood to the third decade with generalized dystonia leading to unsteady gait and speech disturbance followed by extrapyramidal signs including akinetic-rigid parkinsonism. Cardiomyopathy develops in some and skeletal involvement occurs in most. Intellectual impairment is common late in the disease with prognosis directly related to the degree of neurologic impairment. MPS IVB is characterized by skeletal dysplasia with specific findings of axial and appendicular dysostosis multiplex, short stature (below 15th centile in adults), kyphoscoliosis, coxa/genu valga, joint laxity, platyspondyly, and odontoid hypoplasia. First signs and symptoms may be apparent at birth. Bony involvement is progressive, with more than 84% of adults requiring ambulation aids; life span does not appear to be limited. Corneal clouding is detected in some individuals and cardiac valvular disease may develop.

PLOD1-related kyphoscoliotic Ehlers-Danlos syndrome (kEDS) is an autosomal recessive generalized connective tissue disorder characterized by hypotonia, early-onset kyphoscoliosis, and generalized joint hypermobility in association with skin fragility and ocular abnormality. Intelligence is normal. Life span may be normal, but affected individuals are at risk for rupture of medium-sized arteries. Adults with severe kyphoscoliosis are at risk for complications from restrictive lung disease, recurrent pneumonia, and cardiac failure.

COL1A1/2 osteogenesis imperfecta (COL1A1/2-OI) is characterized by fractures with minimal or absent trauma, variable dentinogenesis imperfecta (DI), and, in adult years, hearing loss. The clinical features of COL1A1/2-OI represent a continuum ranging from perinatal lethality to individuals with severe skeletal deformities, mobility impairments, and very short stature to nearly asymptomatic individuals with a mild predisposition to fractures, normal dentition, normal stature, and normal life span. Fractures can occur in any bone but are most common in the extremities. DI is characterized by gray or brown teeth that may appear translucent, wear down, and break easily. COL1A1/2-OI has been classified into four types based on clinical presentation and radiographic findings. This classification system can be helpful in providing information about prognosis and management for a given individual. The four more common OI types are now referred to as follows: Classic non-deforming OI with blue sclerae (previously OI type I). Perinatally lethal OI (previously OI type II). Progressively deforming OI (previously OI type III). Common variable OI with normal sclerae (previously OI type IV).

Alström syndrome is characterized by cone-rod dystrophy, obesity, progressive bilateral sensorineural hearing impairment, acute infantile-onset cardiomyopathy and/or adolescent- or adult-onset restrictive cardiomyopathy, insulin resistance / type 2 diabetes mellitus (T2DM), nonalcoholic fatty liver disease (NAFLD), and chronic progressive kidney disease. Cone-rod dystrophy presents as progressive visual impairment, photophobia, and nystagmus usually starting between birth and age 15 months. Many individuals lose all perception of light by the end of the second decade, but a minority retain the ability to read large print into the third decade. Children usually have normal birth weight but develop truncal obesity during their first year. Sensorineural hearing loss presents in the first decade in as many as 70% of individuals and may progress to the severe or moderately severe range (40-70 db) by the end of the first to second decade. Insulin resistance is typically accompanied by the skin changes of acanthosis nigricans, and proceeds to T2DM in the majority by the third decade. Nearly all demonstrate hypertriglyceridemia. Other findings can include endocrine abnormalities (hypothyroidism, hypogonadotropic hypogonadism in males, and hyperandrogenism in females), urologic dysfunction / detrusor instability, progressive decrease in renal function, and hepatic disease (ranging from elevated transaminases to steatohepatitis/NAFLD). Approximately 20% of affected individuals have delay in early developmental milestones, most commonly in gross and fine motor skills. About 30% have a learning disability. Cognitive impairment (IQ <70) is very rare. Wide clinical variability is observed among affected individuals, even within the same family.

Systemic primary carnitine deficiency (CDSP) is a disorder of the carnitine cycle that results in defective fatty acid oxidation. It encompasses a broad clinical spectrum including the following: Metabolic decompensation in infancy typically presenting between age three months and two years with episodes of hypoketotic hypoglycemia, poor feeding, irritability, lethargy, hepatomegaly, elevated liver transaminases, and hyperammonemia triggered by fasting or common illnesses such as upper respiratory tract infection or gastroenteritis. Childhood myopathy involving heart and skeletal muscle with onset between age two and four years. Pregnancy-related decreased stamina or exacerbation of cardiac arrhythmia. Fatigability in adulthood. Absence of symptoms. The latter two categories often include mothers diagnosed with CDSP after newborn screening has identified low carnitine levels in their infants.

Familial cutaneous collagenoma is a connective tissue nevus characterized by multiple, flesh-colored asymptomatic nodules distributed symmetrically on the trunk and upper arms (mainly on the upper two-thirds of the back), manifesting around adolescence. The skin biopsy reveals an accumulation of collagen fibers with reduction in the number of elastic fibers. Cardiac anomalies may be observed. Familial cutaneous collagenoma follows an autosomal dominant mode of transmission.

Monosomy 18q is a partial deletion of the long arm of chromosome 18 characterized by highly variable phenotype, most commonly including hypotonia, developmental delay, short stature, growth hormone deficiency, hearing loss and external ear anomalies, intellectual disability, palatal defects, dysmorphic facial features, skeletal anomalies (foot deformities, tapering fingers, scoliosis) and mood disorders.

Hydrops fetalis is a descriptive term for generalized edema of the fetus, with fluid accumulation in extravascular components and body cavities. It is not a diagnosis in itself, but a symptom and end-stage result of a wide variety of disorders. In the case of immune hydrops fetalis, a frequent cause is maternofetal incompatibility as in that related to a number of genetic anemias and metabolic disorders expressed in the fetus; in other instances, it remains idiopathic and likely multifactorial (summary by Bellini et al., 2009). Nonimmune hydrops fetalis accounts for 76 to 87% of all described cases of hydrops fetalis (Bellini et al., 2009). Genetic Heterogeneity of Hydrops Fetalis In southeast Asia, alpha-thalassemia (604131) is the most common cause of hydrops fetalis, accounting for 60 to 90% of cases. Almost all of these cases result from homozygous deletion of the HBA1 (141800) and HBA2 (141850) genes. A few cases have been reported that had 1 apparently normal alpha-globin gene, termed the hemoglobin H (613978) hydrops fetalis syndrome (summary by Chui and Waye, 1998). Other genetic disorders predisposing to NIHF include other congenital anemias, such as erythropoietic porphyria (e.g., 606938.0013), and many metabolic disorders, such as one form of Gaucher disease (e.g., 606463.0009), infantile sialic acid storage disease (269920), mucopolysaccharidosis type VII (253220), glycogen storage disease IV (232500), congenital disorder of glycosylation type Ia (212065), and disorders of lymphatic malformation (see, e.g., LMPHM1, 153100).

Absence of transferrin, a protein that transports iron, in the blood.

Mulibrey nanism (MUL) is a rare autosomal recessive growth disorder with prenatal onset, including occasional progressive cardiomyopathy, characteristic facial features, failure of sexual maturation, insulin resistance with type 2 diabetes, and an increased risk for Wilms tumor (summary by Hamalainen et al., 2006).

Barth syndrome is characterized in affected males by cardiomyopathy, neutropenia, skeletal myopathy, prepubertal growth delay, and distinctive facial gestalt (most evident in infancy); not all features may be present in a given affected male. Cardiomyopathy, which is almost always present before age five years, is typically dilated cardiomyopathy with or without endocardial fibroelastosis or left ventricular noncompaction; hypertrophic cardiomyopathy can also occur. Heart failure is a significant cause of morbidity and mortality; risk of arrhythmia and sudden death is increased. Neutropenia is most often associated with mouth ulcers, pneumonia, and sepsis. The nonprogressive myopathy predominantly affects the proximal muscles, and results in early motor delays. Prepubertal growth delay is followed by a postpubertal growth spurt with remarkable "catch-up" growth. Heterozygous females who have a normal karyotype are asymptomatic and have normal biochemical studies.

Danon disease is a multisystem condition with predominant involvement of the heart, skeletal muscles, and retina, with overlying cognitive dysfunction. Males are typically more severely affected than females. Males usually present with childhood onset concentric hypertrophic cardiomyopathy that is progressive and often requires heart transplantation. Rarely, hypertrophic cardiomyopathy can evolve to resemble dilated cardiomyopathy. Most affected males also have cardiac conduction abnormalities. Skeletal muscle weakness may lead to delayed acquisition of motor milestones. Learning disability and intellectual disability, most often in the mild range, are common. Additionally, affected males can develop retinopathy with subsequent visual impairment. The clinical features in females are broader and more variable. Females are more likely to have dilated cardiomyopathy, with a smaller proportion requiring heart transplantation compared to affected males. Cardiac conduction abnormalities, skeletal muscle weakness, mild cognitive impairment, and pigmentary retinopathy are variably seen in affected females.

Free sialic acid storage disorders (FSASDs) are a spectrum of neurodegenerative disorders resulting from increased lysosomal storage of free sialic acid. Historically, FSASD was divided into separate allelic disorders: Salla disease, intermediate severe Salla disease, and infantile free sialic acid storage disease (ISSD). The mildest type was Salla disease, 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. Salla disease was named for a municipality in Finnish Lapland where a specific founder variant is relatively prevalent. However, the term Salla has been used in the literature to refer to less severe FSASD. More severe FSASD is historically referred to as ISSD, and is characterized by severe developmental delay, coarse facial features, hepatosplenomegaly, and cardiomegaly; death usually occurs in early childhood.

Pseudoxanthoma elasticum (PXE) is a systemic disorder that affects the elastic tissue of the skin, the eye, and vascular system. Individuals most commonly present with angioid streaks of the retina found on routine eye examination or associated with retinal hemorrhage and/or characteristic papules in the skin. The most frequent cause of morbidity and disability in PXE is reduced vision due to complications of subretinal neovascularizations and macular atrophy. Other manifestations include premature gastrointestinal angina and/or bleeding, intermittent claudication of arm and leg muscles, stroke, renovascular hypertension, and cardiovascular complications (angina/myocardial infarction). Most affected individuals live a normal life span.

LMNA-related dilated cardiomyopathy (DCM) is characterized by left ventricular enlargement and/or reduced systolic function preceded (sometimes by many years) by or accompanied by conduction system disease and/or arrhythmias. LMNA-related DCM usually presents in early to mid-adulthood with symptomatic conduction system disease or arrhythmias, or with symptomatic DCM including heart failure or embolus from a left ventricular mural thrombus. Sudden cardiac death can occur, and in some instances is the presenting manifestation; sudden cardiac death may occur with minimal or no systolic dysfunction.

Left ventricular noncompaction is a heart (cardiac) muscle disorder that occurs when the lower left chamber of the heart (left ventricle), which helps the heart pump blood, does not develop correctly. Instead of the muscle being smooth and firm, the cardiac muscle in the left ventricle is thick and appears spongy. The abnormal cardiac muscle is weak and has an impaired ability to pump blood because it either cannot completely contract or it cannot completely relax. For the heart to pump blood normally, cardiac muscle must contract and relax fully.\n\nSome individuals with left ventricular noncompaction experience no symptoms at all; others have heart problems that can include sudden cardiac death. Additional signs and symptoms include abnormal blood clots, irregular heart rhythm (arrhythmia), a sensation of fluttering or pounding in the chest (palpitations), extreme fatigue during exercise (exercise intolerance), shortness of breath (dyspnea), fainting (syncope), swelling of the legs (lymphedema), and trouble laying down flat. Some affected individuals have features of other heart defects. Left ventricular noncompaction can be diagnosed at any age, from birth to late adulthood. Approximately two-thirds of individuals with left ventricular noncompaction develop heart failure.

An autosomal dominant subtype of dilated cardiomyopathy caused by mutation(s) in the LDB3 gene, encoding LIM domain-binding protein 3.

Naxos disease (NXD) is characterized by arrhythmogenic right ventricular cardiomyopathy associated with abnormalities of the skin, hair, and nails. The ectodermal features are evident from birth or early childhood, whereas the cardiac symptoms develop in young adulthood or later. Clinical variability of ectodermal features has been observed, with hair anomalies ranging from woolly hair to alopecia, and skin abnormalities ranging from mild focal palmoplantar keratoderma to generalized skin fragility or even lethal neonatal epidermolysis bullosa (Protonotarios et al., 1986; Cabral et al., 2010; Pigors et al., 2011; Erken et al., 2011; Sen-Chowdhry and McKenna, 2014). Another syndrome involving cardiomyopathy, woolly hair, and keratoderma (DCWHK; 605676) is caused by mutation in the desmoplakin gene (DSP; 125647). Also see 610476 for a similar disorder caused by homozygous mutation in the DSC2 gene (125645).

Mutations in the PRKAG2 gene (602743) give rise to a moderate, essentially heart-specific, nonlysosomal glycogenosis with clinical onset typically in late adolescence or in the third decade of life, ventricular pre-excitation predisposing to supraventricular arrhythmias, mild to severe cardiac hypertrophy, enhanced risk of sudden cardiac death in midlife, and autosomal dominant inheritance with full penetrance (summary by Burwinkel et al., 2005).

Any familial isolated dilated cardiomyopathy in which the cause of the disease is a mutation in the MYH7 gene.

An autosomal dominant subtype of dilated cardiomyopathy caused by mutation(s) in the PLN gene, encoding cardiac phospholamban.

Any hypertrophic cardiomyopathy in which the cause of the disease is a mutation in the MYL3 gene.

Any familial isolated dilated cardiomyopathy in which the cause of the disease is a mutation in the ABCC9 gene.

Any familial isolated dilated cardiomyopathy in which the cause of the disease is a mutation in the CSRP3 gene.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) – previously referred to as arrhythmogenic right ventricular dysplasia (ARVD) – is characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death in young individuals and athletes. It primarily affects the right ventricle, and it may also involve the left ventricle. The presentation of disease is highly variable even within families, and some affected individuals may not meet established clinical criteria. The mean age at diagnosis is 31 years (±13; range: 4-64 years).

Dilated cardiomyopathy, a disorder characterized by cardiac dilation and reduced systolic function, represents an outcome of a heterogeneous group of inherited and acquired disorders. For background and phenotypic information on dilated cardiomyopathy, see CMD1A (115200).

Graves disease (GRD) is an autoimmune disorder in which antibodies to the thyrotropin receptor (TSHR; 603372) result in constitutive activation of the receptor and increased levels of thyroid hormone. Wilkin (1990) reviewed endocrine disorders of hormone excess and hormone deficiency resulting from receptor autoimmunity. Genetic Heterogeneity of Graves Disease Susceptibility to Graves disease-1 (GRD1) has been mapped to chromosome 14q31. Other susceptibility loci for Graves disease include GRD2 (603388) on chromosome 20q13, GRDX1 (300351) on Xp11, and GRDX2 (see 300351) on Xq21.33-q22. Graves disease has also been mapped to several loci that confer susceptibility to autoimmune thyroid diseases, including Hashimoto thyroiditis (HT; 140300): AITD1 (608173) on 6p11; AITD2 (608174) on 5q31-q33; AITD3 (608175) on 8q24; AITD4 (608176) on 10q, and AITD5 (601941) on 18q21.

A rare glycogen storage disease with fetal or neonatal onset of severe cardiomyopathy with non-lysosomal glycogen accumulation and fatal outcome in infancy. Patients present with massive cardiomegaly, severe cardiac and respiratory complications and failure to thrive. Non-specific facial dysmorphism, bilateral cataracts, macroglossia, hydrocephalus, enlarged kidneys and skeletal muscle involvement have been reported in some cases.

Autosomal recessive myosin storage congenital myopathy-7B (CMYP7B) is a skeletal muscle disorder characterized by the onset of scapuloperoneal muscle weakness in early childhood or young adulthood. Affected individuals have difficulty walking, steppage gait, and scapular winging due to shoulder girdle involvement. The severity and progression of the disorder is highly variable, even within families. Most patients develop respiratory insufficiency, nocturnal hypoventilation, and restrictive lung disease; some develop hypertrophic cardiomyopathy. Additional features include myopathic facies, high-arched palate, scoliosis, and muscle wasting with thin body habitus. Serum creatine kinase may be normal or elevated. Skeletal muscle biopsy shows variable findings, including myosin storage disease, type 1 fiber predominance, centralized nuclei, and multiminicore disease (Onengut et al., 2004; Tajsharghi et al., 2007; Beecroft et al., 2019). For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (117000).

Dilated cardiomyopathy with woolly hair and keratoderma (DCWHK) is characterized by the presence of woolly or sparse hair from birth. Some patients exhibit fragile skin with blisters/erosions after minor mechanical trauma, with hyperkeratosis and epidermolytic keratoderma developing in early childhood. Cardiomyopathy may become apparent in the first decade of life, and early death due to heart failure has been reported, but patients may remain asymptomatic into the fourth decade of life. Some patients exhibit an arrhythmogenic form of cardiomyopathy, with sudden death in early adulthood (Carvajal-Huerta, 1998; Whittock et al., 2002; Alcalai et al., 2003; Uzumcu et al., 2006). Another syndrome involving cardiomyopathy, woolly hair, and keratoderma (Naxos disease; 601214) is caused by mutation in the plakoglobin gene (JUP; 173325). Also see 610476 for a similar disorder caused by homozygous mutation in the DSC2 gene (125645). Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis (DCWHKTA; 615821) is caused by heterozygous mutation in DSP. An isolated form of striated PPK (PPKS2; 612908) is also caused by heterozygous mutation in DSP. Reviews In a review of cardiocutaneous syndromes and arrhythmogenic cardiomyopathy, Sen-Chowdhry and McKenna (2014) stated that although the cardiac component of Carvajal syndrome was originally considered dilated cardiomyopathy, many of its features resemble those of arrhythmogenic cardiomyopathy (see 607450). In addition, they noted that different disease subtypes have been found to coexist within the same kindred, suggesting a role for modifier genes and/or environmental influences.

A dilated cardiomyopathy that has material basis in variation in the chromosome region 6q12-q16.

Sensorineural deafness with dilated cardiomyopathy is an extremely rare autosomal dominant syndrome described in two families to date and characterized by moderate to severe sensorineural hearing loss manifesting during childhood, and associated with late-onset dilated cardiomyopathy that generally progresses to heart failure.

With the current widespread use of multigene panels and comprehensive genomic testing, it has become apparent that the phenotypic spectrum of EPG5-related disorder represents a continuum. At the most severe end of the spectrum is classic Vici syndrome (defined as a neurodevelopmental disorder with multisystem involvement characterized by the combination of agenesis of the corpus callosum, cataracts, hypopigmentation, cardiomyopathy, combined immunodeficiency, microcephaly, and failure to thrive); at the milder end of the spectrum are attenuated neurodevelopmental phenotypes with variable multisystem involvement. Median survival in classic Vici syndrome appears to be 24 months, with only 10% of children surviving longer than age five years; the most common causes of death are respiratory infections as a result of primary immunodeficiency and/or cardiac insufficiency resulting from progressive cardiac failure. No data are available on life span in individuals at the milder end of the spectrum.

Friedreich ataxia (FRDA) is characterized by slowly progressive ataxia with onset usually before age 25 years (mean age at onset: 10-15 yrs). FRDA is typically associated with dysarthria, muscle weakness, spasticity particularly in the lower limbs, scoliosis, bladder dysfunction, absent lower-limb reflexes, and loss of position and vibration sense. Approximately two thirds of individuals with FRDA have cardiomyopathy, up to 30% have diabetes mellitus, and approximately 25% have an "atypical" presentation with later onset or retained tendon reflexes.

3-Methylglutaconic aciduria type V (MGCA5) is an autosomal recessive disorder characterized by the onset of dilated or noncompaction cardiomyopathy in infancy or early childhood. Many patients die of cardiac failure. Other features include microcytic anemia, growth retardation, mild ataxia, mild muscle weakness, genital anomalies in males, and increased urinary excretion of 3-methylglutaconic acid. Some patients may have optic atrophy or delayed psychomotor development (summary by Davey et al., 2006 and Ojala et al., 2012). For a discussion of genetic heterogeneity of 3-methylglutaconic aciduria, see MGCA type I (250950).

Any familial isolated dilated cardiomyopathy in which the cause of the disease is a mutation in the DES gene.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) – previously referred to as arrhythmogenic right ventricular dysplasia (ARVD) – is characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death in young individuals and athletes. It primarily affects the right ventricle, and it may also involve the left ventricle. The presentation of disease is highly variable even within families, and some affected individuals may not meet established clinical criteria. The mean age at diagnosis is 31 years (±13; range: 4-64 years).

Left ventricular noncompaction (LVNC) is characterized by numerous prominent trabeculations and deep intertrabecular recesses in hypertrophied and hypokinetic segments of the left ventricle (Sasse-Klaassen et al., 2004). The mechanistic basis is thought to be an intrauterine arrest of myocardial development with lack of compaction of the loose myocardial meshwork. LVNC may occur in isolation or in association with congenital heart disease. Distinctive morphologic features can be recognized on 2-dimensional echocardiography (Kurosaki et al., 1999). Noncompaction of the ventricular myocardium is sometimes referred to as spongy myocardium. Stollberger et al. (2002) commented that the term 'isolated LVNC,' meaning LVNC without coexisting cardiac abnormalities, is misleading, because additional cardiac abnormalities are found in nearly all patients with LVNC. Genetic Heterogeneity of Left Ventricular Noncompaction A locus for autosomal dominant left ventricular noncompaction has been identified on chromosome 11p15 (LVNC2; 609470). LVNC3 (see 605906) is caused by mutation in the LDB3 gene (605906) on chromosome 10q23. LVNC4 (see 613424) is caused by mutation in the ACTC1 gene (102540) on chromosome 15q14. LVNC5 (see 613426) is caused by mutation in the MYH7 gene (160760) on chromosome 14q12. LVNC6 (see 601494) is caused by mutation in the TNNT2 gene (191045) on chromosome 1q32. LVNC7 (615092) is caused by mutation in the MIB1 gene (608677) on chromosome 18q11. LVNC8 (615373) is caused by mutation in the PRDM16 gene (605557) on chromosome 1p36. LVNC9 (see 611878) is caused by mutation in the TPM1 gene (191010) on chromosome 15q22. LVNC10 (615396) is caused by mutation in the MYBPC3 gene (600958) on chromosome 11p11. LVNC can also occur as part of an X-linked disorder, Barth syndrome (302060), caused by mutation in the TAZ gene (300394) on chromosome Xq28.

Dilated cardiomyopathy-1G (CMD1G) is an autosomal dominant disorder characterized by ventricular dilatation and systolic contractile dysfunction (Siu et al., 1999). For a general phenotypic description and a discussion of genetic heterogeneity of dilated cardiomyopathy (CMD), see CMD1A (115200).

Triosephosphate isomerase deficiency (TPID) is an autosomal recessive multisystem disorder characterized by congenital hemolytic anemia, and progressive neuromuscular dysfunction beginning in early childhood. Many patients die from respiratory failure in childhood. The neurologic syndrome is variable, but usually includes lower motor neuron dysfunction with hypotonia, muscle weakness and atrophy, and hyporeflexia. Some patients may show additional signs such as dystonic posturing and/or spasticity. Laboratory studies show intracellular accumulation of dihydroxyacetone phosphate (DHAP), particularly in red blood cells (summary by Fermo et al., 2010).

Nonfamilial hypertrophic cardiomyopathy tends to be milder. This form typically begins later in life than familial hypertrophic cardiomyopathy, and affected individuals have a lower risk of serious cardiac events and sudden death than people with the familial form.\n\nThe symptoms of familial hypertrophic cardiomyopathy are variable, even within the same family. Many affected individuals have no symptoms. Other people with familial hypertrophic cardiomyopathy may experience chest pain; shortness of breath, especially with physical exertion; a sensation of fluttering or pounding in the chest (palpitations); lightheadedness; dizziness; and fainting.\n\nIn familial hypertrophic cardiomyopathy, cardiac thickening usually occurs in the interventricular septum, which is the muscular wall that separates the lower left chamber of the heart (the left ventricle) from the lower right chamber (the right ventricle). In some people, thickening of the interventricular septum impedes the flow of oxygen-rich blood from the heart, which may lead to an abnormal heart sound during a heartbeat (heart murmur) and other signs and symptoms of the condition. Other affected individuals do not have physical obstruction of blood flow, but the pumping of blood is less efficient, which can also lead to symptoms of the condition. Familial hypertrophic cardiomyopathy often begins in adolescence or young adulthood, although it can develop at any time throughout life.\n\nWhile most people with familial hypertrophic cardiomyopathy are symptom-free or have only mild symptoms, this condition can have serious consequences. It can cause abnormal heart rhythms (arrhythmias) that may be life threatening. People with familial hypertrophic cardiomyopathy have an increased risk of sudden death, even if they have no other symptoms of the condition. A small number of affected individuals develop potentially fatal heart failure, which may require heart transplantation.\n\nHypertrophic cardiomyopathy is a heart condition characterized by thickening (hypertrophy) of the heart (cardiac) muscle. When multiple members of a family have the condition, it is known as familial hypertrophic cardiomyopathy. Hypertrophic cardiomyopathy also occurs in people with no family history; these cases are considered nonfamilial hypertrophic cardiomyopathy. 

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.

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.

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder characterized by progressive gait and limb ataxia with associated limb muscle weakness, absent lower limb reflexes, extensor plantar responses, dysarthria, and decreased vibratory sense and proprioception. Onset is usually in the first or second decade, before the end of puberty (summary by Delatycki et al., 2000). For a general phenotypic description of Friedreich ataxia (FRDA), see FRDA1 (229300), which is caused by mutation in the FXN gene (606829) on chromosome 9q13.

Scalp-ear-nipple syndrome is characterized by aplasia cutis congenita of the scalp, breast anomalies that range from hypothelia or athelia to amastia, and minor anomalies of the external ears. Less frequent clinical characteristics include nail dystrophy, dental anomalies, cutaneous syndactyly of the digits, and renal malformations. Penetrance appears to be high, although there is substantial variable expressivity within families (Marneros et al., 2013).

Weill-Marchesani syndrome (WMS) is a connective tissue disorder characterized by abnormalities of the lens of the eye, short stature, brachydactyly, joint stiffness, and cardiovascular defects. The ocular problems, typically recognized in childhood, include microspherophakia (small spherical lens), myopia secondary to the abnormal shape of the lens, ectopia lentis (abnormal position of the lens), and glaucoma, which can lead to blindness. Height of adult males is 142-169 cm; height of adult females is 130-157 cm. Autosomal recessive WMS cannot be distinguished from autosomal dominant WMS by clinical findings alone.

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.

Carney complex (CNC) is characterized by skin pigmentary abnormalities, myxomas, endocrine tumors or overactivity, and schwannomas. Pale brown to black lentigines are the most common presenting feature of CNC and typically increase in number at puberty. Cardiac myxomas occur at a young age, may occur in any or all cardiac chambers, and can manifest as intracardiac obstruction of blood flow, embolic phenomenon, and/or heart failure. Other sites for myxomas include the skin, breast, oropharynx, and female genital tract. Primary pigmented nodular adrenocortical disease (PPNAD), which causes Cushing syndrome, is the most frequently observed endocrine tumor in CNC, occurring in approximately 25% of affected individuals. Large-cell calcifying Sertoli cell tumors (LCCSCTs) are observed in one third of affected males within the first decade and in most adult males. Up to 75% of individuals with CNC have multiple thyroid nodules, most of which are nonfunctioning thyroid follicular adenomas. Clinically evident acromegaly from a growth hormone (GH)-producing adenoma is evident in approximately 10% of adults. Psammomatous melanotic schwannoma (PMS), a rare tumor of the nerve sheath, occurs in an estimated 10% of affected individuals. The median age of diagnosis is 20 years.

GNPTAB-related disorders comprise the phenotypes mucolipidosis II (ML II) and mucolipidosis IIIa/ß (ML IIIa/ß), and phenotypes intermediate between ML II and ML IIIa/ß. ML II is evident at birth and slowly progressive; death most often occurs in early childhood. Orthopedic abnormalities present at birth may include thoracic deformity, kyphosis, clubfeet, deformed long bones, and/or dislocation of the hip(s). Growth often ceases in the second year of life; contractures develop in all large joints. The skin is thickened, facial features are coarse, and gingiva are hypertrophic. All children have cardiac involvement, most commonly thickening and insufficiency of the mitral valve and, less frequently, the aortic valve. Progressive mucosal thickening narrows the airways, and gradual stiffening of the thoracic cage contributes to respiratory insufficiency, the most common cause of death. ML IIIa/ß becomes evident at about age three years with slow growth rate and short stature; joint stiffness and pain initially in the shoulders, hips, and fingers; gradual mild coarsening of facial features; and normal to mildly impaired cognitive development. Pain from osteoporosis becomes more severe during adolescence. Cardiorespiratory complications (restrictive lung disease, thickening and insufficiency of the mitral and aortic valves, left and/or right ventricular hypertrophy) are common causes of death, typically in early to middle adulthood. Phenotypes intermediate between ML II and ML IIIa/ß are characterized by physical growth in infancy that resembles that of ML II and neuromotor and speech development that resemble that of ML IIIa/ß.

Salih myopathy is characterized by muscle weakness (manifest during the neonatal period or in early infancy) and delayed motor development; children acquire independent walking between ages 20 months and four years. In the first decade of life, global motor performance is stable or tends to improve. Moderate joint and neck contractures and spinal rigidity may manifest in the first decade but become more obvious in the second decade. Scoliosis develops after age 11 years. Cardiac dysfunction manifests between ages five and 16 years, progresses rapidly, and leads to death between ages eight and 20 years, usually from heart rhythm disturbances.

SADDAN dysplasia (severe achondroplasia with developmental delay and acanthosis nigricans) is a very rare skeletal dysplasia characterized by the constellation of these features. Radiology reveals 'ram's horn' shaped clavicles and reverse bowing of lower limbs. Approximately half of patients die before the fourth week of life secondary to respiratory failure (summary by Zankl et al., 2008).

Diamond-Blackfan anemia (DBA) is characterized by a profound normochromic and usually macrocytic anemia with normal leukocytes and platelets, congenital malformations in up to 50%, and growth deficiency in 30% of affected individuals. The hematologic complications occur in 90% of affected individuals during the first year of life. The phenotypic spectrum ranges from a mild form (e.g., mild anemia or no anemia with only subtle erythroid abnormalities, physical malformations without anemia) to a severe form of fetal anemia resulting in nonimmune hydrops fetalis. DBA is associated with an increased risk for acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), and solid tumors including osteogenic sarcoma.

An autosomal dominant subtype of familial hypertrophic cardiomyopathy caused by mutation(s) in the ACTC1 gene, encoding actin, alpha cardiac muscle 1.

A dilated cardiomyopathy that has material basis in mutation in the TNNI3 gene on chromosome 19q13.

Dilated cardiomyopathy-1Z (CMD1Z) is characterized by severe reduction in cardiac function, with onset in infancy or early childhood in some patients but diagnosis as late as the fifth decade in others. Patients exhibit biventricular systolic dysfunction, with severely reduced left ventricular ejection fractions. Most affected individuals require transplantation for survival (Mogensen et al., 2004; Kaski et al., 2007; Pinto et al., 2011). For a general phenotypic description and a discussion of genetic heterogeneity of dilated cardiomyopathy, see CMD1A (115200).

Dilated cardiomyopathy-1Y (CMD1Y) is characterized by severe progressive cardiac failure, resulting in death in the third to sixth decades of life in some patients. Electron microscopy shows an abnormal sarcomere structure (Olson et al., 2001). In left ventricular noncompaction-9 (LVNC9), patients may present with cardiac failure or may be asymptomatic. Echocardiography shows noncompaction of the apex and midventricular wall of the left ventricle (Probst et al., 2011). Some patients also exhibit Ebstein anomaly of the tricuspid valve (Kelle et al., 2016) and some have mitral valve insufficiency (Nijak et al., 2018).

A dilated cardiomyopathy that has material basis in mutation in the TNNI3 gene on chromosome 19q13.42.

Any hypertrophic cardiomyopathy in which the cause of the disease is a mutation in the VCL gene.

Any familial isolated dilated cardiomyopathy in which the cause of the disease is a mutation in the MYH6 gene.

An autosomal dominant subtype of familial hypertrophic cardiomyopathy caused by mutation(s) in the MYH6 gene, encoding myosin-6.

An autosomal dominant subtype of dilated cardiomyopathy caused by mutation(s) in the RBM20 gene, encoding RNA-binding protein 20.

Dilated cardiomyopathy-1BB (CMD1BB) is a life-threatening, intractable disease characterized by ventricular dilation and thinning (Shiba et al., 2021). For a phenotypic description and a discussion of genetic heterogeneity of dilated cardiomyopathy, see CMD1A (115200).

CDG IIe is caused by a mutation that impairs the integrity of the conserved oligomeric Golgi (COG) complex and alters Golgi trafficking, resulting in the disruption of multiple glycosylation pathways. For a general discussion of CDGs, see CDG1A (212065).

Autosomal recessive limb-girdle muscular dystrophy-3 (LGMDR3) affects mainly the proximal muscles and results in difficulty walking. Most individuals have onset in childhood; the disorder is progressive. Other features may include scapular winging, calf pseudohypertrophy, and contractures. Cardiomyopathy has rarely been reported (summary by Babameto-Laku et al., 2011). For a discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy, see LGMDR1 (253600).

Any familial isolated dilated cardiomyopathy in which the cause of the disease is a mutation in the ACTC1 gene.

Long QT syndrome (LQTS) is a cardiac electrophysiologic disorder, characterized by QT prolongation and T-wave abnormalities on the EKG that are associated with tachyarrhythmias, typically the ventricular tachycardia torsade de pointes (TdP). TdP is usually self-terminating, thus causing a syncopal event, the most common symptom in individuals with LQTS. Such cardiac events typically occur during exercise and emotional stress, less frequently during sleep, and usually without warning. In some instances, TdP degenerates to ventricular fibrillation and causes aborted cardiac arrest (if the individual is defibrillated) or sudden death. Approximately 50% of untreated individuals with a pathogenic variant in one of the genes associated with LQTS have symptoms, usually one to a few syncopal events. While cardiac events may occur from infancy through middle age, they are most common from the preteen years through the 20s. Some types of LQTS are associated with a phenotype extending beyond cardiac arrhythmia. In addition to the prolonged QT interval, associations include muscle weakness and facial dysmorphism in Andersen-Tawil syndrome (LQTS type 7); hand/foot, facial, and neurodevelopmental features in Timothy syndrome (LQTS type 8); and profound sensorineural hearing loss in Jervell and Lange-Nielson syndrome.

Any familial isolated dilated cardiomyopathy in which the cause of the disease is a mutation in the SDHA gene.

Any familial isolated dilated cardiomyopathy in which the cause of the disease is a mutation in the PSEN2 gene.

An autosomal dominant subtype of dilated cardiomyopathy caused by mutation(s) in the BAG3 gene, encoding BAG family molecular chaperone regulator 3.

Any familial isolated dilated cardiomyopathy in which the cause of the disease is a mutation in the PSEN1 gene.

Generalized arterial calcification of infancy (GACI) is characterized by infantile onset of widespread arterial calcification and/or narrowing of large and medium-sized vessels resulting in cardiovascular findings (which can include heart failure, respiratory distress, edema, cyanosis, hypertension, and/or cardiomegaly). Additional findings can include typical skin and retinal manifestations of pseudoxanthoma elasticum (PXE), periarticular calcifications, development of rickets after infancy, cervical spine fusion, and hearing loss. While mortality in infancy is high, survival into the third and fourth decades has occurred.

FBLN5-related cutis laxa is characterized by cutis laxa, early childhood-onset pulmonary emphysema, peripheral pulmonary artery stenosis, and other evidence of a generalized connective disorder such as inguinal hernias and hollow viscus diverticula (e.g., intestine, bladder). Occasionally, supravalvar aortic stenosis is observed. Intrafamilial variability in age of onset is observed. Cardiorespiratory failure from complications of pulmonary emphysema (respiratory or cardiac insufficiency) is the most common cause of death.

Geleophysic dysplasia, a progressive condition resembling a lysosomal storage disorder, is characterized by short stature, short hands and feet, progressive joint limitation and contractures, distinctive facial features, progressive cardiac valvular disease, and thickened skin. Intellect is normal. Major findings are likely to be present in the first year of life. Cardiac, respiratory, and lung involvement result in death before age five years in approximately 33% of individuals with ADAMTSL2-related geleophysic dysplasia.

HFE hemochromatosis is characterized by inappropriately high absorption of iron by the small intestinal mucosa. The phenotypic spectrum of HFE hemochromatosis includes: Persons with clinical HFE hemochromatosis, in whom manifestations of end-organ damage secondary to iron overload are present; Individuals with biochemical HFE hemochromatosis, in whom transferrin-iron saturation is increased and the only evidence of iron overload is increased serum ferritin concentration; and Non-expressing p.Cys282Tyr homozygotes, in whom neither clinical manifestations of HFE hemochromatosis nor iron overload are present. Clinical HFE hemochromatosis is characterized by excessive storage of iron in the liver, skin, pancreas, heart, joints, and anterior pituitary gland. In untreated individuals, early symptoms include: abdominal pain, weakness, lethargy, weight loss, arthralgias, diabetes mellitus; and increased risk of cirrhosis when the serum ferritin is higher than 1,000 ng/mL. Other findings may include progressive increase in skin pigmentation, congestive heart failure, and/or arrhythmias, arthritis, and hypogonadism. Clinical HFE hemochromatosis is more common in men than women.

Hypertrophic cardiomyopathy (HCM) is typically defined by the presence of unexplained left ventricular hypertrophy (LVH). Such LVH occurs in a non-dilated ventricle in the absence of other cardiac or systemic disease capable of producing the observed magnitude of increased LV wall thickness, such as pressure overload (e.g., long-standing hypertension, aortic stenosis) or storage/infiltrative disorders (e.g., Fabry disease, amyloidosis). The clinical manifestations of HCM range from asymptomatic LVH to progressive heart failure to sudden cardiac death (SCD), and vary from individual to individual even within the same family. Common symptoms include shortness of breath (particularly with exertion), chest pain, palpitations, orthostasis, presyncope, and syncope. Most often the LVH of HCM becomes apparent during adolescence or young adulthood, although it may also develop late in life, in infancy, or in childhood.

X-linked intellectual disability-cardiomegaly-congestive heart failure syndrome is a rare X-linked syndromic intellectual disability disorder characterized by profound intellectual disability, global developmental delay with absent speech, seizures, large joint contractures, abnormal position of thumbs and middle-age onset of cardiomegaly and atrioventricular valve abnormalities, resulting in subsequent congestive heart failure. Additional features include variable facial dysmorphism (notably large ears with overfolded helix) and large testes.

Any familial isolated dilated cardiomyopathy in which the cause of the disease is a mutation in the GATAD1 gene.

Multiple types of congenital heart defects-2 (CHTD2) is characterized by variable congenital heart defects, primarily involving the valves, but also including septal defects or aneurysms, and complex defects such as tetralogy of Fallot. Dilated cardiomyopathy and myocardial noncompaction have been reported in some patients. In addition, some affected individuals exhibit facial dysmorphism and features of connective tissue disease (Thienpont et al., 2010; Ackerman et al., 2016; Ritelli et al., 2018). For a discussion of genetic heterogeneity of CHTD, see 306955.

Any dilated cardiomyopathy in which the cause of the disease is a mutation in the MYPN gene.

Left ventricular noncompaction is a heart (cardiac) muscle disorder that occurs when the lower left chamber of the heart (left ventricle), which helps the heart pump blood, does not develop correctly. Instead of the muscle being smooth and firm, the cardiac muscle in the left ventricle is thick and appears spongy. The abnormal cardiac muscle is weak and has an impaired ability to pump blood because it either cannot completely contract or it cannot completely relax. For the heart to pump blood normally, cardiac muscle must contract and relax fully.\n\nSome individuals with left ventricular noncompaction experience no symptoms at all; others have heart problems that can include sudden cardiac death. Additional signs and symptoms include abnormal blood clots, irregular heart rhythm (arrhythmia), a sensation of fluttering or pounding in the chest (palpitations), extreme fatigue during exercise (exercise intolerance), shortness of breath (dyspnea), fainting (syncope), swelling of the legs (lymphedema), and trouble laying down flat. Some affected individuals have features of other heart defects. Left ventricular noncompaction can be diagnosed at any age, from birth to late adulthood. Approximately two-thirds of individuals with left ventricular noncompaction develop heart failure.

Some individuals with left ventricular noncompaction experience no symptoms at all; others have heart problems that can include sudden cardiac death. Additional signs and symptoms include abnormal blood clots, irregular heart rhythm (arrhythmia), a sensation of fluttering or pounding in the chest (palpitations), extreme fatigue during exercise (exercise intolerance), shortness of breath (dyspnea), fainting (syncope), swelling of the legs (lymphedema), and trouble laying down flat. Some affected individuals have features of other heart defects. Left ventricular noncompaction can be diagnosed at any age, from birth to late adulthood. Approximately two-thirds of individuals with left ventricular noncompaction develop heart failure.\n\nLeft ventricular noncompaction is a heart (cardiac) muscle disorder that occurs when the lower left chamber of the heart (left ventricle), which helps the heart pump blood, does not develop correctly. Instead of the muscle being smooth and firm, the cardiac muscle in the left ventricle is thick and appears spongy. The abnormal cardiac muscle is weak and has an impaired ability to pump blood because it either cannot completely contract or it cannot completely relax. For the heart to pump blood normally, cardiac muscle must contract and relax fully.

Combined oxidative phosphorylation deficiency-17 (COXPD17) is an autosomal recessive disorder of mitochondrial dysfunction characterized by onset of severe hypertrophic cardiomyopathy in the first year of life. Other features include hypotonia, poor growth, lactic acidosis, and failure to thrive. The disorder may be fatal in early childhood (summary by Haack et al., 2013).

A rare, genetic form of obesity characterized by morbid obesity, hypertension, type 2 diabetes mellitus and dyslipidemia leading to early coronary disease, myocardial infarction and congestive heart failure. Intellectual disability and decreased sperm counts or azoospermia have also been reported.

Polyglucosan body myopathy-1 (PGBM1) is an autosomal recessive disorder characterized by onset in childhood of progressive proximal muscle weakness, resulting in difficulties in ambulation. Most patients also develop progressive dilated cardiomyopathy, which may necessitate cardiac transplant in severe cases. A small subset of patients present with severe immunodeficiency and a hyperinflammatory state in very early childhood (summary by Boisson et al., 2012 and Nilsson et al., 2013). Genetic Heterogeneity of Polyglucosan Body Myopathy See also PGBM2 (616199), caused by mutation in the GYG1 gene (603942) on chromosome 3q24.

Any familial isolated dilated cardiomyopathy in which the cause of the disease is a mutation in the RAF1 gene.

A rare genetic cardiac disease characterized by variably expressed atrial tachyarrhythmia (such as atrial flutter, paroxysmal or chronic atrial fibrillation, ectopic atrial tachycardia, or multifocal atrial tachycardia), infra-Hisian conduction system disease, and vulnerability to dilated cardiomyopathy. Age of onset ranges between childhood and adulthood.

Spinal muscular atrophy with congenital bone fractures is an autosomal recessive severe neuromuscular disorder characterized by onset of severe hypotonia with fetal hypokinesia in utero. This results in congenital contractures, consistent with arthrogryposis multiplex congenita, and increased incidence of prenatal fracture of the long bones. Affected infants have difficulty breathing and feeding and often die in the first days or months of life (summary by Knierim et al., 2016). Genetic Heterogeneity of Spinal Muscular Atrophy With Congenital Bone Fractures See also SMABF2 (616867), caused by mutation in the ASCC1 gene (614215) on chromosome 10q22.

Singleton-Merten syndrome (SGMRT) is an uncommon autosomal dominant disorder characterized by abnormalities of blood vessels, teeth, and bone. Calcifications of the aorta and aortic and mitral valves occur in childhood or puberty and can lead to early death. Dental findings include delayed primary tooth exfoliation and permanent tooth eruption, truncated tooth root formation, early-onset periodontal disease, and severe root and alveolar bone resorption associated with dysregulated mineralization, leading to tooth loss. Osseous features consist of osteoporosis, either generalized or limited to distal extremities, distal limb osteolysis, widened medullary cavities, and easy tearing of tendons from bone. Less common features are mild facial dysmorphism (high anterior hair line, broad forehead, smooth philtrum, thin upper vermilion border), generalized muscle weakness, psoriasis, early-onset glaucoma, and recurrent infections. The disorder manifests with variable inter- and intrafamilial phenotypes (summary by Rutsch et al., 2015). Genetic Heterogeneity of Singleton-Merten Syndrome An atypical form of Singleton-Merten syndrome (SGMRT2; 616298) is caused by mutation in the DDX58 gene (609631) on chromosome 9p21.

MPSPS is an autosomal recessive inborn error of metabolism resulting in a multisystem disorder with features of the mucopolysaccharidosis lysosomal storage diseases (see, e.g., 607016). Patients present in infancy or early childhood with respiratory difficulties, cardiac problems, anemia, dysostosis multiplex, renal involvement, coarse facies, and delayed psychomotor development. Most patients die of cardiorespiratory failure in the first years of life (summary by Kondo et al., 2017).

Any Seckel syndrome in which the cause of the disease is a mutation in the NSMCE2 gene.

Any mitochondrial DNA depletion syndrome in which the cause of the disease is a mutation in the TFAM gene.

Familial cardiomyopathy caused by mutation in the FLNC gene has been described as hypertrophic, restrictive, dilated, or arrhythmogenic right ventricular cardiomyopathy. Affected individuals, especially those with dilated cardiomyopathy, are at risk for arrhythmias and sudden death. Arrhythmias without cardiomyopathy, and left ventricular noncompaction, have also been reported (Ortiz-Genga et al., 2016; Verdonschot et al., 2020).

Autosomal recessive cutis laxa type IID (ARCL2D) is characterized by generalized skin wrinkling with sparse subcutaneous fat and dysmorphic progeroid facial features. Most patients also exhibit severe hypotonia as well as cardiovascular and neurologic involvement (summary by Van Damme et al., 2017). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive cutis laxa, see ARCL1A (219100).

Combined oxidative phosphorylation deficiency-8 (COXPD8) is an autosomal recessive disorder caused by dysfunction of the mitochondrial respiratory chain. The main clinical manifestation is a lethal infantile hypertrophic cardiomyopathy, but there may also be subtle skeletal muscle and brain involvement. Biochemical studies show combined respiratory chain complex deficiencies in complexes I, III, and IV in cardiac muscle, skeletal muscle, and brain. The liver is not affected (summary by Gotz et al., 2011). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

Generalized arterial calcification of infancy (GACI) is characterized by infantile onset of widespread arterial calcification and/or narrowing of large and medium-sized vessels resulting in cardiovascular findings (which can include heart failure, respiratory distress, edema, cyanosis, hypertension, and/or cardiomegaly). Additional findings can include typical skin and retinal manifestations of pseudoxanthoma elasticum (PXE), periarticular calcifications, development of rickets after infancy, cervical spine fusion, and hearing loss. While mortality in infancy is high, survival into the third and fourth decades has occurred.

This autosomal recessive systemic autoinflammatory disorder is characterized by early childhood onset of annular erythematous plaques on the face and extremities with subsequent development of partial lipodystrophy and laboratory evidence of immune dysregulation. More variable features include recurrent fever, severe joint contractures, muscle weakness and atrophy, hepatosplenomegaly, basal ganglia calcifications, and microcytic anemia (summary by Agarwal et al., 2010; Kitamura et al., 2011; Arima et al., 2011). This disorder encompasses Nakajo-Nishimura syndrome (NKJO); joint contractures, muscular atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP syndrome); and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (CANDLE). Among Japanese patients, this disorder is best described as Nakajo-Nishimura syndrome, since both Nakajo (1939) and Nishimura et al. (1950) contributed to the original phenotypic descriptions. Genetic Heterogeneity of Proteasome-Associated Autoinflammatory Syndrome See also PRAAS2 (618048), caused by mutation in the POMP gene (613386) on chromosome 13q12; PRAAS3 (617591), caused by mutation in the PSMB4 gene (602177) on chromosome 1q21; PRAAS4 (619183), caused by mutation in the PSMG2 gene (609702) on chromosome 18p11; and PRAAS5 (619175), caused by mutation in the PSMB10 gene (176847) on chromosome 16q22.

MC1DN20 is an autosomal recessive multisystem disorder characterized by infantile onset of acute metabolic acidosis, hypertrophic cardiomyopathy, and muscle weakness associated with a deficiency of mitochondrial complex I activity in muscle, liver, and fibroblasts (summary by Haack et al., 2010). For a discussion of genetic heterogeneity of mitochondrial complex I deficiency, see 252010.

CMH27 is a severe, early-onset cardiomyopathy with morphologic features of both dilated and hypertrophic disease, characterized by biventricular involvement and atypical distribution of hypertrophy. Heterozygotes are at increased risk of developing cardiomyopathy (Almomani et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of hypertrophic cardiomyopathy, see CMH1 (192600). An oligogenic form of hypertrophic cardiomyopathy, involving heterozygous mutations in the ALPK3, TTN (188840), and MYL3 (160790) genes has also been reported in 1 family.

Congenital myopathy-8 (CMYP8) is an autosomal dominant disorder of the skeletal muscle characterized by hypotonia and delayed motor development apparent from infancy or childhood, resulting in difficulties walking or loss of ambulation within the first few decades. Affected individuals show respiratory insufficiency, high-arched palate, and scoliosis; external ophthalmoplegia may also be present. Skeletal muscle biopsy shows cores and myofibrillar disorganization (Lornage et al., 2019). For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (117000).

Mitochondrial complex IV deficiency nuclear type 4 (MC4DN4) is an autosomal recessive multisystem metabolic disorder characterized by the onset of symptoms in infancy. Affected individuals show hypotonia, failure to thrive, and neurologic distress. Additional features include hepatomegaly, hepatic steatosis, increased serum lactate, and metabolic acidosis. Some patients may develop hypertrophic cardiomyopathy. Patient tissues show decreased levels and activity of mitochondrial respiratory complex IV. Death usually occurs in infancy (summary by Valnot et al., 2000 and Stiburek et al., 2009). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.

RAB18 deficiency is the molecular deficit underlying both Warburg micro syndrome (characterized by eye, nervous system, and endocrine abnormalities) and Martsolf syndrome (characterized by similar – but milder – findings). To date Warburg micro syndrome comprises >96% of reported individuals with genetically defined RAB18 deficiency. The hallmark ophthalmologic findings are bilateral congenital cataracts, usually accompanied by microphthalmia, microcornea (diameter <10), and small atonic pupils. Poor vision despite early cataract surgery likely results from progressive optic atrophy and cortical visual impairment. Individuals with Warburg micro syndrome have severe to profound intellectual disability (ID); those with Martsolf syndrome have mild to moderate ID. Some individuals with RAB18 deficiency also have epilepsy. In Warburg micro syndrome, a progressive ascending spastic paraplegia typically begins with spastic diplegia and contractures during the first year, followed by upper-limb involvement leading to spastic quadriplegia after about age five years, often eventually causing breathing difficulties. In Martsolf syndrome infantile hypotonia is followed primarily by slowly progressive lower-limb spasticity. Hypogonadism – when present – manifests in both syndromes, in males as micropenis and/or cryptorchidism and in females as hypoplastic labia minora, clitoral hypoplasia, and small introitus.

Neurodegeneration with ataxia and late-onset optic atrophy (NDAXOA) is an autosomal dominant disorder with somewhat variable manifestations. Most affected individuals present in mid-adulthood with slowly progressive cerebellar and gait ataxia, optic atrophy, and myopathy or myalgia. Some patients may have a childhood history of neurologic features, including limited extraocular movements. Additional features can include cardiomyopathy, psychiatric disturbances, and peripheral sensory impairment (summary by Taylor et al., 1996 and Courage et al., 2017).

Mitochondrial complex IV deficiency nuclear type 22 (MC4DN22) is an autosomal recessive metabolic disorder characterized by neonatal hypertrophic cardiomyopathy, encephalopathy, and severe lactic acidosis with fatal outcome (Wintjes et al., 2021). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.

ADCY5 dyskinesia is a hyperkinetic movement disorder (more prominent in the face and arms than the legs) characterized by infantile to late-adolescent onset of chorea, athetosis, dystonia, myoclonus, or a combination of these. To date, affected individuals have had overlapping (but not identical) manifestations with wide-ranging severity. The facial movements are typically periorbital and perioral. The dyskinesia is prone to episodic or paroxysmal exacerbation lasting minutes to hours, and may occur during sleep. Precipitating factors in some persons have included emotional stress, intercurrent illness, sneezing, or caffeine; in others, no precipitating factors have been identified. In some children, severe infantile axial hypotonia results in gross motor delays accompanied by chorea, sometimes with language delays. The overall tendency is for the abnormal movements to stabilize in early middle age, at which point they may improve in some individuals; less commonly, the abnormal movements are slowly progressive, increasing in severity and frequency.

Developmental delay, impaired speech, and behavioral abnormalities (DDISBA) is characterized by global developmental delay apparent from early childhood. Intellectual disability can range from mild to severe. Additional variable features may include dysmorphic facial features, seizures, hypotonia, motor abnormalities such as Tourette syndrome or dystonia, and hearing loss (summary by Cousin et al., 2021).

Combined oxidative phosphorylation deficiency-23 (COXPD23) is an autosomal recessive disorder characterized by early childhood onset of hypertrophic cardiomyopathy and/or neurologic symptoms, including hypotonia and delayed psychomotor development. Laboratory investigations are consistent with a defect in mitochondrial function resulting in lactic acidosis, impaired activities of respiratory complexes I and IV, and defective translation of mitochondrial proteins. Brain imaging shows abnormal lesions in the basal ganglia, thalamus, and brainstem. The severity of the disorder is variable, ranging from death in early infancy to survival into the second decade (summary by Kopajtich et al., 2014). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

Combined oxidative phosphorylation deficiency-28 (COXPD28) is a complex autosomal recessive multisystem disorder associated with mitochondrial dysfunction. The phenotype is variable, but includes episodic metabolic decompensation beginning in infancy that can result in mild muscle weakness, cardiorespiratory insufficiency, developmental delay, or even death. Biochemical studies of patient tissues show variable mitochondrial defects, including decreased activities of respiratory chain enzymes (summary by Kishita et al., 2015). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

CLPB (caseinolytic peptidase B) deficiency is characterized by neurologic involvement and neutropenia, which can range from severe to mild. In severe CLPB deficiency, death usually occurs at a few months of age due to significant neonatal neurologic involvement (hyperekplexia or absence of voluntary movements, hypotonia or hypertonia, swallowing problems, respiratory insufficiency, and epilepsy) and severe neutropenia associated with life-threatening infections. Individuals with moderate CLPB deficiency present with neurologic abnormalities in infancy including hypotonia and feeding problems, and develop spasticity, a progressive movement disorder (ataxia, dystonia, and/or dyskinesia), epilepsy, and intellectual disability. Neutropenia is variable, but not life threatening. In those with mild CLPB deficiency there is no neurologic involvement, intellect is normal, neutropenia is mild and intermittent, and life expectancy is normal.

Dilated cardiomyopathy-2F (CMD2F) is an autosomal recessive early-onset cardiomyopathy associated with refractory ventricular arrhythmias and severe heart failure requiring placement of a left ventricular assist device (Hakui et al., 2022). For a general phenotypic description and discussion of genetic heterogeneity of dilated cardiomyopathy, see 115200.

Stuve-Wiedemann syndrome-2 (STWS2) is an autosomal recessive lethal skeletal dysplasia characterized by short stature, small chest, bowing of the long bones, and neonatal cardiopulmonary and autonomous dysfunction. Additional variable features include congenital thrombocytopenia, eczematoid dermatitis, renal anomalies, and defective acute-phase response (Chen et al., 2020). For a general phenotypic description and discussion of genetic heterogeneity of Stuve-Wiedemann syndrome, see STWS1 (601559).

A dilated cardiomyopathy that has material basis in variation in the chromosome region 9q13.

Neurodevelopmental disorder with microcephaly, cerebral atrophy, and visual impairment (NEDMVIC) is an autosomal recessive disorder characterized by global developmental delay, impaired intellectual development, facial dysmorphism, and microcephaly (Ziegler et al., 2022).

Dilated cardiomyopathy-1OO (CMD1OO) is characterized by enlarged left ventricular end-diastolic diameter and reduced left ventricular ejection fraction, resulting in cardiac failure that may result in premature death. Some patients also exhibit second-degree atrioventricular block and premature ventricular beats (Shi et al., 2023). For a general phenotypic description and discussion of genetic heterogeneity of dilated cardiomyopathy, see CMD1A (115200).