MedGen

Hereditary hemorrhagic telangiectasia (HHT) is characterized by the presence of multiple arteriovenous malformations (AVMs) that lack intervening capillaries and result in direct connections between arteries and veins. The most common clinical manifestation is spontaneous and recurrent nosebleeds (epistaxis) beginning on average at age 12 years. Telangiectases (small AVMs) are characteristically found on the lips, tongue, buccal and gastrointestinal (GI) mucosa, face, and fingers. The appearance of telangiectases is generally later than epistaxis but may be during childhood. Large AVMs occur most often in the lungs, liver, or brain; complications from bleeding or shunting may be sudden and catastrophic. A minority of individuals with HHT have GI bleeding, which is rarely seen before age 50 years. [from GeneReviews]

Hereditary hemorrhagic telangiectasia (HHT) is characterized by the presence of multiple arteriovenous malformations (AVMs) that lack intervening capillaries and result in direct connections between arteries and veins. The most common clinical manifestation is spontaneous and recurrent nosebleeds (epistaxis) beginning on average at age 12 years. Telangiectases (small AVMs) are characteristically found on the lips, tongue, buccal and gastrointestinal (GI) mucosa, face, and fingers. The appearance of telangiectases is generally later than epistaxis but may be during childhood. Large AVMs occur most often in the lungs, liver, or brain; complications from bleeding or shunting may be sudden and catastrophic. A minority of individuals with HHT have GI bleeding, which is rarely seen before age 50 years. [from GeneReviews]

Methemoglobinemia due to NADH-cytochrome b5 reductase deficiency is an autosomal recessive disorder characterized clinically by decreased oxygen carrying capacity of the blood, with resultant cyanosis and hypoxia (review by Percy and Lappin, 2008). There are 2 types of methemoglobin reductase deficiency. In type I, the defect affects the soluble form of the enzyme, is restricted to red blood cells, and causes well-tolerated methemoglobinemia. In type II, the defect affects both the soluble and microsomal forms of the enzyme and is thus generalized, affecting red cells, leukocytes, and all body tissues. Type II methemoglobinemia is associated with mental deficiency and other neurologic symptoms. The neurologic symptoms may be related to the major role played by the cytochrome b5 system in the desaturation of fatty acids (Vives-Corrons et al., 1978; Kaplan et al., 1979). [from OMIM]

Heterotaxy Heterotaxy ('heter' meaning 'other' and 'taxy' meaning 'arrangement'), or situs ambiguus, is a developmental condition characterized by randomization of the placement of visceral organs, including the heart, lungs, liver, spleen, and stomach. The organs are oriented randomly with respect to the left-right axis and with respect to one another (Srivastava, 1997). Heterotaxy is a clinically and genetically heterogeneous disorder. Multiple Types of Congenital Heart Defects Congenital heart defects (CHTD) are among the most common congenital defects, occurring with an incidence of 8/1,000 live births. The etiology of CHTD is complex, with contributions from environmental exposure, chromosomal abnormalities, and gene defects. Some patients with CHTD also have cardiac arrhythmias, which may be due to the anatomic defect itself or to surgical interventions (summary by van de Meerakker et al., 2011). Reviews Obler et al. (2008) reviewed published cases of double-outlet right ventricle and discussed etiology and associations. Genetic Heterogeneity of Visceral Heterotaxy See also HTX2 (605376), caused by mutation in the CFC1 gene (605194) on chromosome 2q21; HTX3 (606325), which maps to chromosome 6q21; HTX4 (613751), caused by mutation in the ACVR2B gene (602730) on chromosome 3p22; HTX5 (270100), caused by mutation in the NODAL gene (601265) on chromosome 10q22; HTX6 (614779), caused by mutation in the CCDC11 gene (614759) on chromosome 18q21; HTX7 (616749), caused by mutation in the MMP21 gene (608416) on chromosome 10q26; HTX8 (617205), caused by mutation in the PKD1L1 gene (609721) on chromosome 7p12; HTX9 (618948), caused by mutation in the MNS1 gene (610766) on chromosome 15q21; HTX10 (619607), caused by mutation in the CFAP52 gene (609804) on chromosome 17p13; HTX11 (619608), caused by mutation in the CFAP45 gene (605152) on chromosome 1q23; and HTX12 (619702), caused by mutation in the CIROP gene (619703) on chromosome 14q11. Genetic Heterogeneity of Multiple Types of Congenital Heart Defects An X-linked form of CHTD, CHTD1, is caused by mutation in the ZIC3 gene on chromosome Xq26. CHTD2 (614980) is caused by mutation in the TAB2 gene (605101) on chromosome 6q25. A form of nonsyndromic congenital heart defects associated with cardiac rhythm and conduction disturbances (CHTD3; 614954) has been mapped to chromosome 9q31. CHTD4 (615779) is caused by mutation in the NR2F2 gene (107773) on chromosome 15q26. CHTD5 (617912) is caused by mutation in the GATA5 gene (611496) on chromosome 20q13. CHTD6 (613854) is caused by mutation in the GDF1 gene (602880) on chromosome 19p13. CHTD7 (618780) is caused by mutation in the FLT4 gene (136352) on chromosome 5q35. CHTD8 (619657) is caused by mutation in the SMAD2 gene (601366) on chromosome 18q21. CHTD9 (620294) is caused by mutation in the PLXND1 gene (604282) on chromosome 3q22. [from OMIM]

Benign familial neonatal-infantile seizures is an autosomal dominant disorder in which afebrile seizures occur in clusters during the first year of life, without neurologic sequelae (Shevell et al., 1986). For a general phenotypic description and a discussion of genetic heterogeneity of benign familial infantile seizures, see BFIS1 (601764). [from OMIM]

Inborn errors of pulmonary surfactant metabolism are genetically heterogeneous disorders resulting in severe respiratory insufficiency or failure in full-term neonates or infants. These disorders are associated with various pathologic entities, including pulmonary alveolar proteinosis (PAP), desquamative interstitial pneumonitis (DIP), or cellular nonspecific interstitial pneumonitis (NSIP) (Clark and Clark, 2005). A clinically similar disorder characterized by respiratory distress (267450) can affect preterm infants, who show developmental deficiency of surfactant. Acquired PAP (610910) is an autoimmune disorder characterized by the presence of autoantibodies to CSF2 (138960). Genetic Heterogeneity of Pulmonary Surfactant Metabolism Dysfunction See also SMDP2 (610913), caused by mutation in the SPTPC gene (178620) on 8p21; SMDP3 (610921), caused by mutation in the ABCA3 gene (601615) on 16p13; SMDP4 (300770), caused by mutation in the CSF2RA gene (306250) on Xp22; and SMDP5 (614370), caused by mutation in the CSF2RB gene (138981) on 22q12. [from OMIM]

Isolated complex I deficiency is a rare inborn error of metabolism due to mutations in nuclear or mitochondrial genes encoding subunits or assembly factors of the human mitochondrial complex I (NADH: ubiquinone oxidoreductase) and is characterized by a wide range of manifestations including marked and often fatal lactic acidosis, cardiomyopathy, leukoencephalopathy, pure myopathy and hepatopathy with tubulopathy. Among the numerous clinical phenotypes observed are Leigh syndrome, Leber hereditary optic neuropathy and MELAS syndrome (see these terms). [from ORDO]

Pulmonary surfactant metabolism dysfunction-2 (SMDP2) is a rare autosomal dominant disease associated with progressive respiratory insufficiency and lung disease with a variable clinical course. The pathophysiology of the disorder is postulated to involve intracellular accumulation of a structurally defective SPC protein (Thomas et al., 2002). For a general phenotypic description and a discussion of genetic heterogeneity of pulmonary surfactant metabolism dysfunction, see SMDP1 (265120). [from OMIM]

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. [from SNOMEDCT_US]

For a general phenotypic description and a discussion of genetic heterogeneity of pulmonary surfactant metabolism dysfunction, see SMDP1 (265120). [from OMIM]

Mitochondrial phosphate carrier deficiency (MPCD) is an autosomal recessive disorder characterized by onset of cardiorespiratory insufficiency soon after birth. Patients usually require intervention in the neonatal period. The disorder may result in death in infancy, although those that survive have stabilization or amelioration of symptoms with age. Most affected individuals have hypotonia, delayed motor development, and exercise intolerance, but cognitive development is normal. Laboratory studies typically show increased serum lactate, although this may not be present. Muscle biopsy shows abnormal mitochondria and lipid accumulation. There is phenotypic variability likely depending on the location of the mutation (summary by Bhoj et al., 2015). [from OMIM]

Methemoglobinemia and ambiguous genitalia (METAG) is due to isolated 17,20-lyase deficiency, defined by apparently normal 17-alpha-hydroxylase activity but severely reduced 17,20-lyase activity of the CYP17A1 enzyme (609300), which results in sex steroid deficiency but normal glucocorticoid and mineralocorticoid reserve. The clinical phenotype is characterized by male undermasculinization, with absent or disturbed pubertal development in both 46,XY and 46,XX individuals. Mild to severe methemoglobinemia has been reported in these patients (Idkowiak et al., 2012). Other autosomal recessive methemoglobinemias include types I and II (see 250800), caused by mutation in the CYB5R3 gene (613213). Isolated 17,20-lyase deficiency can also be caused by mutation in the CYP17A1 gene (609300), and mutation in the POR gene can manifest clinically as isolated 17,20-lyase deficiency (see 124015.0016). [from OMIM]

Cytosolic phosphoenolpyruvate carboxykinase deficiency causes a defect in gluconeogenesis that results in a 'biochemical signature' of fasting hypoglycemia with high tricarboxylic acid cycle intermediate excretion, particularly of fumarate. Other biochemical anomalies that may be seen during metabolic crisis include ketonuria, dicarboxylic aciduria, and urea cycle dysfunction (Vieira et al., 2017). See PCKDM (261650) for a discussion of mitochondrial PCK (PEPCK2; 614095) deficiency. [from OMIM]

Chronic primary adrenal insufficiency (CPAI) is a chronic disorder of the adrenal cortex resulting in the inadequate production of glucocorticoid and mineralocorticoid hormones. [from ORDO]

Chiari malformation type II (CM2), also known as the Arnold-Chiari malformation, consists of elongation and descent of the inferior cerebellar vermis, cerebellar hemispheres, pons, medulla, and fourth ventricle through the foramen magnum into the spinal canal. CM2 is uniquely associated with myelomeningocele (open spina bifida; see 182940) and is found only in this population (Stevenson, 2004). It is believed to be a disorder of neuroectodermal origin (Schijman, 2004). For a general phenotypic description of the different forms of Chiari malformations, see Chiari malformation type I (CM1; 118420). [from OMIM]

PERCHING syndrome is an autosomal recessive multisystem disorder characterized by global developmental delay, dysmorphic facial features, feeding and respiratory difficulties with poor overall growth, axial hypotonia, and joint contractures. The features are variable, even within families, and may also include retinitis pigmentosa, cardiac or genitourinary anomalies, and abnormal sweating. Each letter of the PERCHING acronym represents 2 important phenotypic elements: Postural and Palatal abnormalities; Exophthalmos and Enteral-tube dependency/feeding issues; Respiratory distress and Retinitis pigmentosa; Contractures and Camptodactyly; Hypertelorism and Hirsutism; Intrauterine growth retardation (IUGR)/growth failure and Intellectual disability/developmental delay; Nevus flammeus and Neurologic malformations; and facial Gestalt/grimacing and Genitourinary abnormalities (Jeffries et al., 2019). Death in infancy or early childhood often occurs, although survival to the third decade has been reported. Some of the features, such as contractures, dysmorphic craniofacial features, and severe feeding difficulties, are reminiscent of Bohring-Opitz syndrome (605039) (summary by Kanthi et al., 2019 and Buers et al., 2020). [from OMIM]

Autosomal visceral heterotaxy-7 is an autosomal recessive developmental disorder characterized by complex congenital heart malformations and/or situs inversus and caused by defects in the normal left-right asymmetric positioning of internal organs. The phenotype is variable (summary by Guimier et al., 2015). For a discussion of the genetic heterogeneity of visceral heterotaxy, see HTX1 (306955). [from OMIM]

Any congenital myasthenic syndrome in which the cause of the disease is a mutation in the SLC18A3 gene. [from MONDO]

Restrictive dermopathy is a rare genodermatosis characterized mainly by intrauterine growth retardation, tight and rigid skin with erosions, prominent superficial vasculature and epidermal hyperkeratosis, facial dysmorphism (small mouth, small pinched nose and micrognathia), sparse/absent eyelashes and eyebrows, mineralization defects of the skull, thin dysplastic clavicles, pulmonary hypoplasia, multiple joint contractures, and an early neonatal lethal course. Liveborn children usually die within the first week of life (summary by Navarro et al., 2004). For a discussion of genetic heterogeneity of restrictive dermopathy, see RSDM1 (275210). [from OMIM]

The diagnosis of severe breath-holding spells (BHS) in childhood is based on a distinctive and stereotyped sequence of clinical events beginning with a provocation resulting in crying or emotional upset that leads to a noiseless state of expiration accompanied by color change and ultimately loss of consciousness and postural tone (Lombroso and Lerman, 1967; DiMario, 1992). Two clinical types are recognized based on the child's coloration (cyanotic or pallid) during these events. Most children experience the cyanotic type, although some experience mixed types. BHS is an involuntary, nonvolitional, reflexic, nonepileptic paroxysmal phenomenon of childhood. The episodes occur during full expiration despite its misnomer. Autonomic dysregulation has been hypothesized as an underlying mechanism that results in loss of consciousness (Hunt, 1990; DiMario and Burleson, 1993; Dimario et al., 1998). [from OMIM]