MedGen

Individuals with 22q11.2 deletion syndrome (22q11.2DS) can present with a wide range of features that are highly variable, even within families. The major clinical manifestations of 22q11.2DS include congenital heart disease, particularly conotruncal malformations (ventricular septal defect, tetralogy of Fallot, interrupted aortic arch, and truncus arteriosus), palatal abnormalities (velopharyngeal incompetence, submucosal cleft palate, bifid uvula, and cleft palate), immune deficiency, characteristic facial features, and learning difficulties. Hearing loss can be sensorineural and/or conductive. Laryngotracheoesophageal, gastrointestinal, ophthalmologic, central nervous system, skeletal, and genitourinary anomalies also occur. Psychiatric illness and autoimmune disorders are more common in individuals with 22q11.2DS. [from GeneReviews]

Individuals with 22q11.2 deletion syndrome (22q11.2DS) can present with a wide range of features that are highly variable, even within families. The major clinical manifestations of 22q11.2DS include congenital heart disease, particularly conotruncal malformations (ventricular septal defect, tetralogy of Fallot, interrupted aortic arch, and truncus arteriosus), palatal abnormalities (velopharyngeal incompetence, submucosal cleft palate, bifid uvula, and cleft palate), immune deficiency, characteristic facial features, and learning difficulties. Hearing loss can be sensorineural and/or conductive. Laryngotracheoesophageal, gastrointestinal, ophthalmologic, central nervous system, skeletal, and genitourinary anomalies also occur. Psychiatric illness and autoimmune disorders are more common in individuals with 22q11.2DS. [from GeneReviews]

CHD7 disorder encompasses the entire phenotypic spectrum of heterozygous CHD7 pathogenic variants that includes CHARGE syndrome as well as subsets of features that comprise the CHARGE syndrome phenotype. The mnemonic CHARGE syndrome, introduced in the premolecular era, stands for coloboma, heart defect, choanal atresia, retarded growth and development, genital hypoplasia, ear anomalies (including deafness). Following the identification of the genetic cause of CHD7 disorder, the phenotypic spectrum expanded to include cranial nerve anomalies, vestibular defects, cleft lip and/or palate, hypothyroidism, tracheoesophageal anomalies, brain anomalies, seizures, and renal anomalies. Life expectancy highly depends on the severity of manifestations; mortality can be high in the first few years when severe birth defects (particularly complex heart defects) are present and often complicated by airway and feeding issues. In childhood, adolescence, and adulthood, decreased life expectancy is likely related to a combination of residual heart defects, infections, aspiration or choking, respiratory issues including obstructive and central apnea, and possibly seizures. Despite these complications, the life expectancy for many individuals can be normal. [from GeneReviews]

Disorders of GNAS inactivation include the phenotypes pseudohypoparathyroidism Ia, Ib, and Ic (PHP-Ia, -Ib, -Ic), pseudopseudohypoparathyroidism (PPHP), progressive osseous heteroplasia (POH), and osteoma cutis (OC). PHP-Ia and PHP-Ic are characterized by: End-organ resistance to endocrine hormones including parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), gonadotropins (LH and FSH), growth hormone-releasing hormone (GHRH), and CNS neurotransmitters (leading to obesity and variable degrees of intellectual disability and developmental delay); and The Albright hereditary osteodystrophy (AHO) phenotype (short stature, round facies, and subcutaneous ossifications) and brachydactyly type E (shortening mainly of the 4th and/or 5th metacarpals and metatarsals and distal phalanx of the thumb). Although PHP-Ib is characterized principally by PTH resistance, some individuals also have partial TSH resistance and mild features of AHO (e.g., brachydactyly). PPHP, a more limited form of PHP-Ia, is characterized by various manifestations of the AHO phenotype without the hormone resistance or obesity. POH and OC are even more restricted variants of PPHP: POH consists of dermal ossification beginning in infancy, followed by increasing and extensive bone formation in deep muscle and fascia. OC consists of extra-skeletal ossification that is limited to the dermis and subcutaneous tissues. [from GeneReviews]

Celiac disease is a systemic autoimmune disease that can be associated with gastrointestinal findings (diarrhea, malabsorption, abdominal pain and distension, bloating, vomiting, and weight loss) and/or highly variable non-gastrointestinal findings (dermatitis herpetiformis, chronic fatigue, joint pain/inflammation, iron deficiency anemia, migraines, depression, attention-deficit disorder, epilepsy, osteoporosis/osteopenia, infertility and/or recurrent fetal loss, vitamin deficiencies, short stature, failure to thrive, delayed puberty, dental enamel defects, and autoimmune disorders). Classic celiac disease, characterized by mild to severe gastrointestinal symptoms, is less common than non-classic celiac disease, characterized by absence of gastrointestinal symptoms. [from GeneReviews]

Osteopetrosis (OPT) is a life-threatening disease caused by subnormal osteoclast function, with an incidence of 1 in 250,000 births. The disease usually manifests in the first few months of life with macrocephaly and frontal bossing, resulting in a characteristic facial appearance. Defective bone remodeling of the skull results in choanal stenosis with concomitant respiratory problems and feeding difficulties, which are the first clinical manifestation of disease. The expanding bone encroaches on neural foramina, leading to blindness, deafness, and facial palsy. Complete visual loss invariably occurs in all untreated patients, and hearing loss is estimated to affect 78% of patients with OPT. Tooth eruption defects and severe dental caries are common. Calcium feedback hemostasis is impaired, and children with OPT are at risk of developing hypocalcemia with attendant tetanic seizures and secondary hyperparathyroidism. The most severe complication of OPT, limiting survival, is bone marrow insufficiency. The abnormal expansion of cortical and trabecular bone physically limits the availability of medullary space for hematopoietic activity, leading to life-threatening cytopenia and secondary expansion of extramedullary hematopoiesis at sites such as the liver and spleen (summary by Aker et al., 2012). Genetic Heterogeneity of Autosomal Recessive Osteopetrosis Other forms of autosomal recessive infantile malignant osteopetrosis include OPTB4 (611490), which is caused by mutation in the CLCN7 gene (602727) on chromosome 16p13, and OPTB5 (259720), which is caused by mutation in the OSTM1 gene (607649) on chromosome 6q21. A milder, osteoclast-poor form of autosomal recessive osteopetrosis (OPTB2; 259710) is caused by mutation in the TNFSF11 gene (602642) on chromosome 13q14, an intermediate form (OPTB6; 611497) is caused by mutation in the PLEKHM1 gene (611466) on chromosome 17q21, and a severe osteoclast-poor form associated with hypogammaglobulinemia (OPTB7; 612301) is caused by mutation in the TNFRSF11A gene (603499) on chromosome 18q22. Another form of autosomal recessive osteopetrosis (OPTB8; 615085) is caused by mutation in the SNX10 gene (614780) on chromosome 7p15. A form of autosomal recessive osteopetrosis associated with renal tubular acidosis (OPTB3; 259730) is caused by mutation in the CA2 gene (611492) on chromosome 8q21. OPTB9 (620366) is caused by mutation in the SLC4A2 gene (109280) on chromosome 7q36. Autosomal dominant forms of osteopetrosis are more benign (see OPTA1, 607634). [from OMIM]

The first identified CACNA1C-related disorder, referred to as Timothy syndrome, consists of the combination of prolonged QT interval, autism, and cardiovascular malformation with syndactyly of the fingers and toes. Infrequent findings also include developmental and speech delay, seizures, and recurrent infections. With increased availability of molecular genetic testing, a wider spectrum of pathogenic variants and clinical findings associated with CACNA1C-related disorders has been recognized. Because CACNA1C is associated with calcium channel function, all individuals with a pathogenic variant in this gene are at risk for cardiac arrhythmia of a specific type. The clinical manifestations of a CACNA1C-related disorder include three phenotypes: Timothy syndrome with or without syndactyly. QT prolongation (QTc >480 ms) and arrhythmias in the absence of other syndromic features. Short QT syndrome (QTc <350 ms) or Brugada syndrome with short QT interval. These three phenotypes can be separated into two broad categories on the basis of the functional consequences of the pathogenic variants in CACNA1C: QT prolongation with or without a Timothy syndrome-associated phenotype associated with pathogenic variants inducing a gain of function at the cellular level (i.e., increased calcium current). Short QT interval with or without Brugada syndrome EKG pattern associated with pathogenic variants causing loss of function (i.e., reduced calcium current). [from GeneReviews]

Cranioectodermal dysplasia (CED) is a ciliopathy with skeletal involvement (narrow thorax, shortened proximal limbs, syndactyly, polydactyly, brachydactyly), ectodermal features (widely spaced hypoplastic teeth, hypodontia, sparse hair, skin laxity, abnormal nails), joint laxity, growth deficiency, and characteristic facial features (frontal bossing, low-set simple ears, high forehead, telecanthus, epicanthal folds, full cheeks, everted lower lip). Most affected children develop nephronophthisis that often leads to end-stage kidney disease in infancy or childhood, a major cause of morbidity and mortality. Hepatic fibrosis and retinal dystrophy are also observed. Dolichocephaly, often secondary to sagittal craniosynostosis, is a primary manifestation that distinguishes CED from most other ciliopathies. Brain malformations and developmental delay may also occur. [from GeneReviews]

Disorders of GNAS inactivation include the phenotypes pseudohypoparathyroidism Ia, Ib, and Ic (PHP-Ia, -Ib, -Ic), pseudopseudohypoparathyroidism (PPHP), progressive osseous heteroplasia (POH), and osteoma cutis (OC). PHP-Ia and PHP-Ic are characterized by: End-organ resistance to endocrine hormones including parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), gonadotropins (LH and FSH), growth hormone-releasing hormone (GHRH), and CNS neurotransmitters (leading to obesity and variable degrees of intellectual disability and developmental delay); and The Albright hereditary osteodystrophy (AHO) phenotype (short stature, round facies, and subcutaneous ossifications) and brachydactyly type E (shortening mainly of the 4th and/or 5th metacarpals and metatarsals and distal phalanx of the thumb). Although PHP-Ib is characterized principally by PTH resistance, some individuals also have partial TSH resistance and mild features of AHO (e.g., brachydactyly). PPHP, a more limited form of PHP-Ia, is characterized by various manifestations of the AHO phenotype without the hormone resistance or obesity. POH and OC are even more restricted variants of PPHP: POH consists of dermal ossification beginning in infancy, followed by increasing and extensive bone formation in deep muscle and fascia. OC consists of extra-skeletal ossification that is limited to the dermis and subcutaneous tissues. [from GeneReviews]

Autosomal dominant hypocalcemia-1 is associated with low or normal serum parathyroid hormone concentrations (PTH). Approximately 50% of patients have mild or asymptomatic hypocalcemia; about 50% have paresthesias, carpopedal spasm, and seizures; about 10% have hypercalciuria with nephrocalcinosis or kidney stones; and more than 35% have ectopic and basal ganglia calcifications (summary by Nesbit et al., 2013). Thakker (2001) noted that patients with gain-of-function mutations in the CASR gene, resulting in generally asymptomatic hypocalcemia with hypercalciuria, have low-normal serum PTH concentrations and have often been diagnosed with hypoparathyroidism because of the insensitivity of earlier PTH assays. Because treatment with vitamin D to correct the hypocalcemia in these patients causes hypercalciuria, nephrocalcinosis, and renal impairment, these patients need to be distinguished from those with other forms of hypoparathyroidism (see 146200). Thakker (2001) suggested the designation 'autosomal dominant hypocalcemic hypercalciuria' for this CASR-related disorder. Genetic Heterogeneity of Autosomal Dominant Hypocalcemia Autosomal dominant hypocalcemia-2 (HYPOC2; 615361) is caused by mutation in the GNA11 gene (139313) on chromosome 19p13. [from OMIM]

Johanson-Blizzard syndrome is an autosomal recessive disorder characterized by poor growth, mental retardation, and variable dysmorphic features, including aplasia or hypoplasia of the nasal alae, abnormal hair patterns or scalp defects, and oligodontia. Other features include hypothyroidism, sensorineural hearing loss, imperforate anus, and pancreatic exocrine insufficiency (summary by Al-Dosari et al., 2008). [from OMIM]

Individuals with hereditary distal renal tubular acidosis (dRTA) typically present in infancy with failure to thrive, although later presentations can occur, especially in individuals with autosomal dominant SLC4A1-dRTA. Initial clinical manifestations can also include emesis, polyuria, polydipsia, constipation, diarrhea, decreased appetite, and episodes of dehydration. Electrolyte manifestations include hyperchloremic non-anion gap metabolic acidosis and hypokalemia. Renal complications of dRTA include nephrocalcinosis, nephrolithiasis, medullary cysts, and impaired renal function. Additional manifestations include bone demineralization (rickets, osteomalacia), growth deficiency, sensorineural hearing loss (in ATP6V0A4-, ATP6V1B1-, and FOXI1-dRTA), and hereditary hemolytic anemia (in some individuals with SLC4A1-dRTA). [from GeneReviews]

Congenital disorders of glycosylation (CDG), previously called carbohydrate-deficient glycoprotein syndromes (CDGSs), are a group of hereditary multisystem disorders first recognized by Jaeken et al. (1980). The characteristic biochemical abnormality of CDGs is the hypoglycosylation of glycoproteins, which is routinely determined by isoelectric focusing (IEF) of serum transferrin. Type I CDG comprises those disorders in which there is a defect in the assembly of lipid-linked oligosaccharides or their transfer onto nascent glycoproteins, whereas type II CDG comprises defects of trimming, elongation, and processing of protein-bound glycans. CDG1G is a multisystem disorder characterized by impaired psychomotor development, dysmorphic features, failure to thrive, male genital hypoplasia, coagulation abnormalities, and immune deficiency. More variable features include skeletal dysplasia, cardiac anomalies, ocular abnormalities, and sensorineural hearing loss. Some patients die in the early neonatal or infantile period, whereas others are mildly affected and live to adulthood (summary by Tahata et al., 2019). For a general discussion of CDGs, see CDG1A (212065). [from OMIM]

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is a progressive renal disorder characterized by excessive urinary Ca(2+) and Mg(2+) excretion. There is progressive loss of kidney function, and in about 50% of cases, the need for renal replacement therapy arises as early as the second decade of life (summary by Muller et al., 2006). Amelogenesis imperfecta may also be present in some patients (Bardet et al., 2016). A similar disorder with renal magnesium wasting, renal failure, and nephrocalcinosis (HOMG5; 248190) is caused by mutations in another tight-junction gene, CLDN19 (610036), and is distinguished by the association of severe ocular involvement. For a discussion of phenotypic and genetic heterogeneity of familial hypomagnesemia, see HOMG1 (602014). [from OMIM]

Congenital generalized lipodystrophy, also known as Berardinelli-Seip syndrome, is an autosomal recessive disorder characterized by marked paucity of adipose tissue, extreme insulin resistance, hypertriglyceridemia, hepatic steatosis, and early onset of diabetes (Garg, 2004). For a general description and a discussion of genetic heterogeneity of congenital generalized lipodystrophy, see CGL1 (608594). [from OMIM]

Autosomal recessive osteopetrosis-5 is a form of infantile malignant osteopetrosis, characterized by defective osteoclast function resulting in decreased bone resorption and generalized osteosclerosis. Defective resorption causes development of densely sclerotic fragile bones and progressive obliteration of the marrow spaces and cranial foramina. Marrow obliteration is associated with extramedullary hematopoiesis and hepatosplenomegaly, and results in anemia and thrombocytopenia, whereas nerve entrapment accounts for progressive blindness and hearing loss. Other major manifestations include failure to thrive, pathologic fractures, and increased infection rate. Most affected children succumb to severe bone marrow failure and overwhelming infection in the first few years of life (Quarello et al., 2004). [from OMIM]

Gracile bone dysplasia (GCLEB) is a perinatally lethal condition characterized by gracile bones with thin diaphyses, premature closure of basal cranial sutures, and microphthalmia (summary by Unger et al., 2013). [from OMIM]

A rare, primary bone dysplasia characterized by severe growth retardation, short stature, cortical thickening and medullary stenosis of long bones, delayed closure of the anterior fontanelle, absent diploic space in the skull bones, prominent forehead, macrocephaly, dental anomalies, eye problems (hypermetropia and pseudopapilledema), and hypocalcemia due to hypoparathyroidism, sometimes resulting in convulsions. Intelligence is normal. [from ORDO]

Familial hypomagnesemia with secondary hypocalcemia (HOMG1) is a rare autosomal recessive disorder characterized by very low serum magnesium levels. Hypocalcemia is a secondary consequence of parathyroid failure and parathyroid hormone resistance as a result of severe magnesium deficiency. The disease typically manifests during the first months of life with generalized convulsions or signs of increased neuromuscular excitability, such as muscle spasms or tetany. Untreated, the disease may be fatal or lead to severe neurologic damage. Treatment includes immediate administration of magnesium, usually intravenously, followed by life-long high-dose oral magnesium (review by Knoers, 2009). Genetic Heterogeneity of Hypomagnesemia A form of hypomagnesemia due to kidney defects and high urinary magnesium excretion associated with hypocalciuria (HOMG2; 154020) is caused by mutation in the FXYD2 gene (601814). Renal hypomagnesemia-3 (HOMG3; 248250), associated with hypercalciuria and nephrocalcinosis, is caused by mutation in the CLDN16 gene (603959). Renal hypomagnesemia-4 (HOMG4; 611718), which is normocalciuric, is caused by mutation in the EGF gene (131530). Renal hypomagnesemia-5 (HOMG5; 248190), associated with hypercalciuria, nephrocalcinosis, and severe ocular involvement, is caused by mutation in the CLDN19 gene (610036). Renal hypomagnesemia-6 (HOMG6; 613882) is caused by mutation in the CNNM2 gene (607803). Renal hypomagnesemia-7 with or without dilated cardiomyopathy (HOMG7; 620152) is caused by mutation in the RRAGD gene (608268). Patients with Gitelman syndrome (263800) and Bartter syndrome (see 241200) also show hypomagnesemia, and steatorrhea and severe chronic diarrhea states, such as Crohn disease (see 226600) and Whipple disease, that can result in severe hypomagnesemia. [from OMIM]

A rare, primary bone dysplasia characterized by prenatal and postnatal growth retardation, short stature, cortical thickening and medullary stenosis of the long bones, absent diploic space in the skull bones, hypocalcemia due to the hypoparathyroidism, small hands and feet, delayed mental and motor development, intellectual disability, dental anomalies, and dysmorphic features, including prominent forehead, small deep-set eyes, beaked nose, and micrognathia. [from ORDO]