4p syndrome (Wolf-Hirschhorn syndrome; deletion 4p; monosomy 4p)
MIM 194190; characterized by growth failure of prenatal onset, microcephaly, “Greek helmet” facies (high forehead, prominent glabella, arched eyebrows, straight nose), hypertelorism, hypotonia, neurocognitive impairment, seizures, scoliosis
MIM 264600; autosomal recessive; mutations in SRD5A2; results in defective dihydrotestosterone formation and decreased plasma levels; 46,XY males show ambiguous external genitalia at birth but develop masculinization at puberty.
22q11.2 deletion syndrome
see “22q11.2 Deletion Syndrome.”
22 tetrasomy syndrome
see Glossary entry “cat eye syndrome.”
MIM 305400; X-linked recessive; mutations in FGD1; characterized by short stature, characteristic facies, “shawl” scrotum (penoscrotal transposition), syndactyly, various ocular findings, and prominent umbilicus; delayed bone age; mild to moderate intellectual disability in 1/3; female carriers may show mild features.
Achondrogenesis type I
MIM 200600 and 600972; autosomal recessive; mutations in TRIP11 or SLC26A2; short-limbed dwarfism; most severe form of chondrodysplasia; characterized by deficient ossification of lumbar vertebrae and absent ossification of pelvic bones; stillbirth or early death
MIM 100800; autosomal dominant; mutations in FGFR3; characterized by disproportionate short stature with rhizomelia, macrocephaly, small foramen magnum (risk of cord compression), caudal narrowing of spinal canal, mild hypotonia, and relative glucose intolerance; cognitive development is normal; 90% result from new mutations, usually paternal in origin; American Academy of Pediatrics (AAP) Health Maintenance Guidelines published
Acidotic newborns, metabolic diseases in
MIM 201100; autosomal recessive; mutations in SLC39A4; characterized by abnormal intestinal absorption of zinc, resulting in zinc deficiency; secondary effects include vesiculobullous and eczematous skin lesions in the perioral and perineal areas, cheeks, knees, and elbows; photophobia, conjunctivitis, corneal dystrophy; chronic diarrhea; nail dystrophy; growth retardation; superinfections and candidal infections; treatment requires lifelong zinc supplementation.
Acute intermittent porphyria
MIM 176000; autosomal dominant; mutations in HMBS; characterized by recurrent attacks of severe abdominal pain, GI dysfunction, and neurologic disturbances; attacks may be precipitated by medications, alcohol, endocrine factors, stress, infections, or caloric restriction; attacks are rare before puberty and are more likely in women than in men.
MIM 300100; X-linked recessive; mutations in ABCD1; defect in peroxisomal β-oxidation and accumulation of very long chain fatty acids (VLCFA); onset ranges from childhood to adulthood; progressive neurodegeneration; carrier females may have symptoms; currently included in many state; newborn screening programs in the United States
Agenesis of corpus callosum
multifactorial; complete or partial absence of the major tracts connecting the right and left hemispheres; can be associated with hydrocephalus, seizures, developmental delay, spasticity, and hypertelorism; can be isolated or found with other brain malformations and in many multiple anomaly and chromosomal syndromes
MIM 304050; apparently X-linked dominant; gene remains unknown; characterized by microcephaly, various brain malformations including cysts and heterotopias, infantile spasms, chorioretinal lacunae, and costovertebral skeletal abnormalities; lethal in males
Alagille syndrome (arteriohepatic dysplasia)
MIM 118450 and 610205; autosomal dominant; mutations in JAG1 or NOTCH2; characterized by paucity or absence of intrahepatic bile ducts with progressive destruction of bile ducts and five clinical abnormalities: cholestasis, cardiac disease characteristic facies (broad forehead, deep-set eyes that are widely spaced and underdeveloped, a small, pointed mandible), skeletal defects, and eye abnormalities; 39% also have renal involvement.
see Glossary entry “McCune-Albright syndrome.”
MIM 203450; autosomal dominant; mutations in GFAP; three subtypes: infantile, juvenile, adult; characterized by macrocephaly in infants, neurocognitive delay, spasticity and seizures; older patients show bulbar or pseudobulbar symptoms and spasticity; progressive neurodegenerative with death within 10 years of onset; see also Glossary entry “Canavan disease.”
MIM 104000; multifactorial and heterogeneous; genetically determined, immune-mediated; one of the most common human autoimmune conditions; spectrum of severity; includes nail abnormalities
MIM 613490; autosomal recessive; mutations in SERPINA1; liver disease in children and adults, emphysema in adults; testing most commonly done by protein phenotype; M allele is normal; the most common pathogenic allele is Z.
MIM 301050; X-linked dominant; mutations in COL4A5; characterized by renal failure due to glomerulonephropathy, sensorineural hearing loss, and variable eye anomalies. Usually presents in infancy with hematuria; proteinuria and hearing loss are later findings; carrier mothers may show microscopic hematuria; less common autosomal recessive and dominant forms
see Glossary entry “glycogen storage disease IV (GSD4).”
MIM 300068; X-linked recessive; mutations in AR; affected 46,XY males have female external genitalia with blind-ending vagina, absent uterus, and otherwise female features; testes are present; androgen levels are normal to high with inability of physiologic response.
MIM 105830; imprinting disorder; absence of maternal alleles of 15q11.2 that include the UBE3A gene; mechanisms include deletion on the maternal chromosome, paternal uniparental disomy, and rarely, mutations in the gene itself; ataxic gait (wide-based, arms held upward) seizures, paroxysmal laughter, mental deficiency, absent or severely reduced speech, microcephaly, characteristic facies with maxillary hypoplasia, large mouth, tongue protrusion, and prognathia; deletion cases have relative hypopigmentation.
MIM 101200; autosomal dominant; mutations in FGFR2; characterized by craniosynostosis (typically coronal), turribrachycephaly, underdevelopment of the middle third of the face, hypertelorism and proptosis, variable but pronounced syndactyly. Other anomalies include characteristic facies, malrotation and gastrointestinal atresias, and congenital heart defects; neurocognitive delays are present, but intelligence can be normal.
Aplasia cutis congenita (nonsyndromic)
MIM 107600; mutations in BMS1; congenitally localized absence of skin on the scalp vertex, may be associated with underlying skull defects; may also be found in numerous syndromes including trisomy 13
Arthrogryposis multiplex congenita
a category of conditions rather than a single entity; congenital contracture(s) of many if not all major joints; some syndromes with identified genes and defined heritability; pathogenically variable with origin anywhere along the axis from motor cortex to muscle cell
Ataxia telangiectasia syndrome (Louis-Bar)
MIM 208900; autosomal recessive; mutations in ATM; characterized by progressive ataxia within the 1st year, telangiectasias by age 8 years, neurodegeneration, lymphopenia, immune deficit (low to absent IgA and IgE), and growth deficiency; increased risk of lymphomas and leukemias in patients and carrier parents
MIM 180500; autosomal dominant; mutations in PITX2; characterized by Rieger anomaly of the eye (anterior segment dysgenesis), glaucoma, hypodontia, maxillary hypoplasia, and umbilical abnormalities
MIM 209900; autosomal recessive; mutations in various genes; caused by abnormalities in nonmotile cilia; characterized by mental retardation, retinitis pigmentosa, obesity, polydactyly, renal anomalies, hypogonadism, and neurocognitive impairments (looks superficially like Prader-Willi syndrome with polydactyly)
see Glossary entry “epidermolysis bullosa dystrophica, autosomal dominant.”
MIM 302060; X-linked recessive; mutations in TAZ; affected males have skeletal myopathy and cardiomyopathy, neutropenia, growth delay, and characteristic facies; carrier females usually unaffected
see “Bartter Syndrome.”
Basal cell nevus syndrome
MIM 109400; autosomal dominant; mutations in PTCH1, PTCH2, or SUFU; characterized by basal cell carcinomas, macrocephaly, odontogenic keratocysts of jaws, bifid ribs, pits in the palms and soles, and calcification of the falx cerebri
Becker muscular dystrophy
see “Muscular Dystrophies.”
MIM 130650; imprinting disorder of chromosome 11 or autosomal dominant due to mutations in CDKN1C; characterized by overgrowth of prenatal onset, omphalocele, macroglossia, hemihyperplasia, and characteristic facies; significant risk of Wilms tumor and hepatoblastoma especially in patients with hemihyperplasia; neurocognitive impairment if neonatal hypoglycemia is unrecognized or uncontrolled
MIM 109650; presumed autosomal dominant; gene unidentified; disease mechanism unknown; recurrent inflammatory lesions, oral and genital ulcers, various skin and eye lesions
see Glossary entry “incontinentia pigmenti.”
MIM 210900; autosomal recessive chromosome instability syndrome; mutations in BLM; characterized by growth deficiency of prenatal onset, microcephaly, facial telangiectatic erythema in a butterfly pattern, skin pigmentation changes, mild neurocognitive impairment, and characteristic facies; high risk of malignancy; increased prevalence in Ashkenazi Jews
Blue diaper syndrome
MIM 211000; probably autosomal recessive; gene unidentified; defect in intestinal transport of tryptophan; bacterial degradation of the intraluminal tryptophan forms water-soluble metabolites that turn blue on exposure to oxygen; may be a nongenetic Pseudomonas aeruginosa metabolite; only two brothers have been documented with the transport defect.
Bourneville disease, Bourneville–Pringle disease
see “Tuberous Sclerosis Complex.”
MIM 113650; autosomal dominant; mutations in gene EYA1; characterized by ear malformations, hearing impairment, branchial fistulae and cysts, and renal malformations
see Glossary entry “progressive familial intrahepatic cholestasis.”
see Glossary entry “infantile cortical hyperostosis.”
MIM 114290; autosomal dominant; mutations in SOX9; skeletal dysplasia with bowing of long bones, laryngotracheomalacia, and ambiguous genitalia or sex reversal in 46,XY patients
MIM 271900; autosomal recessive; mutations in ASPA; progressive, degenerative demyelination and leukodystrophy; usually begins in infancy with macrocephaly, hypotonia, and developmental regression; increased prevalence in Ashkenazi Jews; features similar to Alexander disease—see Glossary entry “Alexander Disease.”
MIM 600643; inheritance pattern unclear; gene unidentified; overlaps significantly with the polycystic kidney syndromes and may not represent a separate entity; characterized by cystic dilatation of the intrahepatic bile ducts; recurrent bouts of cholangitis and biliary abscesses secondary to bile stasis and gallstones
Cat eye syndrome (22 Tetrasomy syndrome)
MIM 115470; presence of an extra chromosome comprising two identical segments of chromosome 22 (i.e., the patient has four total copies of chromosome 22); characterized by coloboma of iris, down-slanting palpebral fissures, anal atresia, cardiac defects, renal agenesis; mild neurocognitive impairment; growth is usually normal.
Charcot-Marie-Tooth disease (hereditary motor and sensory neuropathy [HMSN] or peroneal muscular atrophy)
MIM 118200; various inheritance patterns; mutations in various genes; group of sensorineural peripheral polyneuropathies that are most common cause of chronic peripheral neuropathy; characterized by insidious onset of slowly progressive weakness and atrophy of distal limb muscles, impaired sensation
MIM 214800; autosomal dominant; mutations in CHD7; characterized by Coloboma, Heart disease, choanal Atresia, Retarded growth and development and/or CNS anomalies, Genital anomalies and/or hypogonadism, and Ear anomalies and/or deafness. The ear malformation is characteristic: Mondini defect and hypoplastic semicircular canals of the inner ear in the presence of other typical malformations are diagnostic for CHARGE.
MIM 214500; autosomal recessive; mutations in LYST; characterized by oculocutaneous albinism, lack of natural killer cells, decreased neutrophil and monocyte migration, anemia, neurodegeneration, hepatomegaly, and splenomegaly
Chondrodysplasia punctata 2, X-linked dominant
MIM 302960; X-linked dominant; mutations in EBP; characterized by short stature, skeletal changes including stippling of epiphyses and rhizomelic limb shortening, linear or blotchy ichthyosis, and eye findings including cataracts and microphthalmia. Most affected patients are female; germline inheritance considered lethal to males
see Glossary entry “primary ciliary dyskinesia.”
MIM 216400; autosomal recessive; mutations in ERCC6 and ERCC8; characterized by postnatal growth deficiency, microcephaly, neurocognitive impairment, ataxia, hearing loss, seizures, characteristic facies, hypertension, renal dysfunction, and photosensitivity
MIM 303600; X-linked dominant; mutations in RSK2; characterized by severe intellectual disability in affected males, microcephaly, characteristic facies, short stature, fleshy hands; stimulus-induced drop attacks in 20%; carrier females can have intellectual disability.
MIM 216550; autosomal recessive; mutations in VSP13B; characterized by intellectual disability, microcephaly, progressive retinopathy, characteristic facies, obesity, and intermittent congenital neutropenia
MIM 112240; autosomal dominant; mutations in P4HB or SEC24D; characterized by bone fragility, craniosynostosis, proptosis, hydrocephalus, and characteristic facies
Congenital adrenal hyperplasia
Congenital amegakaryocytic thrombocytopenia
MIM 604498; autosomal recessive; mutations in MPL; characterized by thrombocytopenia and megakaryocytopenia
Congenital disorders of glycosylation
any different types, most are autosomal recessive; enzymatic defects in synthesis of glycoproteins; two main groups: type I and type II. Type I defects are abnormalities in glycoprotein assembly. Type II defects involved abnormal processing of protein-bound glycans; more likely a disease mechanism than a set of discrete conditions
see “Hypothyroidism, Congenital.”
Congenital insensitivity to pain
MIM 243000; autosomal recessive; mutations in SCN9A; MIM 147430; autosomal dominant; gene unidentified; characterized by absence of pain perception and hyposmia/anosmia
Congenital rubella syndrome
see Glossary entry “fetal rubella syndrome.”
see Glossary entry “chondrodysplasia punctata 2, X-linked dominant.”
Cornelia de Lange syndrome (Brachmann-De Lange syndrome, de Lange syndrome)
MIM 122470; autosomal dominant; mutations in various genes, most commonly NIPBL; characterized by growth failure of prenatal onset microcephaly, hirsutism, limb reduction defects (particularly ulnar ray defects) gastroesophageal reflux, congenital heart defects, neurocognitive impairment, and characteristic facies
MIM 218040; autosomal dominant; mutations in HRAS; characterized by coarse facial features, short stature, postnatal feeding problems, curly or sparse fine hair, loose soft skin, hypertrophic cardiomyopathy, arrhythmias especially chaotic atrial rhythm/multifocal atrial tachycardia; 15% lifetime risk for malignant tumors
Crigler-Najjar syndrome, types I and II
MIM 218800 and 606785; autosomal recessive; mutations in UGT1A1; absence of hepatic uridine 5′-diphospho-glucuronosyltransferase activity leading to unconjugated hyperbilirubinemia on 1st day of life without evidence of hemolysis; type I treatment requires phototherapy to prevent kernicterus; type II treatable with phenobarbital treatment
Crouzon syndrome (craniofacial dysostosis)
MIM 123500; autosomal dominant; mutations in FGFR2; characterized by craniosynostosis (most often coronal), exophthalmos due to shallow orbits, hypertelorism, high palate, and hypoplasia of maxilla; obstructive sleep apnea is common; hands and feet are not involved.
MIM 162800; autosomal dominant; mutations in ELANE; lack of granulocyte macrophage colony-stimulating factor (GM-CSF); characterized by fever, mouth lesions, cervical adenitis, and gastroenteritis; underlying regular 21-day cyclic fluctuation in number of blood leukocytes
see “Cystic Fibrosis.”
MIM 219800; autosomal recessive; mutations in CTNS; lysosomal storage of cysteine; patients normal at birth with development of rickets, nephrolithiasis, corneal crystal accumulation, peripheral retinopathy, hepatosplenomegaly and pancreatic insufficiency. Multiple organs affected; normal intelligence with deterioration over time
MIM 220100; both autosomal dominant and autosomal recessive forms; mutations in SLC3A1 or SLC7A9; characterized by nephrolithiasis
MIM 300009; X-linked recessive; mutations in CLCN5 or OCRL; proximal renal tubular dysfunction; proteinuria, hypercalcuria, nephrocalcinosis, nephrolithiasis, and chronic kidney disease; end-stage renal disease by 30 to 50 years of age in affected males. Carrier females rarely develop chronic kidney disease.
De Sanctis-Cacchione syndrome
MIM 278800; autosomal recessive; mutations in ERCC6; characterized by xeroderma pigmentosum, dwarfism, gonadal hypoplasia, and neurocognitive impairment with degeneration; see also Glossary entry “xeroderma pigmentosum.”
MIM 105650; autosomal dominant; mutations in RPS19; congenital pure red cell aplasia due to failure of erythropoiesis; characterized by normochromic macrocytic anemia, postnatal growth retardation, craniofacial, limb, heart, and urinary system malformations in 30–50%
see Glossary entry “22q11.2 deletion syndrome.”
see “Down Syndrome (Trisomy 21).”
MIM 237500; autosomal recessive; mutations in ABCC2; characterized by elevated conjugated bilirubin, large amounts of coproporphyrin I in urine, and deposits of melanin-like pigment in hepatocellular lysosomes; otherwise normal liver function
MIM 223370; autosomal recessive; gene unidentified; characterized by growth failure of prenatal onset, microcephaly, eczema-like skin disorder, brachydactyly, various ocular abnormalities, neurocognitive impairment, characteristic facies that resemble fetal alcohol syndrome
Duchenne muscular dystrophy
see “Muscular Dystrophies.”
many types; various inheritance patterns; mutations in various genes; abnormality in telomere stability; characterized by triad of reticulated skin hyperpigmentation, nail dystrophy, and leukoplakia; bone marrow failure and dysplasia that can include leukemia; higher risk of other cancers and other conditions usually associated with aging
see Glossary entry “prune belly syndrome.”
many types; various inheritance patterns; mutations in various genes; most common type is X-linked recessive; characterized by poor development, or absence, of teeth, nails, hair, and sweat glands
Ectrodactyly-ectodermal dysplasia-clefting syndrome
MIM 129900; autosomal dominant; mutations in TP63 cause about half; characterized by split-hand/split-foot, ectodermal dysplasia with keratitis, and cleft lip and/or cleft palate
see Glossary entry “trisomy 18.”
MIM 130000 (classic type); autosomal dominant and autosomal recessive group of conditions classified by type; mutations in some of the collagen genes; hypermobile joints and hyperextensible or fragile skin are characteristic features across the types, but the specific phenotypes vary; classic type (type I) is caused my mutations in COL5A1 or COL5A2. Abnormalities of the vasculature and hollow organs are characteristic of vascular type (type IV), caused by mutations in COL3A1.
four major types: simplex, junctional, dystrophic, and Kindler syndrome; fragility of the skin that manifests as blisters and erosions with minimal trauma; severity varies with type.
Epidermolysis bullosa dystrophica, autosomal dominant
MIM 131750; autosomal dominant; mutations in COL7A1; characterized by congenital aplasia of the skin on the lower legs and feet; nail defects and recurrent blistering of the skin and mucous membranes
MIM 301500; X-linked; mutations in GLA; deficiency α-galactosidase A leading to lysosomal storage of glycosphingolipids; characterized by angiofibromas (buttocks, inguinal area, fingernails, and lips) and vascular involvement; secondary effects of vascular involvement include renal failure, cardiovascular disease, stroke, GI complaints, anhidrosis, and tingling/burning sensation in the periphery; carrier females frequently manifest symptom; enzyme replacement therapy is available.
Familial adenomatous polyposis
MIM 171500; autosomal dominant; mutations in APC; characterized by multiple GI polyps with malignant transformation, skin cysts, supernumerary teeth, and multiple osteoma; Gardner syndrome is a variant in which desmoid tumors and other neoplasms occur along with the colon and rectum adenomas.
Familial dysautonomia (hereditary sensory and autonomic neuropathy)
MIM 223900; autosomal recessive; mutations in IKBKAP; characterized by aberrant sensory and autonomic functions; progressive course of poor growth, alacrima, decreased taste sense, postural hypotension, episodic hyperhidrosis, hypotonia, and decreased pain sensation; increased prevalence in Ashkenazi Jews
Familial Mediterranean fever
MIM 249100; usually autosomal recessive; mutations in MEFV; characterized by recurrent fever with painful inflammation of the peritoneum, synovium, and/or pleura, and amyloidosis with renal failure
MIM 227650; most are autosomal recessive; mutations in various genes; characterized by bone marrow failure, increased risk of malignancy, and physical abnormalities including short stature, abnormal skin pigmentation, skeletal malformations, microcephaly, and eye and genitourinary tract anomalies; radial ray defect that usually includes absent or hypoplastic thumbs, which can distinguish it clinically from thrombocytopenia absent radius (TAR) syndrome, in which the thumbs are spared
MIM 228000; autosomal recessive; mutations in ASAH1; lysosomal storage disease caused by deficiency of acid ceramidase; characterized by subcutaneous nodules, painful and progressively deformed joints, and laryngeal involvement with hoarseness
Fetal alcohol spectrum disorder (FASD)
see “Fetal Alcohol Syndrome” chapter.
Fetal alcohol syndrome
see “Fetal Alcohol Syndrome” chapter.
Fetal brain disruption sequence
brain destruction resulting in collapse of the fetal skull, microcephaly, scalp rugae, and neurologic impairment; has come to recent attention because it can be a result of in utero Zika virus infection
Fetal hydantoin syndrome
hydantoin (phenytoin) exposure during pregnancy; 5–10% of exposed fetuses; characterized by growth deficiency of prenatal onset, characteristic facies, neurocognitive impairment, and nail hypoplasia/aplasia; may have cleft lip and palate, and cardiac defects
Fetal rubella syndrome
rubella virus infection, especially in the first trimester; characterized by mental deficiency, microcephaly, deafness, cataract, glaucoma, patent ductus arteriosus, cardiac septal defects, hepatosplenomegaly, anemia, and thrombocytopenia; hearing impairment is the most common defect; vaccine-preventable disease
Fetal valproate syndrome
valproate exposure in the first trimester; characterized by neurocognitive impairments, neural tube defects, cardiovascular anomalies, and characteristic facies
Fetal warfarin syndrome
warfarin exposure during pregnancy; features vary with exposure window: 6- to 9-week exposure characterized by defects associated with aberrant cartilage: nasal hypoplasia, stippled epiphyses, hypoplastic distal phalanges; 14- to 20-week exposure characterized by central nervous system defects, eye anomalies, and intrauterine growth retardation. Exposure in the third trimester is less concerning.
Fibrodysplasia ossificans progressiva (FOP)
MIM 135100; autosomal dominant; mutations in ACVR1; characterized by short hallux, progressive ossification of muscles and subcutaneous tissues, and hearing loss; any trauma (including iatrogenic such as needle sticks) can cause ectopic ossification.
Five-alpha reductase deficiency
see Glossary entry “5α- reductase deficiency.”
Focal dermal hypoplasia
MIM 305600; X-linked dominant; mutations in PORCN; characterized by linear atrophy of the skin with fat herniation through the dermis, linear pigmentation abnormalities, and papillomata; may have eye, oral, or limb abnormalities; 90% of affected patients are female; germline inheritance considered lethal to males
Fragile X syndrome
MIM 600624; X-linked; triplet repeat mutation in FMR1 with expansion risk increased when inherited from mother; full expansion (>200 repeats) characterized by mental deficiency, autism spectrum disorders, macrocephaly, prognathism, large ears, mild connective tissue dysplasia, and macroorchidism after puberty; female full mutation carriers can manifest the phenotype; female carriers of premutations (55 to 200 repeats) have increased risk of premature ovarian insufficiency; male and female premutation carriers have increased risk of fragile X–associated tremor ataxia syndrome as adults.
Fragile XE syndrome
MIM 309548; X-linked recessive; triplet repeat mutations in AFF2; characterized by mild to moderate intellectual disability and other neurocognitive problems
MIM 229300; autosomal recessive; triplet repeat mutations in FXN; progressive loss of large myelinated axons in peripheral nerves; characterized by progressive cerebellar and spinal cord dysfunction; symptoms usually appearing in late childhood or adolescence; patients have high-arched foot, hammer toes, and cardiac failure.
Fukuyama muscular dystrophy
see Glossary entry “muscular dystrophy-dystroglycanopathy with brain and eye anomalies.”
MIM 230400; autosomal recessive; mutations most commonly in GALT; inability to metabolize lactose; characterized by jaundice, hepatosplenomegaly, liver failure, renal tubular dysfunction, hypotonia, cataracts, and risk of infection; usually symptomatic in the neonatal period; may present with sepsis, particularly from Escherichia coli; treated by restricting lactose; currently included in most state newborn screening programs in the United States
see Glossary entry “familial adenomatous polyposis.”
MIM 230800; autosomal recessive; mutations in GBA; deficiency of glucocerebrosidase, leading to accumulation and storage of glucocerebroside in the reticuloendothelial system; three types: type I includes adult-onset hepatosplenomegaly, cytopenia, and pulmonary disease; type II presents in infancy with the features of type I and bulbar and pyramidal signs as well as cognitive impairment; type III includes the features of type I with juvenile onset as well as oculomotor apraxia, seizure, and progressive myoclonic epilepsy. There are also perinatal-lethal and cardiovascular forms. Enzyme replacement therapy is available.
MIM 143500; autosomal recessive; mutations in UGT1A1; reduced activity of glucuronyltransferase activity leading to mild unconjugated hyperbilirubinemia that worsens with stresses on the body, such as fasting; carriers can manifest symptoms.
Gilles de la Tourette syndrome
MIM 273800; autosomal recessive; mutations in ITGA2B and ITGB3; involves defective primary platelet aggregation (size and survival of platelets is normal); presents as bleeding dyscrasia
Glucose-6-phosphate dehydrogenase deficiency or G6PD deficiency
see “Glucose-6-Phosphate Dehydrogenase.”
Glutauric aciduria I
MIM 231670; autosomal recessive; mutations in GCDH; inability to metabolize lysine, hydroxylysine, and tryptophan; characterized by basal ganglia atrophy and scarring with progressive movement disorder, macrocephaly, hepatomegaly; currently included in many state newborn screening programs in the United States
MIM 605899; autosomal recessive; mutations in genes of the glycine cleavage system AMT, GLDC, or GCSH; most patients present in the neonatal period with lethargy, hypotonia, and myoclonus progressing to apnea; survivors have intractable seizures and profound intellectual disability; currently included in many state newborn screening programs in the United States
Glycogen storage disease 1A (GSD1A; von Gierke)
MIM 232200; autosomal recessive; mutations in G6PC; accumulation of glycogen and defective gluconeogenesis; characterized by fasting hypoglycemia, growth retardation, hepatomegaly, lactic acidosis, hyperlipidemia, and hyperuricemia
Glycogen storage disease IV (GSD4; Andersen disease)
MIM 232500; autosomal recessive; mutations in GBE1; defect of glycogen-branching enzyme; classic form characterized by hepatomegaly and failure to thrive in the 1st few months of life, progressing to liver cirrhosis and splenomegaly; neuromuscular forms can present at any age.
MIM 230500; autosomal recessive; mutations in GLB1; lysosomal storage disease with accumulation of ganglioside substrates. Three types: Type I presents in infancy with CNS dysfunction and life expectancy of 2 to 3 years; type II has onset between 1 and 10 years with developmental delays and regression and may include skeletal dysplasia; type III begins in 2nd or 3rd decade with parkinsonian features and cardiomyopathy.
see Glossary entry “oculo-auriculo-vertebral.”
see Glossary entry “focal dermal hypoplasia.”
see Glossary entry “basal cell nevus syndrome.”
MIM 234100; inheritance undefined; gene unidentified; characterized by hypotrichosis, microphthalmia, cataracts, beaked nose, micrognathia, dental anomalies, and proportionate short stature; typically normal intelligence
MIM 234500; autosomal recessive; mutations in SLC6A19; defect in transport of monoamine monocarboxylic amino acids by intestinal mucosa and renal tubules; characterized by photosensitivity and a pellagra-like skin rash, cerebellar ataxia, emotional instability, and amino aciduria
MIM 235200; autosomal recessive; mutations in HFE or BMP2; excessive iron storage in multiple organs leading to compromise or failure of those organs, especially the liver and pancreas; can have increased apparent skin pigmentation from iron deposition; early symptoms include abdominal pain, weakness/lethargy, and weight loss; treatment is phlebotomy; men have earlier and more severe problems than women, who many not manifest until after menopause.
see “Hereditary Angioedema (C1 Esterase Deficiency).”
Hereditary fructose intolerance
MIM 229600; autosomal recessive; mutations in ALDOB; deficiency of fructose-1-phosphate aldolase or fructose 1,6-diphosphatase; characterized by vomiting, diarrhea, hypoglycemic seizures, and jaundice upon exposure to fructose or sucrose
see “Hereditary Spherocytosis.”
MIM 203300; autosomal recessive; mutations in HPS1; characterized by oculocutaneous albinism, bleeding, and lysosomal ceroid storage; electron micrography shows absence of platelet dense granules and can be diagnostic; increased incidence in Puerto Rico
MIM 142900; autosomal dominant; mutations in TBX5; characterized by upper limb defects, typically radial ray defects, and cardiac anomalies; most common combination is a missing or hypoplastic thumb and atrial septal defect.
MIM 236200; autosomal recessive; mutations in CBS; deficient cystathionine synthetase activity leading to marfanoid habitus and neurocognitive impairment, also thrombotic events, generalized hypopigmentation, and, with progression, seizures; currently included in many state newborn screening programs in the United States
see Glossary entry “mucopolysaccharidosis II.”
MIM 143100; autosomal dominant; triplet repeat mutations in HHT with expansion risk increased when inherited from father; characterized in adults by progressive neurodegeneration including chorea, dystonia, incoordination, and cognitive decline; childhood Huntington manifests as developmental delay and seizures which worsen with time. Youngest documented patient is 2 years of age.
see Glossary entry “mucopolysaccharidosis I.”
Hutchinson-Gilford progeria syndrome
MIM 176670; autosomal dominant; mutations in LMNA; all cases to date have been de novo mutations; characterized by the appearance of premature aging, severe growth failure, atherosclerosis, lipodystrophy, alopecia, and decreased joint mobility; cognitive development is normal.
Hyperammonemic newborns, metabolic diseases in
MIM 149400; autosomal dominant and autosomal recessive types; mutations in GLRA1; characterized by exaggerated startle response with intense generalized hypertonia that may be prolonged; prolonged episodes put an infant at risk for apnea or aspiration; residual effects in adulthood include nocturnal myoclonus and startle-induced falls.
Hyperimmunoglobulinemia E syndrome
Hypoglycemic newborns, metabolic diseases in
Hypogonadotropic hypogonadism with or without anosmia
MIM 308700; X-linked or autosomal dominant; some digenic inheritance; multiple genes involved; characterized by some degree of hypogonadism and altered or absent sense of smell due to olfactory lobe agenesis; bimanual synkinesia; not all affected persons are infertile.
see “Hypophosphatemic Disorders.”
see “Hypothyroidism, Congenital.”
a group of conditions that result from abnormal hyperkeratosis; the most common and least severe type is ichthyosis vulgaris, an autosomal dominant condition caused by mutations in FLG. The X-linked type of Ichthyosis is caused by steroid sulfatase deficiency and mutations in STS. Most of the remainder are autosomal recessive, caused by mutations in a variety of genes. They can be severe, especially at birth when they can present with a collodion membrane.
see “Immune Deficiency.”
Immune dysregulation, polyendocrinopathy, enteropathy X-linked syndrome (IPEX)
MIM 304790; X-linked recessive; mutations in FOXP3; characterized by enteropathy and severe diarrhea in infancy, type I diabetes mellitus, and dermatitis
Incontinentia pigmenti (IP)
MIM 308300; X-linked dominant; mutations in IKBKG (NEMO); characterized by four-stage evolving skin lesions and abnormalities of skin appendages, eosinophilia, high risk of neonatal stroke; neurocognitive problems in patients with stroke or CNS anomalies, but majority of patients are neurocognitively normal; malformations of internal organs and the skeleton are not characteristic of IP.
Infantile cortical hyperostosis
MIM 114000; autosomal dominant; mutations in COL1A1; inflammation of bone with cortical changes that appears before 5 months of age and usually resolves by 2 years
Jansen metaphyseal chondrodysplasia
MIM 156400; autosomal dominant; mutations in PTHR1; metaphyseal chondrodysplasia; characterized by severe short stature, short bowed limbs, small jaw, and hypercalcemia/hypophosphatemia despite normal parathyroid function
MIM 243800; autosomal recessive; mutations in UBR1; characterized by growth failure, hypoplastic alae nasae, abnormal hair patterns, oligodontia, hypothyroidism, sensorineural hearing loss, imperforate anus, and exocrine pancreatic insufficiency
MIM 147920; autosomal dominant; mutations in KMT2D or KDM6A; characterized by growth deficiency of postnatal onset, intellectual disability, hypotonia, characteristic facies resembling Kabuki dance makeup (long palpebral fissures with lateral ectropion, ptosis, arching eyebrows), skeletal anomalies, cardiac defects, and neurocognitive impairment
see Glossary entry “hypogonadotropic hypogonadism with or without anosmia.”
see Glossary entry “primary ciliary dyskinesia.”
Kleine-Levin hibernation syndrome
MIM 148840; inheritance undefined; gene unidentified; characterized by episodes of compulsive megaphagia, somnolence, and abnormal behavior predominantly in males
47 XXY karyotype; paternal meiosis error; characterized by hypogonadism, tall stature with long limbs, mild neurocognitive impairments, although many are cognitively normal. Infertility is not universal.
multifactorial; cervical spine fusion of varying degrees; characterized by a short neck, limited neck motion, and low occipital hairline; isolated defect or can appear as part of a multisystem syndrome
MIM 245200; autosomal recessive; mutations in GALC; deficiency in galactosylceramidase; lysosomal storage disorder primarily affecting white matter of the central and peripheral nervous systems; characterized classically by early, severe neurodegeneration leading, in the infantile form, to death by 2 years of age. There are later onset forms.
MIM 307000; X-linked recessive; mutations in L1CAM; hydrocephalus due to aqueductal stenosis, adducted thumbs, spasticity, and severe intellectual disability; one manifestations of L1CAM mutations, of which there is a spectrum
MIM 150250; autosomal recessive; mutations in B3GAT3; characterized by osteochondrodysplasia, hyperlaxity, multiple congenital dislocations, short stature, heart defects, and characteristic facies
see Glossary entry “Bardet-Biedl syndrome.”
Leber hereditary optic neuropathy
MIM 535000; mitochondrial inheritance; mutations in any of a number of genes active in mitochondria; characterized by central vision loss leading to blindness; most commonly presents in adults
LEOPARD syndrome (Noonan syndrome with multiple lentigines)
MIM 151100; autosomal dominant; mutations in PTPN11, RAF1, or BRAF; characterized by Lentigines, EKG abnormalities, Ocular hypertelorism, Pulmonic stenosis, Abnormalities of genitalia, Retardation of growth, and sensorineural Deafness
MIM 300322; X-linked recessive; mutations in HPRT1; diminished or absent hypoxanthine guanine phosphoribosyl transferase (HPRT) activity leading to abnormal purine metabolism; characterized by hyperuricemia, spastic cerebral palsy, choreoathetosis, uric acid urinary stones; compulsive self-mutilation, and neurocognitive impairment
see “Histiocytosis” chapter.
MIM 151623; autosomal dominant; various genes, the most common being TP53; this is a cancer predisposition syndrome that increases the risk of many different cancers, classically but not limited to soft tissue sarcoma, osteosarcoma, premenopausal breast cancer, brain tumors, adrenocortical carcinoma, and leukemias; there is some genotype-phenotype correlation with the type of mutation; there are currently two genetic modifiers which lead to earlier or more severe tumor growth.
MIM 609192; autosomal dominant; mutations in TGFBR1 or TGFBR2; characterized by skeletal findings similar to Marfan syndrome and vascular abnormalities including aneurysms and tortuous blood vessels as well as craniofacial malformations; vascular abnormalities include aggressive arterial aneurysms anywhere in the body; high incidence of pregnancy-related complications including uterine rupture
Long QT interval
see “Long QT Syndrome.”
see Glossary entry “ataxia telangiectasia syndrome.”
Lowe oculocerebrorenal syndrome
MIM 309000; X-linked recessive; mutations in OCRL; characterized by congenital cataracts, microphthalmia, vitamin D-resistant rickets, amino aciduria, hyporeflexia, hypotonia, renal Fanconi syndrome, and neurocognitive impairment; carrier females have characteristic lens findings on slit-lamp examination.
MIM 153400; autosomal dominant; mutations in FOXC2; characterized by lymphedema of the lower limbs and double rows of eyelashes; complications include corneal irritation and ulceration, cardiac defects, varicose veins, cleft palate, extradural spinal cysts, and photophobia; lymphedema usually appears in late childhood or at puberty and is more severe in males.
Lysosomal acid lipase deficiency (Wolman disease)
MIM 278000; autosomal recessive; mutations in LIPA; lysosomal storage disease leading to cholesteryl ester and triglyceride deposition in visceral organs; characterized by intractable vomiting, failure to thrive, abdominal distention, steatorrhea, hepatosplenomegaly, and adrenal calcification; lethal in infancy
see Glossary entry “multiple enchondromatosis, Maffucci type.”
Malignant hyperthermia, susceptibility to
MIM 145600; autosomal dominant; mutations in RYR1; pharmacogenetic disorder of skeletal muscle calcium metabolism precipitated by some volatile anesthetics (e.g., halothane) alone or used with succinylcholine; characterized by muscle contracture and increased cellular metabolism leading to hyperthermia, compartment syndrome, and rhabdomyolysis, the latter of which can precipitate renal failure via myoglobinuria or cardiac arrhythmia via hyperkalemia
see Glossary entry “Treacher Collins syndrome.”
MIM 154700; autosomal dominant; mutations in FBN1; characterized by ectopia lentis, dilatation of the aorta, scoliosis, pneumothorax, pectus deformities, and long, thin extremities. Diagnostic criteria have been published.
Maternal phenylketonuria (PKU) effects
in children born to women with poorly controlled phenylketonuria, high maternal plasma phenylalanine is a teratogen; characterized by microcephaly, intellectual disability, behavior abnormalities, congenital heart defects, and other malformations; PKU is a recessive condition, so the infants usually are not affected and do not need dietary management; dietary control during pregnancy is necessarily stricter than baseline because phenylalanine concentrates in the fetus.
MIM 174800; autosomal dominant; mutations in GNAS; surviving cases are somatic mosaics as the nonmosaic state is presumed to be an embryonic lethal; characterized by polyostotic fibrous dysplasia, café-au-lait skin pigmentation, and peripheral precocious puberty; diagnosis most appropriately made via biopsy of affected tissue
MIM 249000; autosomal recessive; there are 12 types differentiated by mutations in various genes, most commonly MKS1; caused by abnormalities in nonmotile cilia; characterized by cystic renal disease, CNS malformation, and hepatic abnormalities, +/− postaxial polydactyly
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency
MIM 201450; autosomal recessive; mutations in ACADM; abnormal mitochondrial fatty acid oxidation and intolerance of fasting; can present as hypoketotic hypoglycemia, vomiting, lethargy, seizures, and sudden death; prognosis is excellent with dietary and medical management; currently included in many state newborn screening programs in the United States
MIM 153200; inheritance and gene unidentified; characterized by edema, primarily below the waist, which develops at puberty; may be associated with facial swelling, cleft palate, and/or yellow nails
MIM 540000; mitochondrial or autosomal recessive; mutations in any of a number of genes active in mitochondria most commonly MTTL1; characterized by Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Strokelike episodes; causes seizures, hemiparesis, hemianopsia, or cortical blindness, and episodic vomiting
Menkes disease (kinky hair disease)
MIM 309400; X-linked recessive; mutations in ATP7A; impaired GI transport of copper results in copper deficiency; characterized by low serum copper and ceruloplasmin, short, friable, colorless scalp hair, growth failure of postnatal onset, microcephaly, progressive neurocognitive impairment; death usually by 3 years of age
Metabolic diseases in acidotic newborns
Metabolic diseases in hyperammonemic newborns
Metabolic diseases in hypoglycemic newborns
MIM 250100; autosomal recessive; mutations in ARSA; characterized by progressive neurologic dysfunction and MRI evidence of leukodystrophy; three types: late infantile, juvenile, and adult. Types run within families; infantile type presents with physical neurologic features, others start with neurocognitive and behavioral changes.
MIM 247200; autosomal dominant; contiguous gene deletion syndrome of 17p13.3; characterized by lissencephaly, microcephaly, characteristic facies, heart malformations, male hypogonadism, growth deficiency, and neurologic abnormalities including seizures; often fatal in infancy
Mismatch repair cancer syndrome
MIM 276300; autosomal dominant inheritance, autosomal recessive in manifestation; dominant inheritance of one mutated allele, with somatic mutation (“second hit”) of the other; mutations in any of four separate genes; characterized by adenomatous colonic polyposis associated with malignant brain tumors, especially medulloblastoma and glioblastoma; there may be skin findings similar to those in neurofibromatosis type I.
Möbius (or Moebius) syndrome
MIM 157900; mostly isolated cases, may be autosomal dominant; gene unidentified; classically characterized by cranial nerve dysfunction causing bilateral facial weakness, feeding difficulties, and impairment of ocular abduction; the term has come to include any condition that includes congenital cranial nerve VII palsy and is, therefore, less useful than previously.
MIM 158000; autosomal dominant; mutations in KRT86, KRT81, or KRT83; characterized by normal hair at birth that transitions in a few months to brittle, easily broken hair and dystrophic alopecia; spectrum of involvement from just the occipital scalp to facial and axillary/pubertal hair; follicular hyperkeratosis often present; may improve with puberty and pregnancy
see Glossary entry “mucopolysaccharidosis IV.”
Mucopolysaccharidosis I (Hurler, Scheie)
MIM 607014; autosomal recessive; mutations in IDUA; lysosomal storage disease; deficiency of α-L-iduronidase causing accumulation of heparan sulfate and dermatan sulfate; characterized by coarse facial features, growth arrest, dysostosis multiplex, glaucoma, arthritis, cardiac valvular disease, and neurocognitive impairment. There is a spectrum of involvement from severe (Hurler phenotype) to mild (Scheie phenotype), and both may be found in the same family. Enzyme replacement therapy is available.
Mucopolysaccharidosis II (Hunter syndrome)
MIM 309900; X-linked recessive; mutations in IDS; lysosomal storage disease; deficiency of l-iduronate sulfatase causing accumulation of heparan sulfate and dermatan sulfate; characterized by macrocephaly, coarse facial features, hypertrophy of internal organs, dysostosis multiplex, and neurocognitive impairment; female carriers are unaffected; this is the only mucopolysaccharidosis that is not autosomal recessive; enzyme replacement therapy is available.
Mucopolysaccharidosis III (Sanfilippo syndrome)
MIM 252900; autosomal recessive; deficiency in one of four enzymes with clinically similar manifestations; lysosomal storage disease; characterized by accumulation of heparan sulfate and progressive neurocognitive impairment with mild somatic features. Type A—mutations in SGSH and deficiency of heparin N-sulfatase; type B—mutations in NAGLU and deficiency of N-α-acetylglucosaminidase; type C—mutations in HGSNAT and deficiency of acetyl CoA:alpha-glucosaminide N-acetyltransferase; type D—mutations in GNS and deficiency of N-acetylglucosamine-6-sulfatase
Mucopolysaccharidosis IV (Morquio syndrome)
MIM 253000; autosomal recessive; mutations in GALNS; lysosomal storage disease; deficiency of galactosamine-6-sulfate sulfatase causing accumulation of keratin sulfate and chondroitin-6-sulfate; characterized by skeletal dysplasia with short-trunk dwarfism, corneal clouding, small joint hyperlaxity, and cardiac valve disease; patients have laxity of the odontoid processes and are at risk for life-threatening atlantoaxial subluxation. Enzyme replacement therapy is available.
Multiple enchondromatosis, Maffucci type
MIM 614569; all cases to date have been sporadic; presumed to be somatic mosaicism for mutations in currently unidentified gene; characterized by multiple enchondromas of the bone and soft tissue hemangiomas; patients have short stature, skeletal deformities, scoliosis, and high risk of malignant transformation.
Multiple endocrine neoplasia type I
MIM 131100; autosomal dominant; mutations in MEN1; characterized by varying combinations of endocrine and non-endocrine tumors, primarily parathyroid tumors, prolactinomas of the pituitary, endocrine tumors of the GI tract and pancreas, carcinoid, and adrenocortical tumors
Multiple endocrine neoplasia types 2A, 2B
MIM 171400 and 162300; autosomal dominant; mutations in RET; characterized by medullary thyroid carcinoma; type 2A has pheochromocytoma and parathyroid adenomas; type 2B has variable pheochromocytoma and ganglioneuromas of lips, tongue, and colon, without hyperparathyroidism.
Multiple epiphyseal dysplasia
MIM 132400; autosomal dominant; mutations in various genes, most commonly COMP; short-limbed skeletal dysplasia clinically affecting the lower extremities more; presents in childhood with hip and/or knee pain with intolerance of long-distance walking; waddling gait; early onset osteoarthritis; adult height is around the lower range of normal.
Multiple exostoses, type I
MIM 133700; autosomal dominant; mutations in EXT1; characterized by multiple osteochondromas (exostoses) occurring most commonly on the long bone metaphyses, but any bone can be involved except the skull. Secondary deformity of legs, forearms, and hands typically occur.
Multiple hereditary exostosis
see Glossary entry “multiple exostoses, type I.”
see Glossary entry “muscular dystrophy-dystroglycanopathy with brain and eye anomalies.”
see “Muscular Dystrophies.”
Muscular dystrophy-dystroglycanopathy with brain and eye anomalies
MIM 235800; autosomal recessive; mutations in FKTN; characterized by cobblestone lissencephaly, cerebellar and retinal malformations, muscular dystrophy, profound intellectual disability, and early death. The most severe dystroglycanopathy is Walker-Warburg syndrome.
MIM 254450; somatic (acquired) activating mutations in various genes; kinase activation leads to uncontrolled cells expansion; characterized by bone marrow fibrosis and reduced hematopoiesis; myelofibrosis associated with mutations in MPL includes myeloid metaplasia.
MIM 160900; autosomal dominant; triplet repeat mutations in DMPK with expansion risk increased when inherited from mother; characterized by myotonia, muscular dystrophy, cataracts, hypogonadism, frontal balding, and cardiomyopathy. Mild type (50 to 150 repeats) includes cataracts and mild myotonia with adult onset. Classic type (100 to 1,000 repeats) includes weakness, myotonia, cataracts, balding, cardiac arrhythmia, and other features. Congenital (>1,000 repeats) includes infantile hypotonia, respiratory distress, intellectual disability, and classic signs presenting if there is survival to adulthood.
MIM 161200; autosomal dominant; mutations in LMX1B; characterized by dystrophic and hypoplastic nails, hypoplastic patellae, iliac horns, malformed radial heads, and nephrotic syndrome
MIM 256100; autosomal recessive; mutations in NPHP1; caused by abnormalities in nonmotile cilia; characterized by progressive renal disease starting from reduced concentrating ability progressing through tubulointerstitial nephritis and cystic renal disease to end-stage renal disease before age 30 years. Infantile type can present prenatally with oligohydramnios and related malformations; can also manifest in teenage years; 80–90% of patients have isolated renal problems.
see “Neurofibromatosis-1” chapter.
MIM 101000; autosomal dominant; mutations in NF2; characterized by tumors of cranial nerve VIII, brain meningiomas, and dorsal root schwannomas; can have subcapsular lens opacities; no characteristic skin findings
MIM 256500; autosomal recessive; mutations in SPINK5; characterized by trichorrhexis nodosa (“bamboo hair”), congenital ichthyosiform erythroderma, and atopic diathesis including hypereosinophilia, elevated IgE, urticaria, angioedema, and enteropathy; all reported patients to date are female.
Niemann-Pick types A and B
MIM 257200 and 607616; autosomal recessive; mutations in SMPD1; lipid storage disorder; deficiency of acid sphingomyelinase causes accumulation of sphingomyelin in reticuloendothelial and other cells; characterized by failure to thrive, organomegaly, macular cherry red spot, and rapidly progressive neurodegeneration; in its most severe form, patients are normal at birth but by 6 months experience delayed development and loss of developmental milestones with death by 3 years; increased prevalence in Ashkenazi Jews
Niemann-Pick type C
MIM 257220; autosomal recessive; mutations in NPC1; lipid storage disorder; can present as neonatal liver disease with respiratory failure; otherwise characterized by neurologic abnormalities in infants—hypotonia and delays—or children—ataxia, vertical supranuclear gaze palsy, and dementia; dystonia seizures, dysarthria, and dysphagia are major problems; death in 2nd or 3rd decade; adult onset presents with psychiatric symptoms.
see Glossary entry “glycine encephalopathy.”
MIM 163950; autosomal dominant; mutations in various genes, most commonly PTPN11; characterized by short stature, heart defects (most commonly pulmonic stenosis and hypertrophic cardiomyopathy), bleeding diathesis, and characteristic facies; neurocognitive function varies and is often average.
MIM 310600; X-linked recessive; mutations in NDP; characterized by retinal vasculopathy leading to detachment and pseudogliomas causing congenital blindness; about half of patients have progressive mental disorders including psychosis, and about a third develop sensorineural hearing loss.
Oculo-auriculo-vertebral spectrum (OAV, hemifacial microsomia, Goldenhar)
multifactorial; characterized by craniofacial malformations—typically unilateral—starting with microtia and involving ipsilateral skull and face bones, globe, and facial soft tissue structures. Severe cases may also involve vertebrae. Cognitive function tends to be normal.
see Glossary entry “Hallerman-Streif syndrome.”
MIM 603554; autosomal recessive; mutations in RAG1, RAG2, or DCLRE1C; severe combined immunodeficiency (SCID) syndrome with reticuloendotheliosis and eosinophilia; characterized otherwise by generalized erythroderma, alopecia, hepatosplenomegaly, and short stature; documented in the Irish Traveller population
Omphalocele-exstrophy-imperforate anus-spina bifida (OEIS)
see “Exstrophy–Epispadias Complex.”
There are seven syndromes that in some fashion are or have been referred to as Opitz syndrome. In this text, it is mentioned in the differential of fetal alcohol syndrome neurocognitive problems. This may be true of all conditions referred to as Opitz. Other sources indicate a similarity with some physical features. It is best remembered that there are single gene syndromes in the differential diagnosis of fetal alcohol syndrome, and in the absence of a clear history and classic presentation, further evaluation is warranted.
Orofacialdigital syndrome type I
MIM 311200; X-linked dominant; mutations in OFD1; characterized by malformations of the face, mouth, and digits but also has polycystic kidney disease; 15 types differing by gene and inheritance pattern
Osler-Weber-Rendu syndrome (hereditary hemorrhagic telangiectasia)
MIM 187300; autosomal dominant; mutations in ENG; vascular dysplasia; characterized by telangiectasias and arteriovenous malformation of the skin, mucosa, and viscera (lung, liver, brain)
see “Osteogenesis Imperfecta.”
MIM 259700 and 166600; various inheritance patterns; mutations in various genes; widely varying phenotypes; characterized by dense bones that are prone to fracture, mild anemia, and craniofacial disproportion; radiologic changes include increased cortical bone density, longitudinal and transverse dense striations at the ends of the long bones, lucent and dense bands in the vertebrae, and thickening at the base of the skull; bone marrow insufficiency limits survival.
Paroxysmal nocturnal hemoglobinuria
MIM 300818; acquired; somatic mutations in PIGA; characterized by complement-mediated hemolysis and anemia manifesting as hemoglobinuria, abdominal pain, smooth muscle dystonia, fatigue, and thrombosis
see Glossary entry “trisomy 13.”
MIM 557000; mitochondrial inheritance; contiguous gene deletion syndrome of mitochondrial DNA; characterized by sideroblastic anemia and exocrine pancreas dysfunction; typically lethal in infancy
MIM 312080; X-linked recessive; mutations in PLP1; characterized by failure of normal CNS myelination, nystagmus, spastic quadriplegia, ataxia, and neurocognitive impairment; patients may also have optic atrophy and seizures; infantile and adult onset subtypes
MIM 274600; autosomal recessive; mutations in SLC26A4; characterized by prelingual (congenital) severe-to-profound bilateral sensorineural hearing loss, vestibular dysfunction, enlarged vestibular aqueducts, and euthyroid goiter
MIM 175200; autosomal dominant; mutations in STK11; characterized by melanotic macules on the lips, mucous membranes, and digits, intestinal polyposis, and increased risk of malignancy
MIM 101600; autosomal dominant; mutations in FGFR1 or FGFR2; characterized by craniosynostosis and limb anomalies; presentation ranges from limited craniosynostosis with broad thumbs and toes to a severe form with cloverleaf skull, ankylosis of knees and elbows, and high risk of early mortality.
see Glossary entry “progressive familial intrahepatic cholestasis.”
MIM 606519; sporadic; no identified gene; characterized by Posterior fossa brain malformations, large or complex Hemangiomas of the face, Arterial anomalies, Cardiac anomalies, Eye abnormalities, +/− Sternal clefting; definite diagnosis requires presence of characteristic facial/scalp hemangioma plus one major and two minor additional criteria involving other body systems.
MIM 261600; autosomal recessive; mutations in PAH; inability to catalyze phenylalanine into tyrosine causes accumulation of phenylalanine, which is toxic; characterized by impaired cognitive development, relative hypopigmentation, “mousy” odor; treatable with phenylalanine-restricted diet; currently included in most state newborn screening programs in the United States
see Glossary entry “pseudohypoparathyroidism IA.”
Pierre Robin sequence
multifactorial; characterized by micrognathia, glossoptosis, and cleft soft palate; may be found as an isolated entity or a component of multisystem syndromes, most commonly 22q11.2 deletion syndrome and Stickler syndrome.
multifactorial; characterized by a unilateral absence or hypoplasia of the pectoralis major muscle with ipsilateral breast hypoplasia and sometimes associated upper limb abnormalities; may be found as an isolated entity or a component of multisystem syndromes
Polycystic kidney disease
see “Polycystic Kidney Disease.”
MIM 232300; autosomal recessive; mutations in GAA; lysosomal storage disease involving glycogen, so also a glycogen storage disease; deficiency of acid maltase causes accumulation of glycogen; infantile type characterized by profound hypotonia and cardiomegaly with a characteristic high-voltage EKG; hepatomegaly, hypoglycemia, and acidosis do not occur; usually lethal in the 1st year of life; later onset types involve skeletal muscle more than cardiac; enzyme replacement therapy is available.
inherited defects of heme biosynthesis. See also Glossary entry “acute intermittent porphyria.”
MIM 176270; imprinting disorder; absence of paternal alleles of 15q11.2 that include SNRPN; mechanisms include deletion on the paternal chromosome, maternal uniparental disomy or, rarely, mutations in the gene itself; characterized by hypotonia and initial failure to thrive due to poor feeding, followed by marked obesity due to an insatiable appetite; other features include mental retardation, hypogonadism, small hands and feet, and short stature; appropriate treatment with growth hormone and diet control ameliorates the obesity, increased lean muscle mass, and raises height.
Primary ciliary dyskinesia
MIM 244400; autosomal recessive except for type 36, which is X-linked recessive; mutations in various genes; results from loss of function of the primary ciliary apparatus, most often the dynein arms; characterized by heterotaxy, mucociliary dysfunction in the respiratory tract, immotile sperm, and hydrocephalus
see Glossary entry “Hutchinson-Gilford progeria syndrome.”
Progressive familial intrahepatic cholestasis (PFIC) (Byler disease)
MIM 211600; autosomal recessive; mutations in ATP8B1, PFIC2, or PFIC3; characterized by intrahepatic cholestasis leading to cirrhosis and end-stage liver disease before adulthood and anticipated secondary effects of liver failure; short stature, failure to thrive, splenomegaly
Proximal focal femoral deficiency
multifactorial; high association with maternal pregestational diabetes; partial or complete absence of the femur, with pelvis and sometimes sacral abnormalities
Prune belly sequence
multifactorial; characterized by deficiency of the abdominal musculature; may be primary malformation of the abdominal wall or secondary to fetal abdominal distention; abdominal distention most commonly due to a grossly distended urinary system with bladder outlet obstruction; the primary defect is variable, even within the urinary system; obstruction and dilation of other viscera or presence of a mass can lead to prune belly as a secondary feature.
MIM 103580; autosomal dominant with imprinting; mutations in GNAS inherited from the mother; characterized by parathyroid hormone resistance as well as resistance to other hormones including thyroid-stimulating hormone and gonadotropins; additionally, there are physical features of Albright hereditary osteodystrophy such as short stature, obesity, round face, subcutaneous ossifications, and skeletal anomalies.
MIM 605309; autosomal dominant; mutations in PTEN; characterized by large head circumference, abnormal facies, and neuropsychiatric abnormalities including autism; mutations in PTEN are also associated with some genetic cancer syndromes.
MIM 608354; autosomal dominant; capillary malformation–arteriovenous malformation syndrome and Parkes Weber syndrome; characterized by multiple small capillary malformations and arteriovenous malformations and/or fistulas which can be life-threatening due to bleeding, congestive heart failure, and/or neurologic impairment; Parkes Weber includes hemihyperplasia; somatic mutations can cause basal cell carcinoma.
MIM 268000; various inheritance patterns; mutations in various genes; can be found as an isolated problem or part of a syndrome; characterized by progressive retinal degeneration including night blindness, tunnel vision, and progressive decreased macular vision; there are characteristic findings on retinal exam.
MIM 312750; X-linked dominant; mutations in MECP2; characterized by a period of normal growth and development over weeks to months with onset of developmental regression, lack of head growth leading to microcephaly, lack of purposeful hand use, autistic features, seizures, and fits of screaming; “classic” features include hand wringing, bruxism, and stereotypic breathing patterns; vast majority of affected patients are female; germline inheritance considered lethal to males
see Glossary entry “Axenfeld-Rieger syndrome.”
see Glossary entry “familial dysautonomia.”
MIM 237450; autosomal recessive; digenic inheritance of homozygous mutations in SLCO1B1 and SLCO1B3; characterized by mild conjugated bilirubinemia and jaundice that may be exacerbated by infection, surgery, pregnancy, or drugs; usually asymptomatic with normal life expectancy; clinically, similar to Dubin-Johnson syndrome, but patients with Rotor have normal-appearing hepatocytes
MIM 180840; autosomal dominant; mutations in CREBBP: characterized by growth deficiency of postnatal onset, microcephaly, broad thumbs and halluces, neurocognitive impairment, and characteristic facies; increased risk of neoplasia
MIM 180860; multifactorial; 20–60% caused by imprinting abnormalities of chromosome 11, 10% by maternal uniparental disomy of chromosome 7; characterized by growth failure and short stature of prenatal onset with head sparing (relative but not absolute macrocephaly) and characteristic facies; can have 5th finger clinodactyly, body asymmetry due to hemihypoplasia, and hyperpigmented macules
Sandhoff Disease (GM2-gangliosidosis type II)
MIM 268800; autosomal recessive; mutations in HEXB; deficiency of hexosaminidase B leading to accumulation of GM2 gangliosides, particularly in neurons; progressive neurodegenerative disorder; hypotonia in the first 6 months of life, startle reaction, macular cherry-red spots, macrocephaly, organomegaly, and progressive neurocognitive impairment; manifestations similar to Tay-Sachs disease; no ethnic predilection
Sanfilippo syndrome, types A, B, C, and D
see Glossary entry “mucopolysaccharidosis III.”
see Glossary entry “mucopolysaccharidosis I.”
MIM 210600; autosomal recessive; multiple subtypes differentiated by gene involved; characterized by growth failure of prenatal onset, extreme short stature, microcephaly, neurocognitive impairment, and characteristic facies
Short-rib thoracic dysplasia (with or without polydactyly)
MIM 208500; autosomal recessive; mutations in various genes; a set of conditions caused by abnormalities in nonmotile cilia; characterized by skeletal dysplasia, short ribs, polydactyly, orofacial clefts, and abnormalities of the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia; includes Jeune, Ellis-van Creveld syndrome, hydrolethalus, and others
MIM 260400; autosomal recessive; mutations in SBDS; characterized by exocrine pancreatic dysfunction, bone marrow dysfunction with risk of malignant transformation, and skeletal abnormalities with disproportionate short stature
see “Sickle Cell Disease.”
MIM 270400; autosomal recessive; mutations in DHCR7; disorder of cholesterol synthesis; characterized by growth retardation, microcephaly, hypospadias with cryptorchidism, characteristic 2 to 3 toe Y-shaped syndactyly, photosensitivity, neurocognitive impairment, and characteristic facies; dietary cholesterol supplementation may result in clinical improvement of behavior.
Sotos syndrome (cerebral gigantism)
MIM 117550; autosomal dominant; mutations in NSD1; characterized by macrocephaly, rapid somatic growth (final height usually average for the family), large hands and feet, neurocognitive impairment that may be mild, and characteristic facies
Spinal cerebellar ataxia
MIM 164400; autosomal dominant; mutations in various genes; characterized by cerebellar degeneration with progressive ataxia, dysarthria, and deterioration of bulbar functions; onset typically in 20s and 30s
Spinal muscular atrophy
see “Spinal Muscular Atrophy.”
MIM 183900; autosomal dominant; mutations in COL2A1; chondrodysplasia characterized by short-trunk dwarfism, abnormal epiphyses, and platyspondyly; may include myopia and/or retinal detachment and cleft palate
MIM 248200; autosomal recessive; mutations in ABCA4 or CNGB3; characterized by macular degeneration and central retinitis pigmentosa; onset usually by age 20 years
MIM 108300; autosomal dominant; mutation in COL2A1, COL11A1 or COL11A2; characterized by Pierre Robin anomaly at birth and mild skeletal features with more obvious problems later, vitreous and retinal abnormalities, high-frequency hearing loss, and osteoarthritis before age 40 years; cognition usually normal
Stiff man syndrome
see Glossary entry “hyperekplexia.”
Stiff skin syndrome
MIM 184900; autosomal dominant; mutations in FBN1; characterized by hard, thick skin throughout, limited joint mobility, and flexion contractures; can include hypotonia and lipodystrophy
MIM 185300; multifactorial, can be caused by autosomal dominant somatic mutation of GNAQ; characterized by facial port-wine stain at the 1st branch of the trigeminal nerve, ipsilateral leptomeningeal angiomatosis with intracranial calcifications leading to seizures and intellectual disability; possible ocular complications such as glaucoma
Tay-Sachs disease (GM2-gangliosidosis type I)
MIM 272800; autosomal recessive; mutations in HEXA; deficiency of hexosaminidase A activity leading to accumulation of GM2 gangliosides in the CNS; characterized by motor development regression, seizures, macular cherry-red spot, and progressive neurodegeneration leading to blindness, paralysis, and death within the 2nd or 3rd year of life; highest prevalence in Ashkenazi Jews and Cajuns
Testicular regression syndrome
see Glossary entry “vanishing testes syndrome.”
see Glossary entry “cat eye syndrome.”
Thalassemia (includes β-thalassemia)
MIM 187600; autosomal dominant; mutations in FGFR3; characterized by severe short-limb dwarfism, cloverleaf skull; usually neonatal lethal due to respiratory insufficiency
Thrombocytopenia-absent radius (TAR)
MIM 274000; autosomal recessive; mutations in RBM8A; characterized by bilateral absence of the radius with thumbs present and waxing/waning thrombocytopenia; cow milk allergy is common and can exacerbate thrombocytopenia; can be clinically differentiated from Fanconi anemia in which the radial ray defect usually includes absent or hypoplastic thumbs
see Glossary entry “Gilles de la Tourette syndrome.”
MIM 107480; autosomal dominant; mutations in SALL1; characterized by imperforate anus, thumb polydactyly, and dysplastic ears; high incidence of structural and functional renal involvement, congenital heart malformations, and other skeletal involvement
Treacher Collins syndrome
MIM 154500; autosomal dominant; mutations in TCOF1; characterized by mandibulofacial dysostosis with characteristic finding of hypoplastic zygomatic arches and mandibles, micrognathia, downward slanting palpebral fissures, coloboma of the lower eyelid, microtia with associated conductive hearing deficits, and a cleft palate with or without cleft lip; cognitive function is usually normal.
MIM 190350; autosomal dominant; mutations in TRPS1; characterized by distinctive facies (particularly the nose), abnormalities of hair and other skin appendages, short stature with other skeletal anomalies; cognitive development is usually normal; when TRPS1 is included in a contiguous gene deletion, the manifestations include exostoses and a higher incidence of intellectual disability.
sporadic; the presence of an entire extra set of chromosomes resulting in 69 total chromosomes: 69,XXX, 69,XXY, or 69,XYY; most often the result of two sperm fertilizing a single ovum; the vast majority will spontaneously abort.
Trisomy 13 (Patau syndrome)
characterized by holoprosencephaly, aplasia cutis congenita, cleft lip and/or cleft palate, microphthalmia, postaxial polydactyly; cardiovascular anomalies in 80%; majority abort spontaneously; median survival is 7 days.
Trisomy 18 (Edwards syndrome)
characterized by severe neurocognitive impairment, growth failure of prenatal onset, and characteristic facies, prominent occiput, and micrognathia; other common features are clenched hands with overriding fingers, a short sternum, and rocker bottom feet; cardiac and renal anomalies in up to 50% of cases; the majority abort spontaneously.
Trisomy 21 (Down Syndrome)
see “Down Syndrome (Trisomy 21).”
Tuberous sclerosis (Bourneville disease, Bourneville-Pringle disease)
see “Tuberous Sclerosis Complex.”
see Glossary entry “mismatch repair cancer syndrome.”
Turner syndrome (monosomy X)
see “Turner Syndrome.”
MIM 276700; autosomal recessive; mutations in FAH; characterized by progressive liver disease and secondary renal tubulopathy leading to hypophosphatemic rickets; may present with acute liver failure after birth; currently included in many state newborn screening programs in the United States
MIM 276900; autosomal recessive; mutations in various genes; characterized by early retinitis pigmentosa, vestibular dysfunction, and sensorineural hearing loss
statistical association of common malformations; characterized by Vertebral defects, Anal atresia, Congenital heart defects, Tracheoesophageal fistula with Esophageal atresia, Renal and Limb anomalies; at least two noncardiac components must be present for the diagnosis; overlaps with diagnosable genetic conditions which must be considered; VACTERL is a diagnosis of exclusion rather than a primary diagnosis.
van der Woude syndrome
MIM 119300; autosomal dominant; mutations in IRF6; characterized by cleft lip and/or cleft palate and pits or sinuses of the lower lip
Vanishing testes syndrome
MIM 273250; gene remains unknown; characterized by bilateral gonadal absence in a person with 46 XY karyotype; phenotype depends on the amount of early testicular tissue present and active and ranges from unambiguous female to anorchic but unambiguous male.
von Gierke disease
see Glossary entry “glycogen storage disease IA (GSD1A).”
von Hippel–Lindau disease
MIM 193300; autosomal dominant; mutations in VHL or CCND1; familial cancer syndrome; benign and malignant tumors, most frequently retinal, cerebellar, and spinal hemangioblastoma, renal cell carcinoma, pheochromocytoma, and pancreatic tumors
see “von Willebrand Disease.”
MIM 193500; autosomal dominant; mutations most commonly in PAX3; multiple types and subtypes; pigmentary abnormalities of the hair, skin, and eyes, (white forelock, heterochromia iridis, premature graying of hair), congenital sensorineural hearing loss, and characteristic facies
WAGR (Wilms tumor, Aniridia, Genitourinary anomalies, and mental Retardation)
MIM 194072; autosomal dominant; contiguous gene deletion syndrome of 11p13 involving the WT1 and PAX6 genes; characterized by aniridia, genitourinary anomalies (hypospadias or uterine malformations), and high risk of Wilms tumor
MIM 236670; autosomal recessive; mutations in POMT1; most severe of the dystroglycanopathies; characterized by congenital muscular dystrophy, cobblestone lissencephaly, cerebellar and retinal malformations; death often before a year of age
MIM 608710; complex genetics; necrotizing granulomatous vasculitis involving (i) the airways, leading to rhinorrhea, chronic sinusitis, nasal ulceration; (ii) the lungs, causing hemoptysis, dyspnea, and cough; (iii) the kidneys, manifested as hematuria and/or proteinuria due to glomerulonephritis; other symptoms include fever, malaise, weight loss, myalgias, arthralgias, ophthalmic involvement, neuropathies, and cutaneous nodules or ulcers.
MIM 277700; autosomal recessive; mutations in RECQL2; characterized by scleroderma-like skin changes, premature arteriosclerosis, diabetes mellitus, an appearance of premature aging, short stature, slender limbs, and a stocky trunk.
MIM 194050; autosomal dominant; hemizygous deletion of 7q11.23; characterized by hypercalcemia in infants; supravalvular aortic stenosis; peripheral pulmonary artery stenosis; short stature; neurocognitive impairment, particularly in math; hypersocial with affinity for music; hyperacusis; characteristic facies
see “Wilson Disease.”
see “Wiskott-Aldrich Syndrome.”
MIM 194200; can be autosomal dominant or acquired; when inherited, caused by mutations in PRKAG2; Accessory conduction pathway found in 25% of patients with supraventricular tachycardia; typical electrocardiographic findings include a short PR interval and slow upstroke of the QRS (delta wave); may be an isolated finding, or related to structural cardiac defects
see Glossary entry “Lysosomal Acid Lipase Deficiency.”
MIM 278700; autosomal recessive; mutations in XPA; defective DNA repair after exposure to ultraviolet light; characterized by extreme sunlight sensitivity, slowly progressive neurocognitive impairment, photophobia, and cutaneous and ocular malignancies; patients may have freckling, progressive skin atrophy, erythema, scaling bullae, and crusting telangiectasia.
Zellweger syndrome (cerebrohepatorenal syndrome; peroxisome biogenesis disorder 1A)
MIM 214100; autosomal recessive; mutations in PEX1; disorder of peroxisome biogenesis (absence of peroxisomes); characterized by severe neurologic dysfunction, hepatic cirrhosis, and characteristic facies; the vast majority of patients die within the 1st year of life.
Angela E. Scheuerle, MD
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